RBCC

Full text data of HTT

HTT (HD, IT15) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Huntingtin (Huntington disease protein; HD protein)

UniProt P42858
ID HD_HUMAN Reviewed; 3142 AA.
AC P42858; Q9UQB7;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 18-MAY-2010, sequence version 2.
DT 22-JAN-2014, entry version 144.
DE RecName: Full=Huntingtin;
DE AltName: Full=Huntington disease protein;
DE Short=HD protein;
GN Name=HTT; Synonyms=HD, IT15;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Retina;
RX PubMed=8458085;
RA Macdonald M., Ambrose C.M., Duyao M.P., Myers R.H., Lin C.S.,
RA Srinidhi J., Barnes G., Taylor S.A., James M., Groot N., McFarlane H.,
RA Jenkins B., Anderson M.A., Wexler N.S., Gusella J.F., Bates G.P.,
RA Baxendale S., Hummerich H., Kirby S., North M., Youngman S., Mott R.,
RA Zehetner G., Sedlacek Z., Poustka A., Frischauf A.-M., Lehrach H.,
RA Buckler A.J., Church D., Doucette-Stamm L., O'Donovan M.C.,
RA Riba-Ramirez L., Shah M., Stanton V.P., Strobel S.A., Draths K.M.,
RA Wales J.L., Dervan P., Housman D.E., Altherr M., Shiang R.,
RA Thompson L., Fielder T., Wasmuth J.J., Tagle D., Valdes J., Elmer L.,
RA Allard M., Castilla L., Swaroop M., Blanchard K., Collins F.S.,
RA Snell R., Holloway T., Gillespie K., Datson N., Shaw S., Harper P.S.;
RT "A novel gene containing a trinucleotide repeat that is expanded and
RT unstable on Huntington's disease chromosomes.";
RL Cell 72:971-983(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=11013077; DOI=10.1006/geno.2000.6317;
RA Matsuyama N., Hadano S., Onoe K., Osuga H., Shouguchi-Miyata J.,
RA Gondo Y., Ikeda J.-E.;
RT "Identification and characterization of the miniature pig Huntington's
RT disease gene homolog: evidence for conservation and polymorphism in
RT the CAG triplet repeat.";
RL Genomics 69:72-85(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-203.
RX PubMed=8197474; DOI=10.1007/BF02257483;
RA Ambrose C.M., Duyao M.P., Barnes G., Bates G.P., Lin C.S.,
RA Srinidhi J., Baxendale S., Hummerich H., Lehrach H., Altherr M.,
RA Wasmuth J., Buckler A., Church D., Housman D., Berks M., Micklem G.,
RA Durbin R., Dodge A., Read A., Gusella J.F., Macdonald M.E.;
RT "Structure and expression of the Huntington's disease gene: evidence
RT against simple inactivation due to an expanded CAG repeat.";
RL Somat. Cell Mol. Genet. 20:27-38(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-88.
RX PubMed=7759106; DOI=10.1016/0888-7543(95)80014-D;
RA Lin B., Nasir J., Kalchman M.A., McDonald H., Zeisler J.,
RA Goldberg Y.P., Hayden M.R.;
RT "Structural analysis of the 5' region of mouse and human Huntington
RT disease genes reveals conservation of putative promoter region and di-
RT and trinucleotide polymorphisms.";
RL Genomics 25:707-715(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2561-3142, AND VARIANT ILE-2786.
RC TISSUE=Brain, Caudate nucleus, Frontal cortex, Muscle, and Retina;
RX PubMed=7903579; DOI=10.1093/hmg/2.10.1541;
RA Lin B., Rommens J.M., Graham R.K., Kalchman M., Macdonald H.,
RA Nasir J., Delaney A., Goldberg Y.P., Hayden M.R.;
RT "Differential 3' polyadenylation of the Huntington disease gene
RT results in two mRNA species with variable tissue expression.";
RL Hum. Mol. Genet. 2:1541-1545(1993).
RN [7]
RP SUBCELLULAR LOCATION.
RX PubMed=7647777; DOI=10.1038/ng0595-104;
RA Trottier Y., Devys D., Imbert G., Saudou F., An I., Lutz Y., Weber C.,
RA Agid Y., Hirsch E.C., Mandel J.-L.;
RT "Cellular localization of the Huntington's disease protein and
RT discrimination of the normal and mutated form.";
RL Nat. Genet. 10:104-110(1995).
RN [8]
RP CLEAVAGE BY APOPAIN.
RX PubMed=8696339; DOI=10.1038/ng0896-442;
RA Goldberg Y.P., Nicholson D.W., Rasper D.M., Kalchman M.A., Koide H.B.,
RA Graham R.K., Bromm M., Kazemi-Esfarjani P., Thornberry N.A.,
RA Vaillancourt J.P., Hayden M.R.;
RT "Cleavage of huntingtin by apopain, a proapoptotic cysteine protease,
RT is modulated by the polyglutamine tract.";
RL Nat. Genet. 13:442-449(1996).
RN [9]
RP INTERACTION WITH PRPF40A AND SETD2.
RX PubMed=9700202; DOI=10.1093/hmg/7.9.1463;
RA Faber P.W., Barnes G.T., Srinidhi J., Chen J., Gusella J.F.,
RA MacDonald M.E.;
RT "Huntingtin interacts with a family of WW domain proteins.";
RL Hum. Mol. Genet. 7:1463-1474(1998).
RN [10]
RP INTERACTION WITH PQBP1.
RC TISSUE=Brain;
RX PubMed=10332029; DOI=10.1093/hmg/8.6.977;
RA Waragai M., Lammers C.-H., Takeuchi S., Imafuku I., Udagawa Y.,
RA Kanazawa I., Kawabata M., Mouradian M.M., Okazawa H.;
RT "PQBP-1, a novel polyglutamine tract binding protein, inhibits
RT transcription activation by Brn-2 and affects cell survival.";
RL Hum. Mol. Genet. 8:977-987(1999).
RN [11]
RP INTERACTION WITH SETD2.
RX PubMed=10958656; DOI=10.1093/hmg/9.14.2175;
RA Passani L.A., Bedford M.T., Faber P.W., McGinnis K.M., Sharp A.H.,
RA Gusella J.F., Vonsattel J.-P., MacDonald M.E.;
RT "Huntingtin's WW domain partners in Huntington's disease post-mortem
RT brain fulfill genetic criteria for direct involvement in Huntington's
RT disease pathogenesis.";
RL Hum. Mol. Genet. 9:2175-2182(2000).
RN [12]
RP INTERACTION WITH SETD2.
RX PubMed=11461154; DOI=10.1006/mcne.2001.1004;
RA Rega S., Stiewe T., Chang D.-I., Pollmeier B., Esche H.,
RA Bardenheuer W., Marquitan G., Puetzer B.M.;
RT "Identification of the full-length huntingtin-interacting protein
RT p231HBP/HYPB as a DNA-binding factor.";
RL Mol. Cell. Neurosci. 18:68-79(2001).
RN [13]
RP NUCLEAR EXPORT SIGNAL.
RX PubMed=12783847; DOI=10.1093/hmg/ddg156;
RA Xia J., Lee D.H., Taylor J., Vandelft M., Truant R.;
RT "Huntingtin contains a highly conserved nuclear export signal.";
RL Hum. Mol. Genet. 12:1393-1403(2003).
RN [14]
RP INTERACTION WITH TPR, AND SUBCELLULAR LOCATION.
RX PubMed=15654337; DOI=10.1038/ng1503;
RA Cornett J., Cao F., Wang C.E., Ross C.A., Bates G.P., Li S.H.,
RA Li X.J.;
RT "Polyglutamine expansion of huntingtin impairs its nuclear export.";
RL Nat. Genet. 37:198-204(2005).
RN [15]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=16391387; DOI=10.1385/NMM:7:4:297;
RA Sayer J.A., Manczak M., Akileswaran L., Reddy P.H., Coghlan V.M.;
RT "Interaction of the nuclear matrix protein NAKAP with HypA and
RT huntingtin: implications for nuclear toxicity in Huntington's disease
RT pathogenesis.";
RL NeuroMolecular Med. 7:297-310(2005).
RN [16]
RP INTERACTION WITH SYVN, AND UBIQUITINATION.
RX PubMed=17141218; DOI=10.1016/j.yexcr.2006.10.031;
RA Yang H., Zhong X., Ballar P., Luo S., Shen Y., Rubinsztein D.C.,
RA Monteiro M.J., Fang S.;
RT "Ubiquitin ligase Hrd1 enhances the degradation and suppresses the
RT toxicity of polyglutamine-expanded huntingtin.";
RL Exp. Cell Res. 313:538-550(2007).
RN [17]
RP PHOSPHORYLATION AT SER-1179 AND SER-1199.
RX PubMed=17611284; DOI=10.1523/JNEUROSCI.1831-07.2007;
RA Anne S.L., Saudou F., Humbert S.;
RT "Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced
RT by DNA damage and regulates wild-type and mutant huntingtin toxicity
RT in neurons.";
RL J. Neurosci. 27:7318-7328(2007).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1870, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [20]
RP INTERACTION WITH PFN1.
RX PubMed=18573880; DOI=10.1128/MCB.00079-08;
RA Shao J., Welch W.J., Diprospero N.A., Diamond M.I.;
RT "Phosphorylation of profilin by ROCK1 regulates polyglutamine
RT aggregation.";
RL Mol. Cell. Biol. 28:5196-5208(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-411; SER-1870 AND
RP SER-1874, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-432 AND SER-1874, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1870 AND SER-1874, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [26]
RP ACETYLATION AT LYS-9; LYS-176; LYS-234; LYS-343 AND LYS-442.
RX PubMed=21685499; DOI=10.1074/mcp.M111.009829;
RA Cong X., Held J.M., Degiacomo F., Bonner A., Chen J.M., Schilling B.,
RA Czerwieniec G.A., Gibson B.W., Ellerby L.M.;
RT "Mass spectrometric identification of novel lysine acetylation sites
RT in huntingtin.";
RL Mol. Cell. Proteomics 0:0-0(2011).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS) OF 1-64, AND DOMAIN.
RX PubMed=19748341; DOI=10.1016/j.str.2009.08.002;
RA Kim M.W., Chelliah Y., Kim S.W., Otwinowski Z., Bezprozvanny I.;
RT "Secondary structure of Huntingtin amino-terminal region.";
RL Structure 17:1205-1212(2009).
CC -!- FUNCTION: May play a role in microtubule-mediated transport or
CC vesicle function.
CC -!- SUBUNIT: Binds SH3GLB1 (By similarity). Interacts through its N-
CC terminus with PRPF40A. Interacts with PQBP1, SETD2 and SYVN.
CC Interacts with PFN1. Interacts with TPR; the interaction is
CC inhibited by forms of Huntingtin with expanded polyglutamine
CC stretch.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-466029, EBI-466029;
CC Q12873:CHD3; NbExp=3; IntAct=EBI-466029, EBI-523590;
CC Q14194:CRMP1; NbExp=2; IntAct=EBI-466029, EBI-473101;
CC Q13011:ECH1; NbExp=2; IntAct=EBI-466029, EBI-711968;
CC Q2NKX8:ERCC6L; NbExp=2; IntAct=EBI-466029, EBI-1042535;
CC Q9UI08-2:EVL; NbExp=2; IntAct=EBI-466029, EBI-6448852;
CC Q99689:FEZ1; NbExp=3; IntAct=EBI-466029, EBI-396435;
CC P02792:FTL; NbExp=2; IntAct=EBI-466029, EBI-713279;
CC Q9Y2X7:GIT1; NbExp=10; IntAct=EBI-466029, EBI-466061;
CC Q9H4A5:GOLPH3L; NbExp=2; IntAct=EBI-466029, EBI-4403434;
CC Q9UBP5:HEY2; NbExp=2; IntAct=EBI-466029, EBI-750630;
CC O00291:HIP1; NbExp=2; IntAct=EBI-466029, EBI-473886;
CC P68431:HIST1H3D; NbExp=2; IntAct=EBI-466029, EBI-79722;
CC Q9NP66:HMG20A; NbExp=2; IntAct=EBI-466029, EBI-740641;
CC O95163:IKBKAP; NbExp=4; IntAct=EBI-466029, EBI-347559;
CC Q9P2H0:KIAA1377; NbExp=2; IntAct=EBI-466029, EBI-473176;
CC Q8N7X4:MAGEB6; NbExp=2; IntAct=EBI-466029, EBI-6447163;
CC Q9UIS9:MBD1; NbExp=2; IntAct=EBI-466029, EBI-867196;
CC Q9Y3C7:MED31; NbExp=3; IntAct=EBI-466029, EBI-394707;
CC Q96HT8:MRFAP1L1; NbExp=3; IntAct=EBI-466029, EBI-748896;
CC O43312:MTSS1; NbExp=3; IntAct=EBI-466029, EBI-473954;
CC Q14596:NBR1; NbExp=3; IntAct=EBI-466029, EBI-742698;
CC O00746:NME4; NbExp=2; IntAct=EBI-466029, EBI-744871;
CC Q13177:PAK2; NbExp=2; IntAct=EBI-466029, EBI-1045887;
CC P35080:PFN2; NbExp=4; IntAct=EBI-466029, EBI-473138;
CC Q8N2W9:PIAS4; NbExp=3; IntAct=EBI-466029, EBI-473160;
CC O75400:PRPF40A; NbExp=12; IntAct=EBI-466029, EBI-473291;
CC P36578:RPL4; NbExp=2; IntAct=EBI-466029, EBI-348313;
CC Q99963:SH3GL3; NbExp=9; IntAct=EBI-466029, EBI-473910;
CC P37840:SNCA; NbExp=4; IntAct=EBI-466029, EBI-985879;
CC O14776:TCERG1; NbExp=3; IntAct=EBI-466029, EBI-473271;
CC P04637:TP53; NbExp=4; IntAct=EBI-466029, EBI-366083;
CC Q8IZQ1:WDFY3; NbExp=10; IntAct=EBI-466029, EBI-1569256;
CC Q8WTP9:XAGE3; NbExp=3; IntAct=EBI-466029, EBI-6448284;
CC P12956:XRCC6; NbExp=3; IntAct=EBI-466029, EBI-353208;
CC Q8IUH5:ZDHHC17; NbExp=2; IntAct=EBI-466029, EBI-524753;
CC G3V1X1:ZFC3H1; NbExp=2; IntAct=EBI-466029, EBI-6448783;
CC Q96NC0:ZMAT2; NbExp=2; IntAct=EBI-466029, EBI-2682299;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=The mutant
CC Huntingtin protein colocalizes with AKAP8L in the nuclear matrix
CC of Huntington disease neurons. Shuttles between cytoplasm and
CC nucleus in a Ran GTPase-independent manner.
CC -!- TISSUE SPECIFICITY: Expressed in the brain cortex (at protein
CC level). Widely expressed with the highest level of expression in
CC the brain (nerve fibers, varicosities, and nerve endings). In the
CC brain, the regions where it can be mainly found are the cerebellar
CC cortex, the neocortex, the striatum, and the hippocampal
CC formation.
CC -!- DOMAIN: The N-terminal Gln-rich and Pro-rich domain has great
CC conformational flexibility and is likely to exist in a fluctuating
CC equilibrium of alpha-helical, random coil, and extended
CC conformations.
CC -!- PTM: Cleaved by apopain downstream of the polyglutamine stretch.
CC The resulting N-terminal fragment is cytotoxic and provokes
CC apoptosis.
CC -!- PTM: Forms with expanded polyglutamine expansion are specifically
CC ubiquitinated by SYVN1, which promotes their proteasomal
CC degradation.
CC -!- PTM: Phosphorylation at Ser-1179 and Ser-1199 by CDK5 in response
CC to DNA damage in nuclei of neurons protects neurons against
CC polyglutamine expansion as well as DNA damage mediated toxicity.
CC -!- POLYMORPHISM: The poly-Gln region of HTT is highly polymorphic (10
CC to 35 repeats) in the normal population and is expanded to about
CC 36-120 repeats in Huntington disease patients. The repeat length
CC usually increases in successive generations, but contracts also on
CC occasion. The adjacent poly-Pro region is also polymorphic and
CC varies between 7-12 residues. Polyglutamine expansion leads to
CC elevated susceptibility to apopain cleavage and likely result in
CC accelerated neuronal apoptosis.
CC -!- DISEASE: Huntington disease (HD) [MIM:143100]: A neurodegenerative
CC disorder characterized by involuntary movements (chorea), general
CC motor impairment, psychiatric disorders and dementia. Onset of the
CC disease occurs usually in the third or fourth decade of life.
CC Onset and clinical course depend on the degree of poly-Gln repeat
CC expansion, longer expansions resulting in earlier onset and more
CC severe clinical manifestations. Neuropathology of Huntington
CC disease displays a distinctive pattern with loss of neurons,
CC especially in the caudate and putamen. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the huntingtin family.
CC -!- SIMILARITY: Contains 5 HEAT repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HTT";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Huntingtin entry;
CC URL="http://en.wikipedia.org/wiki/Huntingtin";
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DR EMBL; L12392; AAB38240.1; -; mRNA.
DR EMBL; AB016794; BAA36753.1; -; mRNA.
DR EMBL; Z49154; CAA89024.1; -; Genomic_DNA.
DR EMBL; Z49155; CAA89025.1; -; Genomic_DNA.
DR EMBL; Z49208; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; Z49769; CAA89839.1; -; Genomic_DNA.
DR EMBL; Z68756; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; Z69649; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; L27350; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; L27351; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; L27352; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; L27353; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; L27354; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; L34020; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; L20431; AAA52702.1; -; mRNA.
DR PIR; A46068; A46068.
DR RefSeq; NP_002102.4; NM_002111.6.
DR UniGene; Hs.518450; -.
DR PDB; 2D3X; Model; -; A=199-325.
DR PDB; 2LD0; NMR; -; A=1-17.
DR PDB; 2LD2; NMR; -; A=1-17.
DR PDB; 3IO4; X-ray; 3.63 A; A/B/C=1-64.
DR PDB; 3IO6; X-ray; 3.70 A; A/B/C=1-64.
DR PDB; 3IOR; X-ray; 3.60 A; A/B/C=1-64.
DR PDB; 3IOT; X-ray; 3.50 A; A/B/C=1-64.
DR PDB; 3IOU; X-ray; 3.70 A; A/B/C=1-64.
DR PDB; 3IOV; X-ray; 3.70 A; A/B/C=1-64.
DR PDB; 3IOW; X-ray; 3.50 A; A/B/C=1-64.
DR PDB; 3LRH; X-ray; 2.60 A; B/D/F/H/J/L/N/P=5-18.
DR PDB; 4FE8; X-ray; 3.00 A; A/B/C=1-64.
DR PDB; 4FEB; X-ray; 2.80 A; A/B/C=1-64.
DR PDB; 4FEC; X-ray; 3.00 A; A/B/C=1-64.
DR PDB; 4FED; X-ray; 2.81 A; A/B/C=1-64.
DR PDBsum; 2D3X; -.
DR PDBsum; 2LD0; -.
DR PDBsum; 2LD2; -.
DR PDBsum; 3IO4; -.
DR PDBsum; 3IO6; -.
DR PDBsum; 3IOR; -.
DR PDBsum; 3IOT; -.
DR PDBsum; 3IOU; -.
DR PDBsum; 3IOV; -.
DR PDBsum; 3IOW; -.
DR PDBsum; 3LRH; -.
DR PDBsum; 4FE8; -.
DR PDBsum; 4FEB; -.
DR PDBsum; 4FEC; -.
DR PDBsum; 4FED; -.
DR ProteinModelPortal; P42858; -.
DR IntAct; P42858; 105.
DR MINT; MINT-133355; -.
DR STRING; 9606.ENSP00000347184; -.
DR ChEMBL; CHEMBL5514; -.
DR PhosphoSite; P42858; -.
DR DMDM; 296434520; -.
DR PaxDb; P42858; -.
DR PRIDE; P42858; -.
DR Ensembl; ENST00000355072; ENSP00000347184; ENSG00000197386.
DR GeneID; 3064; -.
DR KEGG; hsa:3064; -.
DR UCSC; uc021xkv.1; human.
DR CTD; 3064; -.
DR GeneCards; GC04P003076; -.
DR HGNC; HGNC:4851; HTT.
DR HPA; CAB002756; -.
DR HPA; HPA026114; -.
DR MIM; 143100; phenotype.
DR MIM; 613004; gene.
DR neXtProt; NX_P42858; -.
DR Orphanet; 399; Huntington disease.
DR Orphanet; 248111; Juvenile Huntington disease.
DR PharmGKB; PA164741646; -.
DR eggNOG; NOG82191; -.
DR HOGENOM; HOG000082472; -.
DR HOVERGEN; HBG005953; -.
DR InParanoid; P42858; -.
DR KO; K04533; -.
DR OMA; SDQVFIG; -.
DR OrthoDB; EOG7JQBMD; -.
DR SignaLink; P42858; -.
DR ChiTaRS; HTT; human.
DR EvolutionaryTrace; P42858; -.
DR GeneWiki; Huntingtin; -.
DR GenomeRNAi; 3064; -.
DR NextBio; 12121; -.
DR PRO; PR:P42858; -.
DR ArrayExpress; P42858; -.
DR Bgee; P42858; -.
DR CleanEx; HS_HTT; -.
DR Genevestigator; P42858; -.
DR GO; GO:0005776; C:autophagic vacuole; IDA:UniProtKB.
DR GO; GO:0030424; C:axon; IDA:UniProtKB.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0030425; C:dendrite; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0016234; C:inclusion body; IEA:Ensembl.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0048487; F:beta-tubulin binding; IDA:UniProtKB.
DR GO; GO:0050809; F:diazepam binding; IEA:Ensembl.
DR GO; GO:0045505; F:dynein intermediate chain binding; IDA:UniProtKB.
DR GO; GO:0008134; F:transcription factor binding; IBA:RefGenome.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IEA:Ensembl.
DR GO; GO:0008088; P:axon cargo transport; IEA:Ensembl.
DR GO; GO:0007569; P:cell aging; IEA:Ensembl.
DR GO; GO:0000052; P:citrulline metabolic process; IEA:Ensembl.
DR GO; GO:0008340; P:determination of adult lifespan; IEA:Ensembl.
DR GO; GO:0007212; P:dopamine receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0007029; P:endoplasmic reticulum organization; IEA:Ensembl.
DR GO; GO:0016197; P:endosomal transport; IEA:Ensembl.
DR GO; GO:0006888; P:ER to Golgi vesicle-mediated transport; IEA:Ensembl.
DR GO; GO:0000132; P:establishment of mitotic spindle orientation; IMP:UniProtKB.
DR GO; GO:0007030; P:Golgi organization; IMP:UniProtKB.
DR GO; GO:0042445; P:hormone metabolic process; IEA:Ensembl.
DR GO; GO:0030073; P:insulin secretion; IEA:Ensembl.
DR GO; GO:0055072; P:iron ion homeostasis; IEA:Ensembl.
DR GO; GO:0051938; P:L-glutamate import; IEA:Ensembl.
DR GO; GO:0019244; P:lactate biosynthetic process from pyruvate; IEA:Ensembl.
DR GO; GO:0007626; P:locomotory behavior; IEA:Ensembl.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0021990; P:neural plate formation; IEA:Ensembl.
DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0048666; P:neuron development; IEA:Ensembl.
DR GO; GO:0021988; P:olfactory lobe development; IEA:Ensembl.
DR GO; GO:0048513; P:organ development; IBA:RefGenome.
DR GO; GO:0048341; P:paraxial mesoderm formation; IEA:Ensembl.
DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl.
DR GO; GO:0019805; P:quinolinate biosynthetic process; IEA:Ensembl.
DR GO; GO:0046902; P:regulation of mitochondrial membrane permeability; IEA:Ensembl.
DR GO; GO:0051881; P:regulation of mitochondrial membrane potential; IEA:Ensembl.
DR GO; GO:0046825; P:regulation of protein export from nucleus; IMP:UniProtKB.
DR GO; GO:0034047; P:regulation of protein phosphatase type 2A activity; IMP:dictyBase.
DR GO; GO:0048167; P:regulation of synaptic plasticity; IEA:Ensembl.
DR GO; GO:0051592; P:response to calcium ion; IEA:Ensembl.
DR GO; GO:0006890; P:retrograde vesicle-mediated transport, Golgi to ER; IMP:UniProtKB.
DR GO; GO:0035176; P:social behavior; IEA:Ensembl.
DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
DR GO; GO:0021756; P:striatum development; IEA:Ensembl.
DR GO; GO:0000050; P:urea cycle; IEA:Ensembl.
DR GO; GO:0047496; P:vesicle transport along microtubule; IMP:UniProtKB.
DR GO; GO:0008542; P:visual learning; IEA:Ensembl.
DR Gene3D; 1.25.10.10; -; 4.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000091; Huntingtin.
DR InterPro; IPR028426; Huntingtin_fam.
DR InterPro; IPR024613; Huntingtin_middle-repeat.
DR PANTHER; PTHR10170; PTHR10170; 1.
DR PANTHER; PTHR10170:SF5; PTHR10170:SF5; 1.
DR Pfam; PF12372; DUF3652; 2.
DR PRINTS; PR00375; HUNTINGTIN.
DR SUPFAM; SSF48371; SSF48371; 6.
DR PROSITE; PS50077; HEAT_REPEAT; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Apoptosis; Complete proteome; Cytoplasm;
KW Disease mutation; Neurodegeneration; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat; Triplet repeat expansion;
KW Ubl conjugation.
FT CHAIN 1 3142 Huntingtin.
FT /FTId=PRO_0000083942.
FT REPEAT 204 241 HEAT 1.
FT REPEAT 246 283 HEAT 2.
FT REPEAT 316 360 HEAT 3.
FT REPEAT 802 839 HEAT 4.
FT REPEAT 902 940 HEAT 5.
FT REGION 3 13 Sufficient for interaction with TPR.
FT MOTIF 2395 2404 Nuclear export signal (By similarity).
FT COMPBIAS 18 38 Poly-Gln.
FT COMPBIAS 39 49 Poly-Pro.
FT COMPBIAS 63 78 Poly-Pro.
FT COMPBIAS 1437 1440 Poly-Thr.
FT COMPBIAS 2341 2345 Poly-Glu.
FT COMPBIAS 2638 2643 Poly-Glu.
FT SITE 511 512 Cleavage; by apopain (Potential).
FT SITE 528 529 Cleavage; by apopain (Potential).
FT SITE 550 551 Cleavage; by apopain (Potential).
FT SITE 587 588 Cleavage; by apopain (Potential).
FT MOD_RES 9 9 N6-acetyllysine.
FT MOD_RES 176 176 N6-acetyllysine.
FT MOD_RES 234 234 N6-acetyllysine.
FT MOD_RES 343 343 N6-acetyllysine.
FT MOD_RES 411 411 Phosphoserine.
FT MOD_RES 432 432 Phosphoserine.
FT MOD_RES 442 442 N6-acetyllysine.
FT MOD_RES 1179 1179 Phosphoserine; by CDK5.
FT MOD_RES 1199 1199 Phosphoserine; by CDK5.
FT MOD_RES 1870 1870 Phosphoserine.
FT MOD_RES 1874 1874 Phosphoserine.
FT VARIANT 18 18 Q -> QQQ.
FT /FTId=VAR_005268.
FT VARIANT 893 893 G -> R (in dbSNP:rs363075).
FT /FTId=VAR_060170.
FT VARIANT 1064 1064 V -> I (in dbSNP:rs35892913).
FT /FTId=VAR_060171.
FT VARIANT 1091 1091 I -> M (in dbSNP:rs1143646).
FT /FTId=VAR_060172.
FT VARIANT 1173 1173 T -> A (in dbSNP:rs3025843).
FT /FTId=VAR_060173.
FT VARIANT 1260 1260 T -> M (in dbSNP:rs34315806).
FT /FTId=VAR_060174.
FT VARIANT 1382 1382 E -> A (in dbSNP:rs3025837).
FT /FTId=VAR_054017.
FT VARIANT 1385 1385 N -> H (in dbSNP:rs3025837).
FT /FTId=VAR_060175.
FT VARIANT 1720 1720 T -> N (in dbSNP:rs363125).
FT /FTId=VAR_060176.
FT VARIANT 2113 2113 D -> Y (in dbSNP:rs1143648).
FT /FTId=VAR_060177.
FT VARIANT 2309 2309 Y -> H (in dbSNP:rs362331).
FT /FTId=VAR_060178.
FT VARIANT 2786 2786 V -> I (in dbSNP:rs362272).
FT /FTId=VAR_060179.
FT CONFLICT 823 823 C -> S (in Ref. 2; BAA36753).
FT HELIX 6 17
SQ SEQUENCE 3142 AA; 347603 MW; A267509E84D52F0D CRC64;
MATLEKLMKA FESLKSFQQQ QQQQQQQQQQ QQQQQQQQPP PPPPPPPPPQ LPQPPPQAQP
LLPQPQPPPP PPPPPPGPAV AEEPLHRPKK ELSATKKDRV NHCLTICENI VAQSVRNSPE
FQKLLGIAME LFLLCSDDAE SDVRMVADEC LNKVIKALMD SNLPRLQLEL YKEIKKNGAP
RSLRAALWRF AELAHLVRPQ KCRPYLVNLL PCLTRTSKRP EESVQETLAA AVPKIMASFG
NFANDNEIKV LLKAFIANLK SSSPTIRRTA AGSAVSICQH SRRTQYFYSW LLNVLLGLLV
PVEDEHSTLL ILGVLLTLRY LVPLLQQQVK DTSLKGSFGV TRKEMEVSPS AEQLVQVYEL
TLHHTQHQDH NVVTGALELL QQLFRTPPPE LLQTLTAVGG IGQLTAAKEE SGGRSRSGSI
VELIAGGGSS CSPVLSRKQK GKVLLGEEEA LEDDSESRSD VSSSALTASV KDEISGELAA
SSGVSTPGSA GHDIITEQPR SQHTLQADSV DLASCDLTSS ATDGDEEDIL SHSSSQVSAV
PSDPAMDLND GTQASSPISD SSQTTTEGPD SAVTPSDSSE IVLDGTDNQY LGLQIGQPQD
EDEEATGILP DEASEAFRNS SMALQQAHLL KNMSHCRQPS DSSVDKFVLR DEATEPGDQE
NKPCRIKGDI GQSTDDDSAP LVHCVRLLSA SFLLTGGKNV LVPDRDVRVS VKALALSCVG
AAVALHPESF FSKLYKVPLD TTEYPEEQYV SDILNYIDHG DPQVRGATAI LCGTLICSIL
SRSRFHVGDW MGTIRTLTGN TFSLADCIPL LRKTLKDESS VTCKLACTAV RNCVMSLCSS
SYSELGLQLI IDVLTLRNSS YWLVRTELLE TLAEIDFRLV SFLEAKAENL HRGAHHYTGL
LKLQERVLNN VVIHLLGDED PRVRHVAAAS LIRLVPKLFY KCDQGQADPV VAVARDQSSV
YLKLLMHETQ PPSHFSVSTI TRIYRGYNLL PSITDVTMEN NLSRVIAAVS HELITSTTRA
LTFGCCEALC LLSTAFPVCI WSLGWHCGVP PLSASDESRK SCTVGMATMI LTLLSSAWFP
LDLSAHQDAL ILAGNLLAAS APKSLRSSWA SEEEANPAAT KQEEVWPALG DRALVPMVEQ
LFSHLLKVIN ICAHVLDDVA PGPAIKAALP SLTNPPSLSP IRRKGKEKEP GEQASVPLSP
KKGSEASAAS RQSDTSGPVT TSKSSSLGSF YHLPSYLKLH DVLKATHANY KVTLDLQNST
EKFGGFLRSA LDVLSQILEL ATLQDIGKCV EEILGYLKSC FSREPMMATV CVQQLLKTLF
GTNLASQFDG LSSNPSKSQG RAQRLGSSSV RPGLYHYCFM APYTHFTQAL ADASLRNMVQ
AEQENDTSGW FDVLQKVSTQ LKTNLTSVTK NRADKNAIHN HIRLFEPLVI KALKQYTTTT
CVQLQKQVLD LLAQLVQLRV NYCLLDSDQV FIGFVLKQFE YIEVGQFRES EAIIPNIFFF
LVLLSYERYH SKQIIGIPKI IQLCDGIMAS GRKAVTHAIP ALQPIVHDLF VLRGTNKADA
GKELETQKEV VVSMLLRLIQ YHQVLEMFIL VLQQCHKENE DKWKRLSRQI ADIILPMLAK
QQMHIDSHEA LGVLNTLFEI LAPSSLRPVD MLLRSMFVTP NTMASVSTVQ LWISGILAIL
RVLISQSTED IVLSRIQELS FSPYLISCTV INRLRDGDST STLEEHSEGK QIKNLPEETF
SRFLLQLVGI LLEDIVTKQL KVEMSEQQHT FYCQELGTLL MCLIHIFKSG MFRRITAAAT
RLFRSDGCGG SFYTLDSLNL RARSMITTHP ALVLLWCQIL LLVNHTDYRW WAEVQQTPKR
HSLSSTKLLS PQMSGEEEDS DLAAKLGMCN REIVRRGALI LFCDYVCQNL HDSEHLTWLI
VNHIQDLISL SHEPPVQDFI SAVHRNSAAS GLFIQAIQSR CENLSTPTML KKTLQCLEGI
HLSQSGAVLT LYVDRLLCTP FRVLARMVDI LACRRVEMLL AANLQSSMAQ LPMEELNRIQ
EYLQSSGLAQ RHQRLYSLLD RFRLSTMQDS LSPSPPVSSH PLDGDGHVSL ETVSPDKDWY
VHLVKSQCWT RSDSALLEGA ELVNRIPAED MNAFMMNSEF NLSLLAPCLS LGMSEISGGQ
KSALFEAARE VTLARVSGTV QQLPAVHHVF QPELPAEPAA YWSKLNDLFG DAALYQSLPT
LARALAQYLV VVSKLPSHLH LPPEKEKDIV KFVVATLEAL SWHLIHEQIP LSLDLQAGLD
CCCLALQLPG LWSVVSSTEF VTHACSLIYC VHFILEAVAV QPGEQLLSPE RRTNTPKAIS
EEEEEVDPNT QNPKYITAAC EMVAEMVESL QSVLALGHKR NSGVPAFLTP LLRNIIISLA
RLPLVNSYTR VPPLVWKLGW SPKPGGDFGT AFPEIPVEFL QEKEVFKEFI YRINTLGWTS
RTQFEETWAT LLGVLVTQPL VMEQEESPPE EDTERTQINV LAVQAITSLV LSAMTVPVAG
NPAVSCLEQQ PRNKPLKALD TRFGRKLSII RGIVEQEIQA MVSKRENIAT HHLYQAWDPV
PSLSPATTGA LISHEKLLLQ INPERELGSM SYKLGQVSIH SVWLGNSITP LREEEWDEEE
EEEADAPAPS SPPTSPVNSR KHRAGVDIHS CSQFLLELYS RWILPSSSAR RTPAILISEV
VRSLLVVSDL FTERNQFELM YVTLTELRRV HPSEDEILAQ YLVPATCKAA AVLGMDKAVA
EPVSRLLEST LRSSHLPSRV GALHGVLYVL ECDLLDDTAK QLIPVISDYL LSNLKGIAHC
VNIHSQQHVL VMCATAFYLI ENYPLDVGPE FSASIIQMCG VMLSGSEEST PSIIYHCALR
GLERLLLSEQ LSRLDAESLV KLSVDRVNVH SPHRAMAALG LMLTCMYTGK EKVSPGRTSD
PNPAAPDSES VIVAMERVSV LFDRIRKGFP CEARVVARIL PQFLDDFFPP QDIMNKVIGE
FLSNQQPYPQ FMATVVYKVF QTLHSTGQSS MVRDWVMLSL SNFTQRAPVA MATWSLSCFF
VSASTSPWVA AILPHVISRM GKLEQVDVNL FCLVATDFYR HQIEEELDRR AFQSVLEVVA
APGSPYHRLL TCLRNVHKVT TC
//

MIM 143100
*RECORD*
*FIELD* NO
143100
*FIELD* TI
#143100 HUNTINGTON DISEASE; HD
;;HUNTINGTON CHOREA
*FIELD* TX
A number sign (#) is used with this entry because Huntington disease
read more(HD) is caused by an expanded trinucleotide repeat (CAG)n, encoding
glutamine, in the gene encoding huntingtin (HTT; 613004) on chromosome
4p16.3.

In normal individuals, the range of repeat numbers is 9 to 36. In those
with HD, the repeat number is above 37 (Duyao et al., 1993).

DESCRIPTION

Huntington disease (HD) is an autosomal dominant progressive
neurodegenerative disorder with a distinct phenotype characterized by
chorea, dystonia, incoordination, cognitive decline, and behavioral
difficulties. There is progressive, selective neural cell loss and
atrophy in the caudate and putamen. Walker (2007) provided a detailed
review of Huntington disease, including clinical features, population
genetics, molecular biology, and animal models.

CLINICAL FEATURES

The classic signs of Huntington disease are progressive chorea,
rigidity, and dementia. A characteristic atrophy of the caudate nucleus
is seen radiographically. Typically, there is a prodromal phase of mild
psychotic and behavioral symptoms which precedes frank chorea by up to
10 years. Chandler et al. (1960) observed that the age of onset was
between 30 and 40 years. In a study of 196 kindreds, Reed and Neel
(1959) found only 8 in which both parents of a single patient with
Huntington chorea were 60 years of age or older and normal. The clinical
features developed progressively with severe increase in choreic
movements and dementia. The disease terminated in death on average 17
years after manifestation of the first symptoms.

Folstein et al. (1984, 1985) contrasted HD in 2 very large Maryland
pedigrees: an African American family residing in a bayshore tobacco
farming community and a white Lutheran family living in a farming
community in the western Maryland foothills and descended from an
immigrant from Germany. They differed, respectively, in age at onset (33
years vs 50 years), presence of manic-depressive symptoms (2 vs 75),
number of cases of juvenile onset (6 vs 0), mode of onset (abnormal gait
vs psychiatric symptoms), and frequency of rigidity or akinesia (5/21 vs
1/15). In the African American family, the mean age at onset was 25
years when the father was affected and 41 years when the mother was
affected; the corresponding figures in the white family were 49 and 52
years. Allelic mutations were postulated. In another survey in Maryland,
Folstein et al. (1987) found that the prevalence of HD among African
Americans was equal to that in whites.

Adams et al. (1988) found that life-table estimates of age of onset of
motor symptoms have produced a median age 5 years older than the
observed mean when correction for truncated intervals of observation
(censoring) was made. The bias of censoring refers to the variable
intervals of observation and loss to observation at different ages. For
example, gene carriers lost to follow-up, those deceased before onset of
disease, and those who had not yet manifested the disease at the time of
data collection were excluded from the observed distribution of age at
onset.

Kerbeshian et al. (1991) described a patient with childhood-onset
Tourette syndrome (137580) who later developed Huntington disease.

Shiwach (1994) performed a retrospective study of 110 patients with
Huntington disease in 30 families. He found the minimal lifetime
prevalence of depression to be 39%. The frequency of symptomatic
schizophrenia was 9%, and significant personality change was found in
72% of the sample. The age at onset was highly variable: some showed
signs in the first decade and some not until over 60 years of age.

The results of a study by Shiwach and Norbury (1994) clashed with the
conventional wisdom that psychiatric symptoms are a frequent
presentation of Huntington disease before the development of neurologic
symptoms. They performed a control study of 93 neurologically healthy
individuals at risk for Huntington disease. The 20 asymptomatic
heterozygotes showed no increased incidence of psychiatric disease of
any sort when compared to the 33 normal homozygotes in the same group.
However, the whole group of heterozygous and homozygous normal at-risk
individuals showed a significantly greater number of psychiatric
episodes than did their 43 spouses, suggesting stress from the
uncertainty associated with belonging to a family segregating this
disorder. Shiwach and Norbury (1994) concluded that neither depression
nor psychiatric disorders are likely to be significant preneurologic
indicators of heterozygous expression of the disease gene.

Giordani et al. (1995) performed extensive neuropsychologic evaluations
on 8 genotype-positive individuals comparing them to 8 genotype-negative
individuals from families with Huntington disease. They found no
significant differences between these 2 groups, casting further doubt on
earlier reports that suggested cognitive impairments are premonitory
signs of the classical neurologic syndrome of Huntington disease.

Rosenberg et al. (1995) performed a double-blind study on 33 persons at
risk for HD who had applied for genetic testing. Significantly inferior
cognitive functioning was disclosed in gene carriers by a battery of
neuropsychologic tests covering attentional, visuospatial, learning,
memory, and planning functions. Primarily, attentional, learning, and
planning functions were affected.

Bamford et al. (1995) performed a prospective analysis of
neuropsychologic performance and CT scans of 60 individuals with
Huntington disease. They found that psychomotor skills showed the most
significant consistent decline among cognitive functions assessed.

Lovestone et al. (1996) described an unusual HD family in which all 4
affected members presented first with a severe psychiatric syndrome
which in 3 cases was schizophreniform in nature. Two other living
members with no apparent signs of motor disorder had received
psychiatric treatment, 1 for schizophrenia.

Mochizuki et al. (1999) described a case of late-onset Huntington
disease with the first symptom of dysphagia. The 61-year-old man was
admitted with dysphagia and dysarthria, which had developed gradually
over 2 years. The patient had no psychologic signs, dementia, paresis,
involuntary movements, ataxia, or sensory disturbance in the limbs.
Dysphagia and dysarthria appeared to be caused by a 'cough-like
movement' just before or during speaking or swallowing. Because the
'cough-like movement' progressed for 3 years and was eventually
suppressed with disappearance of dysphagia after administration of
haloperidol, this symptom was thought to be due to HD.

Paulsen et al. (2006) studied the brain structure of 24 preclinical HD
patients as measured by brain MRI and compared them to 24 healthy
control subjects matched by age and gender. Preclinical HD individuals
had substantial morphologic differences throughout the cerebrum compared
to controls. The volume of cerebral cortex was significantly increased
in preclinical HD, whereas basal ganglion and cerebral white matter
volumes were substantially decreased. Although decreased volumes of the
striatum and cerebral white matter could represent early degenerative
changes, the finding of an enlarged cortex suggested that developmental
pathology occurs in HD.

Marshall et al. (2007) compared psychiatric manifestations among 29 HD
mutation carriers with no clinical symptoms, 20 HD mutation carriers
with mild motor symptoms, 34 manifesting HD patients, and 171
nonmutation controls. The mild motor symptoms group and the manifesting
HD group showed significantly higher scores for obsessive-compulsive
behavior, interpersonal sensitivity, anxiety, paranoia, and psychoticism
compared to the nonmutation control group. The mutation carriers without
symptoms had higher scores for anxiety, paranoid ideation, and
psychoticism compared to the nonmutation control group. The results
indicated that individuals in the preclinical stage of HD exhibit
specific psychiatric symptoms and that additional symptoms may manifest
later in the disease course. Walker (2007) noted that suicidal ideation
is a frequent finding in Huntington disease and that physicians should
be aware of increased suicide risk both in asymptomatic at-risk patients
and symptomatic patients.

- Clinical Variability

Behan and Bone (1977) reported hereditary chorea without dementia. The
oldest affected person in their family was aged 61 years.

- Juvenile Onset

Juvenile-onset Huntington disease, typically defined as onset before age
20 years, is estimated to comprise less than 10% of all HD cases. It is
usually transmitted from an affected father, is associated with very
large CAG repeat sizes (60 or more) in the HTT gene, and typically shows
rigidity and seizures (Nance and Myers, 2001; Ribai et al., 2007).

The juvenile form of Huntington disease was first described by Hoffmann
(1888) using data from a 3-generation family. He identified 2 daughters
with onset at 4 and 10 years who showed rigidity, hypokinesia, and
seizures.

Barbeau (1970) pointed out that patients with the juvenile form of
Huntington chorea seem more often to have inherited their disorder from
the father than from the mother. Ridley et al. (1988) showed that
Huntington disease shows anticipation, but only on paternal inheritance,
with the consequence that patients with juvenile Huntington disease
inherit the disease from their fathers.

Navarrete et al. (1994) described a family in which a brother and sister
had very early onset of Huntington disease. Clinical manifestations were
apparent in both sibs at the age of 8 years; the brother died at age 10.
The father of these sibs was affected from the age of 29 years.

Milunsky et al. (2003) described 1 of the youngest children ever
reported with juvenile HD. The girl, 5 years old at the time of report,
had been adopted because of the inability of her biologic parents to
care for her. Her biologic father was subsequently found to have HD. The
girl demonstrated near-normal development until about 18 months of age.
Brain MRI had been normal at 2 years of age; at 3.5 years of age, there
was marked cerebellar atrophy involving the vermis and cerebellar
hemispheres, diminutive middle cerebellar peduncles, and an enlarged
fourth ventricle. By age 3 years and 10 months, the patient required
gastric tube feeding. Choreiform movements, predominantly on the right
side, developed at approximately 4 years of age. Milunsky et al. (2003)
developed a modified PCR method using XL (extra long)-PCR that allowed
them to diagnose 265 triplet repeats on one HTT allele and 14 on the
other.

Nahhas et al. (2005) reported a girl with a maternal family history of
HD who had onset of symptoms at age 3 and died at age 7 due to
complications of HD. The patient's mother had symptoms of HD at age 18.
Molecular analysis revealed that the mother had 70 CAG repeats whereas
the daughter had approximately 130 CAG repeats. Nahhas et al. (2005)
stated that this was the largest reported molecularly confirmed CAG
expansion from a maternal transmission, demonstrating that very large
expansions can also occur through the maternal lineage.

Yoon et al. (2006) reported 3 patients with onset of HD before age 10
years. All had speech delay in early childhood as the first symptom,
which predated motor symptoms by at least 2 years. All children later
developed severe dysarthria. Initial gross motor symptoms included
ataxic gait and falls; initial behavioral problems included aggression,
irritability, and hyperactivity. CAG repeats were 120, 100, and 93,
respectively, and all children inherited the disorder from their
fathers.

Ribai et al. (2007) performed a retrospective analysis of 29 French
patients with juvenile-onset HD. The mean delay before diagnosis was 9
years. The most common signs at onset were severe cognitive and
psychiatric disturbances (65.5% of patients), including severe alcohol
or drug addiction and psychotic disorder. In these patients, motor signs
occurred a mean of 6 years after cognitive or psychiatric signs. Three
other patients presented with myoclonic head tremor, 3 with chorea, and
1 with progressive cerebellar signs. Thirteen (46%) had fewer than 60
CAG repeats (range, 45 to 58). Six patients inherited the disease from
their fathers, and 7 from their mothers, with similar anticipation.
However, all cases with onset before age 10 years were paternally
inherited.

Sakazume et al. (2009) reported a girl with onset of HD beginning at age
2 years with motor regression, speech difficulties due to oromotor
dysfunction, and frequent temper tantrums. Onset of severe prolonged
generalized seizures began at age 4 years. Brain MRI showed severe
cerebellar atrophy in the vermis and cortex, in addition to atrophy in
the caudate, putamen, and globus pallidus. Her mother, grandparent, and
great-grandparent were affected. Molecular analysis showed that the
child had 160 CAG repeats, whereas her mother had 60 repeats. A review
of 7 reported patients with early-onset HD showed that 4 had inherited
the expanded allele from the mother, and that the mothers were
relatively young at the time of pregnancy, ranging from 20 to 27 years.
These findings suggested that the incidence of maternal transmission in
early-onset HD may be higher than that in adult-onset HD. Three of the 7
previously reported patients with early-onset HD had cerebellar atrophy.

BIOCHEMICAL FEATURES

Enna et al. (1976) found 50% reduction in binding at serotonin and
muscarinic cholinergic receptors in the caudate nucleus but not the
cerebral cortex of patients with Huntington chorea. Goetz et al. (1975)
could not confirm a report that fibroblasts grew poorly. Contrariwise,
they found that Huntington disease cells grew to a higher maximal
density than did control fibroblasts.

Reiner et al. (1988) used immunohistochemical methods to study neurons
producing substance P and enkephalin, projecting to the globus pallidus
and to the substantia nigra, in brains from 17 patients with Huntington
disease in various stages of the disorder. The authors found that in the
early and middle stages of HD, the enkephalin-producing neurons with
projections to the external portion of the globus pallidus were more
affected than substance P-containing neurons projecting to the internal
pallidal segment. This result was confirmed by Sapp et al. (1995).
Reiner et al. (1988) also found that substance P-producing neurons
projecting to the substantia nigra pars reticulata were more affected
than those projecting to the pars compacta. In the advanced stages of
the disease, neurons projecting to all striatal areas were depleted.
Richfield and Herkenham (1994) found greater loss of cannabinoid
receptors on striatal nerve terminals in the lateral globus pallidus
compared to the medial pallidum in Huntington disease of all
neuropathologic grades, supporting the preferential loss of striatal
neurons that project to the lateral globus pallidus.

Aronin et al. (1995) detected mutant huntingtin protein in cortical
synaptosomes isolated from brains of Huntington disease heterozygotes
and demonstrated that the mutant species is synthesized and transported
with the normal protein to nerve endings. In half of the juvenile cases,
huntingtin resolved as a complex of bands after electrophoresis and
immunostaining, which confirmed previous DNA evidence for somatic
mosaicism. Mutant huntingtin was present in both normal and affected
regions.

INHERITANCE

Huntington disease is an autosomal dominant disorder. When the number of
CAG repeats reaches 41 or more, the disease is fully penetrant.
Incomplete penetrance can occur with 36 to 40 repeats. The number of
repeats accounts for approximately 60% of the variation in age at onset,
with the remainder determined by modifying genes and environment
(Walker, 2007).

Intrafamilial variability of Huntington disease was illustrated by the
report by Campbell et al. (1961) of the juvenile rigid form in 2
brothers in a kindred in which 3 preceding generations had disease of
the more classic type. Brackenridge (1972) showed a relationship between
age at onset of symptoms in parent and child. Wallace and Hall (1972)
suggested that in Queensland, Australia, 2 possibly allelic forms of HD
may exist, one with early onset and the other with late onset.

Myers et al. (1982) confirmed the preponderance of inheritance from the
father when HD had an early onset. 'Anticipation' was thought to reflect
the finding that persons with early onset in prior generations were
selectively nonreproductive because of manifestation of the disorder. In
238 patients, Myers et al. (1983) correlated age at onset with whether
inheritance was from the father or the mother. More than twice as many
of the late-onset cases (age 50 or later) inherited the HD gene from an
affected mother than from an affected father. Affected offspring of
late-onset females also had late-onset disease while those of late-onset
males had significantly earlier ages of onset. The authors interpreted
these findings as suggesting a heritable extrachromosomal factor,
perhaps mitochondrial. They cited Harding (1981) as suggesting that
autosomal dominant late-onset spinocerebellar ataxia is marked by
earlier age at onset and death in offspring of affected males. After it
was found that both Huntington disease and some forms of spinocerebellar
ataxia are caused by expanded repeats, the mechanism of anticipation in
the paternal line was interpreted as an increase in the extent of the
repeats during paternal meiosis.

Boehnke et al. (1983) tested models to account for the stronger
parent-offspring age-of-onset correlation when the mother is the
affected parent and the excess of paternal transmission in cases with
onset at less than 21 years. They proposed 2 models in which a maternal
factor acts to delay onset: cytoplasmic, possibly mitochondrial, or
autosomal/X-linked.

Went et al. (1984) confirmed the earlier report that early-onset HD is
almost always inherited from the father, but could not confirm the
notion that late-onset disease is more often inherited from the mother.
Farrer and Conneally (1985) postulated that age at onset is governed
generally by a set of independently inherited aging genes, but
expression of the HD genes may be significantly delayed in persons with
a particular maternally transmitted factor. Myers et al. (1985)
presented data that suggested a protective effect conferred on the
offspring of affected women, who show an older mean age at onset than
offspring of affected men, regardless of the onset age in the parent.
Pointing out that some repetitive elements in many chromosomes of the
mouse are methylated differently in males and females, Erickson (1985)
suggested differences such as chromosomal imprinting may be responsible
for the greater severity and earlier onset of Huntington disease in
offspring of affected males and greater severity of myotonic dystrophy
(DM1; 160900) in offspring of affected females.

Among 195 reported cases of juvenile Huntington disease, van Dijk et al.
(1986) found a preponderance of 'rigid cases,' whose affected parent was
the father in a significantly high number of cases. Rigid paternal cases
have a significantly lower age at onset as well as a shorter duration of
disease than choreic paternal cases.

Ridley et al. (1988) found that while the mean age at onset in offspring
of affected mothers did not differ greatly from that in their mothers,
the distribution of age at onset in the offspring of affected fathers
fell into 2 groups; the larger group showed an age at onset only
slightly younger than that in their affected fathers, and a smaller
group had, on average, an age at onset 24 years younger than that of
their affected fathers. Analysis of the grandparental origin of the
Huntington allele suggested that while propensity to anticipation could
be inherited for a number of generations through the male line, it
originated at the time of differentiation of the germline of a male who
acquired the Huntington allele from his mother. Ridley et al. (1988)
suggested that major anticipation indicates an epigenetic change in
methylation of the nucleic acid of the genome, which is imposed in the
course of 'genomic imprinting,' that is, in the mechanism by which the
parental origin of alleles is indicated (Reik et al., 1987; Sapienza et
al., 1987). Differences in gene expression according to the parent from
whom the gene was derived, in HD, in myotonic dystrophy (DM1; 160900)
and perhaps in other conditions, might be due to a difference in
methylation of the genes in the 2 sexes (see review by Marx, 1988).

In South Wales over a 10-year period, Quarrell et al. (1986) found 192
patients with HD in whom there was a positive family history and an
additional 37 patients who had clinical features consistent with HD but
who had no affected relatives despite detailed inquiries. After review,
22 of the 37 were still thought to have HD on clinical grounds; the
diagnosis was considered less likely in 15. Postmortem supported the
diagnosis in 6 of 7 cases so studied; a patient labeled HD on the death
certificate had Kufs disease (204300) at postmortem.

Adams et al. (1988) also found that the offspring of affected males had
significantly younger onset than did offspring of affected females, and
a trend suggested an excess of paternal descent among juvenile-onset
cases. Reik (1988) also suggested genomic imprinting as an alternative
mechanism to maternally inherited extrachromosomal factors to account
for the parental origin effect. By imprinting, the gene itself becomes
modified in a different way depending on whether it passes through the
maternal or the paternal germline. The modification may involve
methylation of DNA and could result in earlier or higher level of
expression of the gene when it is transmitted by the father. Ridley et
al. (1988) reviewed extensively the ascertainment bias producing or
working against the observation of anticipation. Reik (1989) reviewed
the topic of genomic imprinting in relation to genetic disorders of man,
and as possible examples pointed to the earlier onset of spinocerebellar
ataxia (164400) with paternal transmission, the increased severity of
neurofibromatosis I (NF1; 162200) with maternal transmission, the
earlier onset of neurofibromatosis II (NF2; 101000) with maternal
transmission, and the preferential loss of maternal alleles in sporadic
osteosarcoma.

Wolff et al. (1989) reported an isolated case of HD in an extensively
studied family. Nonpaternity appeared to be excluded, and DNA markers
closely linked to the HD gene indicated several clearly unaffected sibs
who shared 1 or the other or both of the patient's haplotypes. The
posterior probability of a new mutation to HD in the patient was
calculated to exceed 99%, even if an a priori probability of
nonpaternity of 10% and a mutation rate of HD of 1 in 10 million gametes
were assumed.

In 2 families with Huntington disease linked to the short arm of
chromosome 4, Sax et al. (1989) demonstrated remarkable intrafamilial
variability. In 1 family, affected persons of 3 generations showed a
50-year variation in age at onset. The member with the latest onset (at
age 67) died at age 91 with autopsy-confirmed HD. The next generation
had hypotonic chorea beginning in the fourth decade with death in the
fifth. In the third generation, a rigid patient, inheriting the illness
from an affected father, had onset at age 16, while her sibs had chorea
beginning in the third decade. In the second family, several members had
cerebellar signs as well as chorea and dementia; MRI and CT showed
olivopontocerebellar and striatal atrophy. Whether these phenotypes were
the result of different allelic genes at the HD locus or of unlinked
autosomal modifying loci was unknown.

A large Tasmanian family with Huntington disease was first described by
Brothers (1949). Pridmore (1990) traced 9 generations, starting with the
father of the woman who brought the disease to Tasmania. From that
woman, 6 lines had living affected descendants and a total of 765 living
descendants at risk. The numbers of affected males and females were
equal. The mean age at onset was 48.6 years and the mean age of death,
61.8 years. Affected members were at least as fertile as members of the
general population. Pridmore (1990) concluded that late-onset disease
(defined as death after 63 years of age) was associated with
significantly greater fertility (in men more so than women) compared
with that of affected sibs of the same sex. Unaffected sibs produced
fewer offspring than in the general population.

Ridley et al. (1991) showed that the age at onset varies between
families and between paternal and maternal transmission and that
rigidity is associated specifically with very early onset, major
anticipation, paternal transmission, and young parental age at onset.
Major anticipation was defined as an age at onset of the proband more
than 15 years less than that in the affected parent. They proposed that
age at onset depends on the state of methylation of the HD locus, which
varies as a familial trait, and as a consequence of 'genomic imprinting'
determined by parental transmission. They further suggested that young
familial age at onset and paternal imprinting occasionally interact to
produce a major change in gene expression, that is, the
early-onset/rigid variant.

Farrer et al. (1993) tested the hypothesis that the normal HD allele or
a closely linked gene on the nonmutant chromosome influences age at
onset of HD. Analysis of the transmission patterns of genetically linked
markers at the D4S10 locus in the normal parent against age at onset in
the affected offspring in 21 sibships and 14 kindreds showed a
significant tendency for sibs who have similar onset ages to share the
same D4S10 allele from the normal parent. Affected sibs who inherited
different D4S10 alleles from the normal parent tended to have more
variable ages at onset, thus providing support for the hypothesis.

Goldberg et al. (1993) reported findings in 3 families in which a new
mutation for HD had arisen. In all 3 families, a parental intermediate
allele (with expansion to 30-38 CAG repeats, greater than that seen in
the population but below the range seen in patients with HD) had
expanded in more than 1 offspring. In one of the families, 2 sibs with
the expanded CAG repeat were clinically affected with HD, thus
presenting a pseudorecessive pattern of inheritance.

The U.S.-Venezuela Collaborative Research Project and Wexler (2004)
genotyped 3,989 members of the 83 Venezuelan HD kindreds for their HD
alleles, representing a subset of the population at greatest genetic
risk. There were 938 heterozygotes, 80 people with variably penetrant
alleles, and 18 homozygotes. Analysis of the 83 Venezuelan HD kindreds
demonstrated that residual variability in age at onset had both genetic
and environmental components. A residual age at onset phenotype was
created from a regression analysis of the log of age at onset on repeat
length. Familial correlations (correlation +/- SE) were estimated for
sib (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07
+/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial
origin for the residual variance in onset. By using a
variance-components approach with all available familial relationships,
the additive genetic heritability of this residual age at onset trait
was 38%. A model, including shared sib environmental effects, estimated
the components of additive genetic (0.37), shared environment (0.22),
and nonshared environment (0.41) variances, confirming that
approximately 40% of the variance remaining in age at onset was
attributable to genes other than the HD gene and 60% was environmental.

- Homozygosity

Wexler et al. (1985, 1987) identified persons homozygous for the
Huntington gene by study of branches of the large Venezuelan kindred in
which there are instances of both parents being affected. Homozygosity
was indicated by homozygosity for the G8 probe. Remarkably, comparison
with the usual heterozygotes revealed no difference of phenotype. Wexler
et al. (1987) suggested that this is the first human disease in which
complete dominance has been demonstrated. Myers et al. (1989) performed
molecular genetic studies in 4 offspring of 3 different affected x
affected matings for possible homozygosity. One of the 4 was found to
have a 95% likelihood of being an HD homozygote. The individual's age at
onset and symptoms were similar to those in affected HD heterozygous
relatives. Thus, the findings from the New England Huntington Disease
Research Center corroborated the finding of Wexler et al. (1987).
Connarty et al. (1996) identified 2 patients in Wessex in the U.K. in
whom expansion of the HD triplet repeat was found on both chromosomes.
Both were males who presented in middle age with typical clinical
features. Unfortunately, no other family members were available for
analysis.

- Twin Studies

Bird and Omenn (1975) reported a family in which a pair of male
monozygotic twins were concordant for Huntington disease. At age 30
years, the twins had a similar degree of cognitive defect but differed
slightly in the severity of chorea. The daughter of 1 of the twins had
childhood-onset HD, and the mother of the twins had the adult-onset
rigid form of HD. Sudarsky et al. (1983) reported a pair of monozygotic
twins with Huntington disease. Although they were raised in separate
households from birth, age at onset, disease course, and behavioral
abnormalities were strikingly similar. The findings supported the
hypothesis that the main features of the disorder are genetically
determined.

Georgiou et al. (1999) reported a pair of monozygotic twins with HD
confirmed by genetic analysis. Twin A was more impaired at a motor
level, with a hyperkinetic hypotonic variant of the disease, whereas
twin B showed greater attentional impairment and demonstrated a more
hypokinetic hypertonic, or rigid, variant. Twin B, who was the more
impaired, showed more progressive deterioration. Georgiou et al. (1999)
concluded that epigenetic environmental factors must play a role in
disease modification.

Norremolle et al. (2004) reported a pair of 34-year-old male monozygotic
twins belonging to a family segregating Huntington disease. The mother
died of the disorder at the age of 41 years. The twins were reported to
have been monochorionic and diamniotic. Twin A had no symptoms and only
minor abnormalities in the form of slight impersistence of lateral gaze
and mild upper limb ataxia. In contrast, twin B had a slow and slurred
speech, headthrust, slow saccades, orolingual apraxia, impaired
coordination, positive milk maid sign, and discrete choreic movements of
the limbs and head. Mini-Mental Status Examination (MMSE) was 29 of 30
in twin A and 26 of 30 in twin B. Twin A worked as a full-time smith,
whereas twin B was unemployed after he was dismissed 2 years previously
from a job he had held for 15 years. The wife of twin B stated that he
had become more introverted and unenterprising. Two different cell
lines, carrying the normal allele together with either an expanded
allele with 47 CAGs or an intermediate allele with 37 CAGs, were
detected in blood and buccal mucosa from both twins. This appeared to
have been the first case described of HD gene CAG repeat length
mosaicism in blood cells. Haplotype analysis established that the 37 CAG
allele most likely arose by contraction of the maternal 47 CAG allele.
The contraction must have taken place postzygotically, possibly at a
very early stage of development, and probably before separation of the
twins. Twin B had presented symptoms of HD for 4 years; his skin
fibroblasts and hair roots carried only the cell line with the 47 CAG
repeat allele. Twin A, who was without symptoms at the time of report,
displayed mosaicism in skin fibroblasts and hair roots. Norremolle et
al. (2004) concluded that if the proportion of the 2 cell lines in the
brain of each twin resembled that of the hair roots (another tissue
originating from the ectoderm), the mosaicism in the unaffected twin
would mean that only a part of his brain cells carried the expanded
allele, which could explain why he, in contrast to his brother, had no
symptoms at the time of report.

Friedman et al. (2005) reported a pair of female monozygotic twins who
were discordant for HD. The affected twin had onset of declining gait
and cognition at age 65 years, and genetic analysis showed a 39-CAG
repeat in the HTT gene, which is considered a borderline expansion in
which the disease may be less than 100% penetrant. Although MRI showed
no caudate atrophy, she had generalized chorea, ataxia, and mild
cognitive impairment. Her twin sister shared the 39-CAG repeat but was
unaffected 7 years after disease onset in the affected twin. Detailed
history suggested possible environmental influences: both twins grew up
near a factory that was later made a federal toxic cleanup site, but the
asymptomatic twin moved away at age 23 years, whereas the affected twin
remained in the same house. The affected twin also smoked until her
sixties, while the unaffected twin quit smoking at age 35 years.
Finally, the affected twin had several comorbid conditions, including
type II diabetes mellitus, chronic bronchitis, rheumatoid arthritis,
hypertension, and chronic anemia, for which she took several
medications. The unaffected twin had only hypertension. Friedman et al.
(2005) suggested that the borderline CAG expansion of 39 repeats as well
as different environmental factors contributed to the disparity in
disease manifestation in these twins.

Panas et al. (2008) reported a pair of 55-year-old monozygotic twin
sisters with HD due to a 45-CAG repeat who showed phenotypic discordance
for the disease. At age 43, twin 1 showed anxiety, irritability, and
mildly aggressive behavior. At age 46, she had prominent hyperkinesias,
behavioral disturbances, and mild cognitive deterioration. By age 54,
she had an independence scale of 30%. Twin 2 had onset at age 51 of
depressive symptoms and mild hyperkinesias. By age 54, she had an
independence scale of 50%. The age of onset differed by 8 years with
regard to behavioral changes, or by 6 years with regard to choreic
movements. The first twin showed prominent choreic hyperkinesias and
aggressivity, while the second had severe depression with marked
withdrawal and mild choreic hyperkinesias. Panas et al. (2008)
postulated that the phenotypic differences may be due to epimutations in
critical DNA regions.

MAPPING

Huntington disease was first mapped to the tip of the short arm of
chromosome 4 in 1983; the HD gene was not isolated until 1993. The
Huntington's Disease Collaborative Research Group, comprising 58
researchers in 6 research groups, used haplotype analysis of linkage
disequilibrium to spotlight a small segment of 4p16.3 as the likely
location of the defect (MacDonald et al., 1992).

The Huntington disease gene was assigned to chromosome 4 by
demonstration of close linkage to an arbitrary DNA segment that had been
mapped to chromosome 4 by somatic cell hybridization. The DNA segment
was detected by a sequence called 'G8' and renamed 'D4S10' at the
seventh Human Gene Mapping Workshop in Los Angeles in August 1983
(Gusella et al., 1984; Wexler et al., 1984).

Gusella et al. (1984) found close linkage of G8 to Huntington disease in
a large Venezuelan kindred and a smaller American kindred. In the
initial study, the total lod score was 8.53 at theta = 0.00. No
obligatory recombinants were found. Linkage was with different
haplotypes in the 2 kindreds studied. The upper limit of 99% confidence
was set at 10 cM. D4S10 and HD were found to be remote from GC and MNS
(known to be on 4q), as indicated by negative lod scores. Gusella et al.
(1984) identified further restriction enzyme polymorphism of the G8
probe found to be linked to HD; with this, the frequency of identifiable
heterozygosity could be raised to about 90%. Folstein et al. (1985)
found close linkage of HD and the G8 probe in both of 2 large Maryland
kindreds (Folstein et al., 1984).

Harper et al. (1985) stated that the polymorphism with 4 enzymes
(HindIII, EcoRI, NciI, and BstI) applied to the G8 locus shows that over
80% of subjects are heterozygous. They further stated that the latest
estimate of the interval between the G8 and the HD loci was 5 cM.

The G8 locus (D4S10) and presumably the Huntington disease locus are
deleted in the Wolf-Hirschhorn (4p-) syndrome (WHS; 194190) (Gusella et
al., 1985). This information helped map the HD locus to 4p. Most 4p-
syndrome patients do not survive long enough to develop manifestations
of HD. Tranebjaerg et al. (1984) concluded that the 'critical segment'
in Wolf syndrome is 4p16.3. McKeown et al. (1987) found that the G8
locus was not deleted in a case of 4p- syndrome.

In 16 British kindreds, Youngman et al. (1986) found 2 recombinants
yielding a maximum lod score of 17.6 at theta = 0.02 for marker D4S10,
providing evidence against multilocus heterogeneity in Huntington
disease.

By in situ hybridization (Wang et al., 1985; Magenis et al., 1985; Zabel
et al., 1985; Wang et al., 1986), the HD-linked marker, G8, was mapped
to 4p16.1. From studies by in situ hybridization to partially deleted
chromosomes with known breakpoints, Magenis et al. (1986) concluded that
the G8 probe is located in the distal half of band 4p16.1. Wang et al.
(1986), also by in situ hybridization in patients with deletions of 4p,
mapped G8 to 4p16.1-p16.3. Of their 2 patients, 1 had the typical
phenotype of the Wolf-Hirschhorn syndrome (WHS) with a minute deletion
of the segment p16.1-p16.3. Wang et al. (1986) concluded that the 4pter
region could be excluded as a site.

Landegent et al. (1986) used a nonfluorescent method of in situ
hybridization to assign the D4S10 locus to 4p16.3 rather than 4p16.1.
The in situ hybridization method involved haptenization of nucleic acids
in the probe by chemical attachment of 2-acetylaminofluorene (AAF)
groups, marking of the hybridized probe by an indirect
immunoperoxidase/diaminobenzidine reaction, and reflection-contrast
microscopic visualization of the precipitated dye.

Froster-Iskenius et al. (1986) described a kindred in which an
apparently balanced reciprocal translocation between 4q and 5p was
segregating together with Huntington disease in 2 generations. In situ
hybridization studies revealed that the linked DNA marker (G8) was
located in the region 4p16 of both the normal and translocated
chromosome 4. Thus, the association may be a chance occurrence.

Collins et al. (1987) applied the strategy of chromosome jumping to
identify new probes from the terminal portion of 4p. Jumping clones were
identified that traveled in each direction from G8. In 2 of 3 persons
recombinant for G8 and HD who were also informative for the newly
identified probes, the jumping clone traveled with HD. Thus, a jump of
approximately 200 kb had crossed 2 out of 3 recombination points between
G8 and HD. The information defined unequivocally the location of HD
distal to G8, and suggested that the physical distance between them may
not be as large as previously suspected.

Gilliam et al. (1987) presented evidence that the HD gene lies in 4p16.3
between D4S10 proximally and the telomere distally. Multipoint linkage
analysis of the 4 loci--HD, D4S10, RAF2 (see 164760), and
D4S62--indicated that D4S62 is close to D4S10 and centromeric to it. One
particularly informative individual from the large Venezuelan kindred
showed recombination between 2 RFLPs within the D4S10 segment. The 2 are
located about 33 kb apart. The information at hand indicated the
direction of cloning necessary for reaching the HD gene.

Gilliam et al. (1987) described an anonymous DNA segment, D4S43, which
is exceedingly tightly linked to HD. Like the disease gene, it is
located in the most distal portion of 4p, flanked by D4S10 and the
telomere. In 3 extended HD kindreds, no recombination with HD was found,
placing it less than 1.5 cM from the genetic defect. Expansion of the
region to include 108 kb of cloned DNA led to the identification of 8
RFLPs and at least 2 independent coding segments. These genes might be
candidates for the site of the HD defect; however, D4S43 RFLPs did not
display linkage disequilibrium with the disease gene as one would expect
if such were the case. Wasmuth et al. (1988) characterized a new RFLP
marker, D4S95, a highly polymorphic locus which displayed no
recombination with HD in the families tested. Robbins et al. (1989) used
genetic linkage analysis to demonstrate that the gene causing Huntington
disease is telomeric to D4S95 and D4S90, both markers known to be
tightly linked to the HD locus.

The fact that no evidence of linkage disequilibrium has been found in HD
with the G8 marker (Conneally et al., 1989) may suggest that the
mutation is ancient and has occurred on very few occasions.

Doggett et al. (1989) prepared a physical map that extended from the
most distal of the loci linked to HD (but proximal to HD) to the
telomere of chromosome 4. The mapping identified at least 2 CpG islands
and placed the most likely location of the HD defect remarkably close
(within 325 kb) to the telomere. Conneally et al. (1989) pooled linkage
data on G8 versus HD from 63 HD families (57 Caucasian, 4 Black
American, and 2 Japanese). The combined maximum lod score was 87.69 at
theta = 0.04 (99% confidence interval, 0.018-0.071). The maximum
frequency of recombination was 0.03 in males and 0.05 in females. The
data suggested that there is only 1 HD locus, though a second rare locus
could not be ruled out. Kanazawa et al. (1990) presented linkage data in
9 Japanese families supporting the view that the Japanese Huntington
disease gene is identical with the 'Western gene,' in spite of the lower
prevalence rate in Japan. The linkage relationships appear to be the
same as those that have been observed in European families.

Pyrimidine oligodeoxyribonucleotides bind in the major groove of DNA
parallel to the purine Watson-Crick strand through formation of specific
Hoogsteen hydrogen bonds to the purine Watson-Crick base. Specificity is
derived from thymine (T) recognition of adenine/thymine (AT) basepairs
(TAT triplets); and N3-protonated cytosine (C+) recognition of
guanine/cytosine (GC) basepairs (C + GC triplets). By combining
oligonucleotide-directed recognition with enzymatic cleavage, near
quantitative cleavage at a single target site can be achieved. Strobel
et al. (1991) used this approach to 'liberate' the tip of 4p that
contains the entire candidate region for the HD gene. A 16-base
pyrimidine oligodeoxyribonucleotide was used with success.

Buetow et al. (1991) provided a genetic map of chromosome 4 with
extensive information on the mapping of 4p16.3. They presented evidence
for linkage heterogeneity in this region and suggested that it might
explain the fact that in some families (Doggett et al., 1989; Robbins et
al., 1989), HD has been localized to the most distal 325 kb of 4p16.3,
telomeric to D4S90, the most distal marker in the map presented by
Buetow et al. (1991), whereas in other families (MacDonald et al., 1989;
Snell et al., 1989) HD has been localized proximal to D4S90. A
microinversion in 4p16.3 in HD patients could provide an explanation. In
10 South African families of black, white, and mixed ancestry, Greenberg
et al. (1991) found tight linkage to D4S10 (G8); maximum lod score =
8.14 at theta = 0.00. Because of the diverse ethnic backgrounds, the
data provided evidence that there is only a single HD locus.

The existence of many genes in the telomeric region of 4p is indicated
by the work of Saccone et al. (1992). By chromosomal in situ
hybridization, they determined the localization of the G+C-richest
fraction of human DNA. Bernardi (1989) pointed out that the human genome
is a mosaic of isochores, i.e., large DNA regions (more than 300 kb, on
the average) that are compositionally homogeneous (above a size of 3 kb)
and belong to a small number of families characterized by different G+C
levels. The G+C-richest fraction of DNA has the highest gene
concentration, the highest concentration of CpG islands, the highest
transcriptional and recombinational activity, and a distinct chromatin
structure. The in situ hybridization results showed a concentration of
this isochore family, called H3, in telomeric bands and in chromomycin
A3-positive/4-prime,6-diamidino-2-phenylindole-negative bands.
Mouchiroud et al. (1991) found that the gene density in the GC-richest
3% of the genome is about 16 times higher than in the GC-poorest 62%.
Figure 2 of Saccone et al. (1992) showed dramatically the concentration
of G+C-rich DNA in the telomeric band of 4p as well as regions on other
chromosomes that have been found to be rich in genes by mapping studies,
e.g., distal 1p and much of chromosomes 19 and 22.

Sabl and Laird (1992) proposed an epigenetic mechanism to explain
inconsistencies in mapping of the candidate HD gene. Dominant
position-effect variegation (PEV) is a variable but clonally stable
inactivation of a euchromatic gene that has been placed adjacent to
heterochromatic sequences. In an example in Drosophila melanogaster, a
fully dominant mutant phenotype, such as HD, results from stable
epigenetic inactivation of an allele adjacent to the structural
alteration (cis-inactivation) combined with a complementary inactivation
of the homologous normal allele (trans-inactivation). Sabl and Laird
(1992) proposed that the trans-inactivation of the normal allele may
occasionally persist through meiosis. This so-called epigene conversion
occurring at the HD locus in a few percent of meioses could account for
anomalies in the region's genetic map.

Bates et al. (1992) characterized a YAC contig spanning the region most
likely to contain the HD mutation. Zuo et al. (1992) prepared a set of
YAC clones spanning 2.2 Mb at the tip of the short arm of chromosome 4
presumably containing the HD gene. Skraastad et al. (1992) detected
highly significant linkage disequilibrium with D4S95 in 45 Dutch
families, consistent with studies in other populations. The area of
linkage disequilibrium extended from D4S10 proximally to D4S95, covering
1,100 kb. The results confirmed the suggestion that the HD gene maps
near D4S95.

Using a direct cDNA selection strategy, Goldberg et al. (1993)
identified at least 7 transcription units within the 2.2-Mb DNA interval
thought to contain the HD gene. Screening with one of the cDNA clones
identified an Alu insertion in genomic DNA from 2 persons with HD, which
showed complete cosegregation with the disease in these families but was
not found in 1,000 control chromosomes. A gene that encodes a 12-kb
transcript, which maps in close proximity to the Alu insertion site, was
considered a strong candidate for the HD gene.

In an analysis of 78 HD chromosomes with multiallelic markers, MacDonald
et al. (1992) found 26 different haplotypes, suggesting a variety of
independent HD mutations. The most frequent haplotype, accounting for
about one-third of disease chromosomes, suggested that the disease gene
is between D4S182 and D4S180. However, alternative mechanisms for
creating haplotype diversity do not require a multiple mutational
origin.

MOLECULAR GENETICS

The Huntington's Disease Collaborative Research Group (1993) identified
an expanded (CAG)n repeat on 1 allele of the HTT gene (613004.0001) in
affected members from all of 75 HD families examined. The families came
from a variety of ethnic backgrounds and demonstrated a variety of
4p16.3 haplotypes. The findings indicated that the HD mutation involves
an unstable DNA segment similar to those previously observed in several
disorders, including the fragile X syndrome (300624), Kennedy syndrome
(313200), and myotonic dystrophy. The fact that the phenotype of HD is
completely dominant suggested that the disorder results from a
gain-of-function mutation in which either the mRNA product or the
protein product of the disease allele has some new property or is
expressed inappropriately (Myers et al., 1989).

Duyao et al. (1993), Snell et al. (1993), and Andrew et al. (1993)
analyzed the number of CAG repeats in a total of about 1,200 HD genes
and in over 2,000 normal controls. Read (1993) summarized and collated
the results. In all 3 studies, the normal range of repeat numbers was
9-11 at the low and 34-37 at the high end, with a mean ranging from
18.29 to 19.71. Duyao et al. (1993) found a range of 37-86 in HD
patients with a mean of 46.42.

Ambrose et al. (1994) found that both normal and HD alleles are
represented in the mRNA population in HD heterozygotes, indicating that
the defect does not eliminate transcription. In a female carrying a
balanced translocation with a breakpoint between exons 40 and 41, the HD
gene was disrupted but the phenotype was normal, arguing against simple
inactivation of the gene as the mechanism by which the expanded
trinucleotide repeat causes HD. The observation suggested that the
dominant HD mutation either confers a new property on the mRNA or, more
likely, alters an interaction at the protein level.

Rubinsztein et al. (1996) studied a large cohort of individuals who
carried between 30 and 40 CAG repeats in the IT15 (HTT) gene. They used
a PCR method that allowed the examination of CAG repeats only, thereby
excluding the CCG repeats, which represent a polymorphism, as a
confounding factor. No individual with 35 or fewer CAG repeats had
clinical manifestations of HD. Most individuals with 36 to 39 CAG
repeats were clinically affected, but 10 persons (aged 67-95 years) had
no apparent symptoms of HD. The authors concluded that the HD mutation
is not fully penetrant in individuals with a borderline number of CAG
repeats.

Gusella et al. (1996) gave a comprehensive review of the molecular
genetic aspects of Huntington disease.

- Genetic Anticipation

Brinkman et al. (1997) defined the relationship between CAG repeat size
and age at onset of HD in a cohort of 1,049 persons, including 321
at-risk and 728 affected individuals with a CAG size of 29 to 121
repeats. Kaplan-Meier analysis provided curves for determining the
likelihood of onset at a given age, for each CAG repeat length in the 39
to 50 range. These curves were significantly different, with relatively
narrow 95% confidence intervals, indicating the correlation between CAG
repeat size and age at onset. Brinkman et al. (1997) stated that,
although complete penetrance of HD was observed for CAG sizes equal to
or greater than 42, 'only a proportion of those with a CAG repeat length
of 36-41 showed signs or symptoms of HD within a normal life span.'
Their data provided information concerning the likelihood of being
affected, by a specific age, with a particular CAG size, and may be
useful in predictive-testing programs and for the design of clinical
trials for persons at increased risk for HD.

Snell et al. (1993) found a negative correlation between the number of
repeats on the normal paternal allele and the age at onset in
individuals with maternally transmitted disease. They interpreted this
as suggesting that normal gene function varies because of the size of
the repeat in the normal range and a sex-specific modifying effect.
However, Read (1993) commented that this was not seen by the other
groups and 'is hard to square with the reported normal age at onset in
homozygotes.'

In an examination of 8 probands with sporadic HD whose parental DNA was
available, Goldberg et al. (1993) found that 1 of the parental HD
alleles was significantly greater than that seen in the general
population, but smaller than that seen in patients. The CAG repeats were
in the range of 30 to 38, and were designated 'intermediate alleles.'
These alleles were found to be unstable and prone to expansion upon
transmission. The expansions occurred on the paternal allele in the 7
cases in which sex of the parent could be determined and were associated
with advanced paternal age.

In a study of the HD mutation and the characteristics of its
transmission in 36 HD families, Trottier et al. (1994) found that
instability of the CAG repeats was more frequent and stronger upon
transmission from a male than from a female, with a clear tendency
toward increased size. They found a significant inverse correlation (p =
0.0001) between the age at onset and the CAG repeat length. The observed
scatter would, however, not allow an accurate individual prediction of
age at onset. An HD mutation of paternal origin was found in 3
juvenile-onset cases analyzed. In at least 2 of these cases, a large
expansion of the HD allele upon paternal transmission may explain the
major anticipation observed.

Illarioshkin et al. (1994) found significant positive correlation
between the rate of progression of clinical symptoms and CAG repeat
length in a group of 28 Russian patients with Huntington disease. Ranen
et al. (1995) found that the change in repeat length with paternal
transmission was significantly correlated with the change in age at
onset between the father and offspring. They confirmed an inverse
relationship between repeat length and age at onset, the higher
frequency of juvenile-onset cases arising from paternal transmission,
anticipation as a phenomenon of paternal transmission, and greater
expansion of the trinucleotide repeat with paternal transmission.

Coles et al. (1997) identified 7 alleles in the conserved 303-bp region
upstream of the +1 translation start site in the HD gene in a sample of
208 English Huntington patients and 56 unrelated control East Anglians,
30 black Africans, and 34 Japanese. There was no correlation between
these alleles and age at onset in the Huntington disease patients.

Using a logarithmic model to regress the age of HD onset on the number
of CAG triplets, Rosenblatt et al. (2001) found that CAG number alone
accounts for 65 to 71% of the variance in age at onset. The
'siblingship' to which an individual belonged accounted for 11 to 19% of
additional variance. They suggested that a linkage study of modifiers
would be feasible given the cooperation of major centers and might be
rendered more efficient by concentrating on sib pairs that are highly
discordant for age at onset.

Djousse et al. (2003) presented evidence that the size of the normal HD
allele influences the relationship between the size of the expanded
repeat and age at onset of HD. Data collected from 2 independent cohorts
were used to test the hypothesis that the unexpanded CAG repeat
interacts with the expanded CAG repeat to influence age at onset. The
effect of the normal allele was seen among persons with large HD repeat
sizes (47 to 83 repeats). The findings suggested that an increase in the
size of the normal repeat may mitigate disease expression among
HD-affected persons with large expanded CAG repeats.

Among 921 patients with HD, Aziz et al. (2009) observed a significant
interaction between CAG repeats in the normal HTT allele and CAG repeats
in the disease allele with age at onset. At the low range of mutant CAG
repeat size (36 to 44 repeats), higher normal CAG repeat sizes were
related to an earlier age at onset, while in the high range of the
mutant repeat size (44 to 64 repeats), higher values of the normal
repeat size were related to a later age at onset. Thus, the known
association between mutant CAG repeat size and age at onset
progressively weakens for higher normal CAG size, suggesting a
protective effect of the normal allele. Statistical modeling indicated
that this interaction term could account for 53.4% of the variance in
the age at onset. Among 512 patients, there was also a significant and
similar interaction between normal and mutant CAG repeat sizes on
severity or progression of motor, cognitive, and functional skills, but
not on behavioral symptoms. Among 16 premanifest HTT mutation carriers,
there was a similar interaction effect on basal ganglia size. Aziz et
al. (2009) concluded that increased CAG size in the normal allele
diminishes the association between mutant CAG repeat size and disease
severity in HD, suggesting an interaction between the 2 proteins.

In 51 families, Semaka et al. (2010) found that 54 (30%) of 181
transmissions of intermediate alleles, defined as 27 to 35 CAG repeats,
were unstable. The unstable transmissions included both 37 expansions
and 17 contractions. Of the expanded alleles, 68% expanded into the HD
range (greater than 36 CAG). Thus, 14% (25 of 181) of the intermediate
allele transmissions examined were consistent with a new mutation for
HD. However, Semaka et al. (2010) cautioned that additional studies were
needed before their findings are used for genetic counseling.

- Modifier Genes

MacDonald et al. (1999) analyzed the age at onset in 258 individuals
with Huntington disease. Variability in the age at onset attributable to
the CAG repeat length alone in this sample was found to be R(2) = 0.743.
The presence of a TAA repeat polymorphism in the GluR6 gene (GRIK2;
138244) explained an additional 0.6% of the variability in age of onset.

Kehoe et al. (1999) showed that the APOE (107741) epsilon-2/epsilon-3
genotype is associated with significantly earlier age at onset of
Huntington disease in males than in females. This sex difference was not
apparent for any other APOE genotypes. Andresen et al. (2007) could not
replicate the findings of Kehoe et al. (1999).

Li et al. (2003) stated that although the variation in age at onset of
HD is partly explained by the size of the expanded CAG repeat, it is
strongly heritable, which suggests that other genes modify the age at
onset. They performed a 10-cM genomewide scan in 629 sib pairs affected
with HD, using ages at onset adjusted for the expanded and normal CAG
repeat sizes. Because all those studied were affected with HD, estimates
of allele sharing identical by descent at and around the HD locus were
adjusted by a positionally weighted method to correct for the increased
allele sharing at 4p. Suggestive evidence for linkage was found at 4p16
(lod = 1.93), 6p23-p21 (lod = 2.29), and 6q24-q26 (lod = 2.28).

Djousse et al. (2004) used data from 535 patients with HD and the cohort
involved in the genome scan of Li et al. (2003) to assess whether age at
onset was influenced by any of 3 markers in the 4p16 region: MSX1
(142983), a deletion within the HD coding sequence, and D4S127 (BJ56).
Suggestive evidence for an association was seen between MSX1 alleles and
age at onset, after adjustment for normal CAG repeat, expanded repeat,
and their product term. Individuals with MSX1 genotype 3/3 tended to
have younger age at onset. No association was found between the other 2
markers and age at onset. These findings supported previous studies
suggesting that there may be a significant genetic modifier for age at
onset in Huntington disease in the 4p16 region. Djousse et al. (2004)
concluded that the modifier may be present on both the HD chromosome and
the chromosome bearing the 3 allele of the MSX1 marker.

Many genetic polymorphisms had been shown to be associated with age of
onset of HD in several different populations. As reviewed by Andresen et
al. (2007), these included 12 polymorphisms in 9 genes. Andresen et al.
(2007) undertook to replicate these genetic association tests in 443
affected people from a large set of kindreds from Venezuela. GRIN2A
(138253) and TCERG1 (605409) were thought to show true association with
residual age of onset for Huntington disease. The purported genetic
association of the other genes could not be replicated. The most
surprising negative result was that for the GRIK2 (TAA)n polymorphism,
which had previously shown association with age of onset in 4
independent populations with Huntington disease. Andresen et al. (2007)
suggested that the lack of association in the Venezuelan kindreds may
have been due to the exceedingly low frequency of the key (TAA)16 allele
in that population.

In a study of 250 HD patients and 15 presymptomatic female mutation
carriers, Arning et al. (2007) observed significant associations between
age at onset in women and 2 intronic SNPs (dbSNP rs2650427 and dbSNP
rs8057394) in the GRIN2A gene and a synonymous 2664C-T SNP in exon 12 of
the GRIN2B gene (138252). The significant findings were predominantly
due to premenopausal women, suggesting a role for hormones. Arning et
al. (2007) concluded that together GRIN2A and GRIN2B genotype variations
explain 7.2% additional variance in age at onset for HD in women.

Among 889 patients with Huntington disease, Metzger et al. (2008) found
a significant association between age at onset and a thr441-to-met
(T441M) substitution in the HAP1 gene (dbSNP rs4523977). In HD patients
with less than 60 CAG repeats, those who were homozygous for the met/met
allele developed symptoms about 8 years later than HD patients with the
thr/met or thr/thr genotypes (p = 0.015). In vitro studies showed that
met441 bound mutated HTT more tightly than thr441, stabilized HTT
aggregates, reduced the number of soluble HTT degraded products, and
protected neurons against HTT-mediated toxicity. Metzger et al. (2008)
concluded that the T441M SNP can modify the age at onset in adult
patients with HD. They estimated that the T441M SNP may represent 2.5%
of the variance in age at onset that cannot be accounted for by expanded
CAG repeats in the HTT gene.

HETEROGENEITY

Andrew et al. (1994) found that 30 (2.9%) of 1,022 persons with HD did
not have an expanded CAG repeat in the disease range. They showed that
most of these individuals with normal-sized alleles, namely 18,
represented misdiagnosis, sample mix-up, or clerical error. The
remaining 12 patients represented possible phenocopies for HD. In at
least 4 cases, family studies of these phenocopies excluded 4p16.3 as
the region responsible for the phenotype. Mutations in the HD gene other
than CAG expansion have not been excluded for the remaining 8 cases;
however, in as many as 7 of these patients, retrospective review of
their clinical features identified characteristics not typical for HD.
Andrew et al. (1994) concluded that on rare occasions mutations in
other, as-yet-undefined genes can present with a clinical phenotype very
similar to that of HD.

Several Huntington disease-like phenotypes have been described,
including HDL1 (603210), caused by repeats in the PRNP gene
(176640.0001); HDL2 (606438), caused by repeats in the JPH3 gene
(605268.0001); HDL4 (see 607136), caused by repeats in the TBP gene
(600075.0001); and HDL3 (604802), which maps to chromosome 4p15.3.

PATHOGENESIS

The mutant huntingtin protein in HD results from an expanded CAG repeat
leading to an expanded polyglutamine strand at the N terminus and a
putative toxic gain of function. Neuropathologic studies show neuronal
inclusions containing aggregates of polyglutamines (polyQ) (Walker,
2007).

Paulson et al. (2000) reviewed the mechanisms of neural cell death in
the so-called polyQ expansion diseases. Reddy et al. (1999) provided a
comprehensive review of the pathogenesis of HD, including cellular and
animal models.

- Aggregation of Mutant Huntingtin

In addition to Huntington disease, there are at least 8 other diseases
of the central nervous system, each of which is known to be associated
with a different protein containing an expanded polyglutamine sequence.
Except for their polyglutamine sequences, the 7 proteins, whose complete
sequences are known, are unrelated; the expanded polyglutamine must
therefore be the primary cause of the disorders. This is supported by
the fact that transgenes expressing little more than an expanded
polyglutamine produce neurologic disease in mice (Ikeda et al., 1996;
Mangiarini et al., 1996). Thus, it appears clear that expanded
polyglutamine is ultimately lethal to neurons and exerts its effect by a
gain of function (Green, 1993). Affected regions of the brain show
aggregates or inclusions containing the protein with expanded
polyglutamine.

DiFiglia et al. (1997) demonstrated that an amino-terminal fragment of
mutant huntingtin localizes to neuronal intranuclear inclusions (NIIs)
and dystrophic neurites (DNs) in the HD cortex and striatum, and that
polyglutamine length influences the extent of huntingtin accumulation in
these structures. Ubiquitin (UBB; 191339), which is thought to be
involved in labeling proteins for disposal by intracellular proteolysis,
was also found in NIIs and DNs, suggesting to DiFiglia et al. (1997)
that abnormal huntingtin is targeted for proteolysis but is resistant to
removal. The aggregation of mutant huntingtin may be part of the
pathogenic mechanism in HD.

Sisodia (1998) reviewed the significance of nuclear inclusions in
glutamine repeat disorders.

Lunkes and Mandel (1998) developed a stable cellular model of HD, using
a neuroblastoma cell line in which the expression of full-length or
truncated forms of wildtype and mutant huntingtin could be induced.
While the wildtype forms had the expected cytoplasmic localization, the
expression of mutant proteins led to the formation of cytoplasmic and
nuclear inclusions in a time- and polyglutamine length-dependent manner.
The inclusions were ubiquitinated, appeared more rapidly in cells
expressing truncated forms of the mutant huntingtin, and were correlated
with enhanced apoptosis. In lines expressing mutant full-length
huntingtin, major characteristics present in HD patients could be
modeled. Selective processing of the mutant, but not the wildtype,
full-length huntingtin was observed at late time points, with appearance
of a breakdown product corresponding to a predicted caspase-3 cleavage
product. A more truncated N-terminal fragment of huntingtin was also
produced, which appeared to be involved in building up cytoplasmic
inclusions at early time points, and later on also nuclear inclusions.
The findings fit with the observation that inclusions in the brain of HD
patients are detected only when using antibodies directed against
epitopes very close to the polyglutamine stretch.

Scherzinger et al. (1999) reported that the formation of amyloid-like
huntingtin aggregates in vitro not only depends on polyglutamine-repeat
length but also critically depends on protein concentration and time.
Furthermore, the in vitro aggregation of huntingtin could be seeded by
preformed fibrils. Together, these results were interpreted as
indicating that amyloid fibrillogenesis in HD, as in Alzheimer disease
(104300), is a nucleation-dependent polymerization. Using a cell culture
model, Narain et al. (1999) investigated the proposal that HD shows true
dominance. Protein aggregate formation was used as an indicator of
pathology. Using constructs comprising part of exon 1 of huntingtin with
varying CAG repeat length, the authors found that the rate of protein
aggregation was dependent on the number of repeats, and that the
presence of wildtype huntingtin neither enhanced nor interfered with
protein aggregation.

Heiser et al. (2000) investigated whether the accumulation of insoluble
protein aggregates in intra- and perinuclear inclusions, a hallmark of
HD and related glutamine-repeat disorders, plays a direct role in
disease pathogenesis. By use of a filter retardation assay, they showed
that a monoclonal antibody that specifically recognizes the polyQ
stretch in huntingtin, and the chemical compounds Congo Red, thioflavine
S, chrysamine G, and direct fast yellow, inhibited HD exon 1 protein
aggregation in a dose-dependent manner. On the other hand, potential
inhibitors of amyloid-beta formation such as thioflavine T, gossypol,
melatonin, and rifampicin had little or no inhibitory effect on
huntingtin aggregation in vitro. Results obtained by the filtration
assay were confirmed by electron microscopy, SDS/PAGE, and mass
spectrometry. Furthermore, cell culture studies showed that the Congo
red dye at micromolar concentrations reduced the extent of HD exon 1
aggregation in transiently transfected COS cells. Heiser et al. (2000)
thought that these findings contributed to a better understanding of the
mechanism of huntingtin fibrillogenesis and provided a possible basis
for the development of new huntingtin aggregation inhibitors that may be
effective in treating HD.

Dyer and McMurray (2001) evaluated huntingtin protein from human brain,
transgenic animals, and cells and observed that mutant huntingtin is
more resistant to proteolysis than normal huntingtin. The N-terminal
cleavage fragments that Dyer and McMurray (2001) observed arose from the
processing of normal huntingtin and were sequestered by full-length
huntingtin. Dyer and McMurray (2001) proposed a model in which
inhibition of proteolysis of mutant huntingtin leads to aggregation and
toxicity through the sequestration of important targets, including
normal huntingtin.

Proteolytic processing of mutant HTT is a key event in the pathogenesis
of HD. Mutant HTT fragments containing a polyglutamine expansion form
intracellular inclusions and are more cytotoxic than full-length mutant
HTT. Lunkes et al. (2002) showed that 2 distinct mutant HTT fragments,
which they termed cp-A and cp-B, differentially build up nuclear and
cytoplasmic inclusions in HD brain and in a cellular model for HD. Cp-A
is released by cleavage of HTT in a 10-amino acid domain and is the
major fragment that aggregates in the nucleus. The authors determined
that cp-A and cp-B are most likely generated by aspartic endopeptidases
acting in concert with the proteasome to ensure the normal turnover of
HTT. They suggested that these proteolytic processes are thus potential
targets for therapeutic intervention in HD.

To examine the role of aggregation of expanded polyglutamine-containing
proteins in the etiology of HD and other disorders with expanded CAG
repeats, Yang et al. (2002) produced aggregates of simple polyglutamine
peptides in vitro and introduced them into mammalian cells in culture.
COS-7 and PC12 cells in culture readily endocytosed aggregates of
chemically synthesized polyglutamine peptides. Simple polyglutamine
aggregates were localized to the cytoplasm and had little impact on cell
viability. However, aggregates of polyglutamine peptides containing a
nuclear localization signal were localized to nuclei and led to dramatic
cell death. Amyloid fibrils of a non-polyglutamine peptide were
nontoxic, whether localized to the cytoplasm or nucleus. Nuclear
localization of an aggregate of a short polyglutamine peptide was just
as toxic as that of a long polyglutamine peptide, supporting the notion
that the influence of polyglutamine repeat length on disease risk and
age at onset is at the level of aggregation efficiency. Yang et al.
(2002) concluded that their results supported a direct role for
polyglutamine aggregates in HD-related neurotoxicity.

To investigate the biophysical basis for the relationship between longer
repeat lengths and earlier ages of onset of HD, Chen et al. (2002)
studied the in vitro aggregation kinetics of a series of polyglutamine
peptides. The peptides, in solution at 37 degrees centigrade, underwent
a random coil-to-beta-sheet transition with kinetics superimposable on
their aggregation kinetics, suggesting the absence of soluble,
beta-sheet-rich intermediates in the aggregation process. Details of the
time course of aggregate growth confirmed that polyglutamine aggregation
occurs by nucleated growth polymerization. In contrast to conventional
models of nucleated growth polymerization of proteins, Chen et al.
(2002) found that the aggregation nucleus is a monomer, i.e., nucleation
of polyglutamine aggregation corresponded to an unfavorable protein
folding reaction. In their experiments, the repeat-length-dependent
differences in predicted aggregation lag times were in the same range as
the length-dependent age-of-onset differences in HD, suggesting that the
biophysics of polyglutamine aggregation nucleation may play a major role
in determining disease onset.

Ravikumar et al. (2002) used both exon 1 of the HD gene with expanded
polyQ repeats and green fluorescent protein (GFP) attached to 19
alanines as models for aggregate-prone proteins. Autophagy is involved
in the degradation of these model proteins, since they accumulated when
cells were treated with different inhibitors acting at distinct stages
of the autophagy-lysosome pathway. Rapamycin, which stimulates
autophagy, enhanced the clearance of these aggregate-prone proteins and
also reduced the appearance of aggregates and the cell death associated
with the polyQ and polyA expansions. Both lactacystin and the specific
proteasomal inhibitor epoxomicin increased soluble protein levels of the
polyQ constructs, suggesting that these are also cleared by the
proteasome. However, while polyQ aggregation was enhanced by lactacystin
in an inducible PC12 cell model, aggregation was reduced by epoxomicin,
suggesting that some other protein(s) induced by epoxomicin may regulate
polyQ aggregation.

In HeLa cells transfected with an expanded polyglutamine repeat (Q79),
Sanchez et al. (2003) showed that Congo red exerted a protective effect
against Q79-induced cytotoxicity. Congo red preserved normal cellular
protein synthesis and degradation functions, prevented ATP and caspase
activation, and decreased cell death by 60%. Although Congo red did not
suppress the expression of Q79, it inhibited the oligomerization of
polyglutamine aggregates and disrupted preformed aggregates, perhaps by
promoting the clearance of the aggregates by increasing accessibility to
cellular protein degradation machinery. Treatment of the R6/2 mouse
model of Huntington disease with Congo red showed protective effects on
survival, weight loss, and motor function, and disrupted and inhibited
the formation of polyglutamine oligomers as shown by brain pathology.
Sanchez et al. (2003) concluded that the oligomerization of expanded
polyglutamine repeats plays a key role in their chronic cytotoxicity,
and suggested that inhibition of polyglutamine oligomerization may be a
viable therapeutic approach to such diseases.

Qin et al. (2003) explored the role of autophagy in Htt processing in
clonal striatal cells, PC12 cells, and rodent cells lacking cathepsin D
(CTSD; 116840). Blocking autophagy with 3-methyladenine raised levels of
exogenously expressed Htt1-287 or Htt1-969, reduced cell viability, and
increased the number of cells bearing mutant Htt aggregates. Stimulating
autophagy by serum reduction in vitro promoted Htt degradation,
including breakdown of caspase-cleaved N-terminal Htt fragments. Htt
expression increased levels of the lysosomal enzyme cathepsin D by an
autophagy-dependent pathway. Cells without cathepsin D accumulated more
N-terminal Htt fragments, and cells with cathepsin D were more efficient
in degrading wildtype Htt than mutant Htt in vitro. Qin et al. (2003)
suggested that autophagy may play a critical role in the degradation of
N-terminal Htt and altered processing of mutant HTT by autophagy and
cathepsin D may contribute to HD pathogenesis.

In human neuroblastoma cells, Szebenyi et al. (2003) showed that
huntingtin and androgen receptor (AR; 313700) polypeptides containing
pathogenic polyQ repeats directly inhibited both fast axonal transport
and elongation of neuritic processes. The effects were greater with
truncated polypeptides and occurred without detectable morphologic
aggregates.

Arrasate et al. (2004) used a novel technique in which an automated
microscope followed single cells in culture to evaluate the impact of
inclusion bodies on neuronal cell survival. The findings showed that the
risk of death of neurons expressing mutant huntingtin was best predicted
by the level of diffuse forms of the mutant protein and by the length of
their polyglutamine expansions. Inclusion body formation reduced
intracellular levels of diffuse mutant huntingtin and increased cell
survival, indicating a protective effect of inclusion bodies and
suggesting that inclusion body formation is an adaptive coping response
of the cell.

A model of polyQ aggregate structure has been proposed on the basis of
studies with synthetic polyQ peptides and includes an alternating
beta-strand/beta-turn structure with 7 glutamine residues per
beta-strand (Thakur and Wetzel, 2002). Poirier et al. (2005) tested this
model in the context of the huntingtin exon-1 N-terminal fragment in
HEK293 cells, mouse neuroblastoma cells, and cultured murine primary
cortical neurons. The data supported this model in the huntingtin
protein and provided better understanding of the structural basis of
polyQ aggregation in toxicity in Huntington disease.

To understand how the presence of misfolded proteins leads to cellular
dysfunction, Gidalevitz et al. (2006) employed C. elegans polyglutamine
aggregation models and found that polyglutamine expansions disrupted the
global balance of protein folding quality control, resulting in loss of
function of diverse metastable proteins with destabilizing
temperature-sensitive mutations. In turn, these proteins, although
innocuous under normal physiologic conditions, enhanced the aggregation
of polyglutamine proteins. Thus, Gidalevitz et al. (2006) suggested that
weak folding mutations throughout the genome can function as modifiers
of polyglutamine phenotypes and toxicity.

Bennett et al. (2007) exploited a mass spectrometry-based method to
quantify polyubiquitin chains and demonstrated that the abundance of
these chains is a faithful endogenous biomarker of ubiquitin-proteasome
system (UPS) dysfunction. Lys48-linked polyubiquitin chains accumulate
early in pathogenesis in brains from the R6/2 transgenic mouse model of
HD, from a knockin model of HD, and from human HD patients, establishing
that ubiquitin-proteasome system dysfunction is a consistent feature of
HD pathology. Lys63- and Lys11-linked polyubiquitin chains, which are
not typically associated with proteasomal targeting, also accumulate in
the R6/2 mouse brain. Bennett et al. (2007) concluded that HD is linked
to global changes in the ubiquitin system to a much greater extent than
previously recognized.

Jeong et al. (2009) found that clearance of mutant human HTT via
autophagy was facilitated by acetylation of HTT at lys444 (K444).
Acetylation resulted in trafficking of mutant HTT into autophagosomes,
significantly improved clearance of mutant protein by macroautophagy,
and reversed the toxic effects of mutant HTT in rat primary striatal and
cortical neurons and in a transgenic C. elegans model of HD. In
contrast, mutant HTT that was resistant to acetylation accumulated and
led to neurodegeneration in cultured neurons and mouse brain. Jeong et
al. (2009) showed that the histone acetyltransferase domain of CREBBP
acetylated mutant HTT at K444.

- Interactions of Mutant Huntingtin with Other Proteins

McLaughlin et al. (1996) found that cytoplasmic protein extracts from
several rat brain regions, including striatum and cortex (sites of
neuronal degeneration in HD), contain a 63 kD RNA-binding protein that
interacts specifically with CAG repeat sequences. They noted that the
protein/RNA interactions were dependent upon the length of the CAG
repeat, and that longer repeats bound substantially more protein.
McLaughlin et al. (1996) identified 2 CAG-binding proteins in human
cortex and striatum, one of 63 kD and another of 49 kD. They concluded
that these data suggest mechanisms by which RNA-binding proteins may be
involved in the pathological course of trinucleotide-associated
neurologic diseases.

The glutamine residues encoded by CAG repeats are involved in the
formation of cross-links within and between proteins, through a reaction
catalyzed by transglutaminases (TGase; see 190195). Cariello et al.
(1996) speculated that TGase may be involved in the molecular process of
neurodegeneration in HD since longer polyglutamine stretches may be
better substrates for TGases; increased glutamine cross-linking could
induce the formation of rigid supramolecular structures, with consequent
neuronal death. Cariello et al. (1996) measured TGase activity in
lymphocytes and found that TGase activity was above control levels in
25% of HD patients. TGase activity increased with age in HD patients,
while in normal subjects it decreased with age. TGase activity was
correlated with the age of the patient and inversely correlated with the
CAG repeat length. Cariello et al. (1996) suggested that TGase activity
may be a factor contributing to variance in the age at onset of HD and
that the length of the CAG repeat expansion/TGase ratio could be
important in the manifestation of HD. In human lymphoblastoid cells,
Kahlem et al. (1998) showed that huntingtin is a substrate of
transglutaminase in vitro and that the rate constant of the reaction
increases with length of the polyglutamine over a range of an order of
magnitude. As a result, huntingtin with expanded polyglutamine is
preferentially incorporated into polymers. Both disappearance of
huntingtin with expanded polyglutamine and its replacement by polymeric
forms are prevented by inhibitors of transglutaminase. The effect of
transglutaminase therefore duplicates the changes in the affected parts
of the brain. In the presence of either tissue or brain
transglutaminase, monomeric huntingtin bearing a polyglutamine expansion
formed polymers much more rapidly than one with a short polyglutamine
sequence.

Faber et al. (1998) used a yeast 2-hybrid interactor screen to identify
proteins whose association with huntingtin might be altered in the
pathogenic process. Although no interactors were found with internal and
C-terminal segments of huntingtin, the N terminus of huntingtin detected
13 distinct proteins, 7 novel and 6 reported previously. Among these,
they identified a major interactor class, comprising 3 distinct WW
domain proteins, HYPA (PRPF40A; 612941), HYPB (612778), and HYPC, that
bind normal and mutant huntingtin in extracts of HD lymphoblastoid
cells. This interaction was mediated by the proline-rich region of
huntingtin and was enhanced by lengthening the adjacent glutamine tract.
Although HYPB and HYPC were novel proteins, HYPA was shown to be FBP11,
a protein implicated in spliceosome function. The emergence of this
class of proteins as huntingtin partners argued that a WW
domain-mediated process, such as nonreceptor signaling, protein
degradation, or pre-mRNA splicing, may participate in HD pathogenesis.
(The WW domain is a protein motif consisting of 35 to 40 amino acids and
is characterized by 4 conserved aromatic residues, 2 of which are
tryptophan; see 602307.)

Pathogenesis in HD appears to include the cytoplasmic cleavage of
huntingtin and release of an amino-terminal fragment capable of nuclear
localization. Steffan et al. (2000) studied potential consequences to
nuclear function of a pathogenic amino-terminal region of Htt (Httex1p),
including aggregation, protein-protein interactions, and transcription.
They found that Httex1p coaggregated with p53 (TP53; 191170) in
inclusions generated in cell culture and interacted with p53 of the in
vitro and in cell culture. Expanded Httex1p repressed transcription of
the p53-regulated promoters p21 (CDKN1A; 116899) and MDR1 (ABCB1;
171050). They also found that Httex1p interacted in vitro with CREBBP
(600140), and that CREBBP localized to neuronal intranuclear inclusions
in a transgenic mouse model of HD. These findings raised the possibility
that expanded repeat HTT causes aberrant transcriptional regulation
through its interaction with cellular transcription factors, possibly
resulting in neuronal dysfunction and cell death in HD.

Peel et al. (2001) showed that an RNA-dependent protein kinase, PKR
(PRKR; 176871), preferentially bound mutant huntingtin RNA transcripts
immobilized on streptavidin columns that had been incubated with human
brain extracts. Immunohistochemical studies demonstrated that PKR was
present in its activated form in both human Huntington autopsy material
and brain tissue derived from Huntington yeast artificial chromosome
transgenic mice. The increased immunolocalization of the activated
kinase was more pronounced in areas most affected by the disease. The
authors suggested a role for PKR activation in the Huntington disease
process.

Steffan et al. (2001) demonstrated that the polyglutamine-containing
domain of huntingtin directly binds the acetyltransferase domains of 2
distinct proteins: CREB-binding protein (CREBBP, CBP; 600140) and
p300/CBP-associated factor (P/CAF; 602303). In cell-free assays, the
polyglutamine-containing domain of huntingtin also inhibited the
acetyltransferase activity of at least 3 enzymes: p300 (602700), P/CAF,
and CBP. Expression of huntingtin exon 1 protein in cultured cells
reduced the level of acetylated histones H3 and H4, and this reduction
was reversible by administration of inhibitors of histone deacetylase
(HDAC; see 601241). In vivo, HDAC inhibitors arrest ongoing progressive
neuronal degeneration induced by polyglutamine repeat expansion, and
they reduced lethality in 2 Drosophila models of polyglutamine disease.
Steffan et al. (2001) suggested that their findings raise the
possibility that therapy with HDAC inhibitors may slow or prevent the
progressive neurodegeneration seen in Huntington disease and other
polyglutamine repeat diseases, even after the onset of symptoms.

Using the yeast 2-hybrid system, Singaraja et al. (2002) isolated a
novel Htt-interacting protein, HIP14 (607799). The interaction of HIP14
with Htt was inversely correlated to the poly(Q) length in Htt. The
HIP14 protein was enriched in the brain, showed partial colocalization
with Htt in the striatum, and was found in medium spiny projection
neurons, the subset of neurons affected in HD. The HIP14 protein has
sequence similarity to Akr1p, a protein essential for endocytosis in S.
cerevisiae. Expression of human HIP14 resulted in rescue of the
temperature-sensitive lethality in akr1-delta yeast cells and,
furthermore, restored their defect in endocytosis, demonstrating a
possible role for HIP14 in intracellular trafficking. The authors
suggested that decreased interaction between Htt and HIP14 could
contribute to the neuronal dysfunction in HD by perturbing normal
intracellular transport pathways in neurons.

Humbert et al. (2002) found that IGF1 (147440) and AKT (164730)
inhibited mutant huntingtin-induced cell death and formation of
intranuclear inclusions of polyQ huntingtin. AKT phosphorylated
serine-421 of huntingtin with 23 glutamines, and this phosphorylation
reduced mutant huntingtin-induced toxicity in primary cultures of rat
striatal neurons. Western blot analysis of cerebellum, cortex, and
striatum from Huntington disease patients detected the 60-kD full-length
AKT protein and a caspase-3 (CASP3; 600636)-generated 49-kD AKT product.
In contrast, normal control brain areas expressed little to no 49-kD
AKT. Humbert et al. (2002) concluded that phosphorylation of huntingtin
through the IGF1/AKT pathway is neuroprotective, and they hypothesized
that the IGF1/AKT pathway may have a role in Huntington disease.

Gervais et al. (2002) found that huntingtin-interacting protein-1 (HIP1;
601767) binds to the HIP1 protein interactor (HIPPI; 606621), which has
partial sequence homology to HIP1 and similar tissue and subcellular
distribution. The availability of free HIP1 is modulated by
polyglutamine length within huntingtin, with disease-associated
polyglutamine expansion favoring the formation of proapoptotic
HIPPI-HIP1 heterodimers. This heterodimer can recruit procaspase-8
(601763) into a complex of HIPPI, HIP1, and procaspase-8, and launch
apoptosis through components of the extrinsic cell death pathway.
Gervais et al. (2002) proposed that huntingtin polyglutamine expansion
liberates HIP1 so that it can form a caspase-8 recruitment complex with
HIPPI, possibly contributing to neuronal death in Huntington disease.

Kita et al. (2002) developed stable cell lines expressing exon 1
fragments of the huntingtin gene driven by an inducible promoter (HD-23Q
or HD-74Q). The authors studied expression levels of 1,824 genes between
0 and 18 hours after induction, using adaptor-tagged competitive PCR
(ATAC-PCR). A total of 126 genes exhibited statistically significant
alterations in the HD-74Q cell lines but no changes in the HD-23Q lines.
Eleven genes were tested for their ability to modulate
polyglutamine-induced cell death in transiently transfected cell models.
Five genes (glucose transporter-1, 138140; phosphofructokinase muscle
isozyme, 610681; prostate glutathione-S-transferase 2, 138380;
RNA-binding motif protein-3 300027; and KRAB-A interacting protein-1,
601742) significantly suppressed cell death in both neuronal precursor
and nonneuronal cell lines, suggesting that these transcriptional
changes were relevant to polyglutamine pathology.

Jiang et al. (2003) confirmed that nuclear inclusions containing
polyQ-expanded Htt recruit the transcriptional cofactor CREBBP. In a
hippocampal cell line, they found that toxicity within individual cells
induced by polyQ-expanded Htt (as revealed by a TUNEL assay) was
associated with the localization of the mutant Htt within either nuclear
or perinuclear aggregates. However, in addition to CREBBP recruitment,
CREBBP ubiquitylation and degradation were selectively enhanced by
polyQ-expanded Htt. Jiang et al. (2003) concluded that selected
substrates may be directed to the ubiquitin/proteasome-dependent protein
degradation pathway in response to polyQ-expanded Htt within the
nucleus.

Willingham et al. (2003) performed genomewide screens in yeast to
identify genes that enhance the toxicity of a mutant huntingtin fragment
or of alpha-synuclein (163890). Of 4,850 haploid mutants containing
deletions of nonessential genes, 52 were identified that were sensitive
to a mutant huntingtin fragment, 86 that were sensitive to
alpha-synuclein, and only 1 mutant that was sensitive to both. Genes
that enhanced toxicity of the mutant huntingtin fragment clustered in
the functionally related cellular processes of response to stress,
protein folding, and ubiquitin-dependent protein catabolism, whereas
genes that modified alpha-synuclein toxicity clustered in the processes
of lipid metabolism and vesicle-mediated transport. Genes with human
orthologs were overrepresented in their screens, suggesting that they
may have discovered conserved and nonoverlapping sets of cell-autonomous
genes and pathways that are relevant to Huntington disease and Parkinson
disease.

Modregger et al. (2002) reported that PACSIN1 (606512), a neurospecific
phosphoprotein with a presumptive role in synaptic vesicle recycling,
interacts with huntingtin via its C-terminal SH3 domain. The interaction
was repeat-length-dependent and was enhanced with mutant huntingtin,
possibly causing the sequestration of PACSIN1. PACSIN2 (604960) and
PACSIN3 (606513), isoforms which show a wider tissue distribution
including the brain, did not interact with huntingtin despite a highly
conserved SH3 domain. Normally, PACSIN1 is located along neurites and
within synaptic boutons, but in HD patient neurons there was a
progressive loss of PACSIN1 immunostaining in synaptic varicosities,
beginning in presymptomatic and early-stage HD. Further, PACSIN1
immunostaining of HD patient tissue revealed a more cytoplasmic
distribution of the protein, with particular concentration in the
perinuclear region coincident with mutant huntingtin. The authors
hypothesized a role for PACSIN1 during early stages of the selective
neuropathology of HD.

Tang et al. (2003) used protein-binding experiments to identify a
protein complex containing Htt, HAP1A (see 600947), and the type 1
inositol 1,4,5-triphosphate (IP3) receptor (ITPR1; 147265) in neurons
from rat brain. Both wildtype and Htt with expanded polyglutamine
repeats bound to the C terminus of ITPR1, but only expanded Htt caused
increased sensitization of the ITPR1 receptor to activation by IP3.
Expression of the expanded Htt protein in medium spiny striatal neurons,
those affected in HD, resulted in an increase in intracellular calcium
levels which may be toxic to neurons.

Goehler et al. (2004) generated a protein-protein interaction network
for HD and identified GIT1 (608434) as a protein that interacts directly
with huntingtin. Using a cell-based assay, they found that coexpression
of GIT1 and HD169Q68, an aggregation-prone N-terminal Htt fragment with
a 68-residue polyglutamine tract, increased the amount of Htt aggregates
3-fold compared with expression of HD169Q68 alone. N-terminally
truncated GIT1 was a more potent enhancer of Htt aggregation than the
full-length protein. Mutation analysis indicated that the C terminus of
GIT1 interacted with the N terminus of Htt. HD169Q68 distributed to the
cytoplasm of transfected human embryonic kidney cells, but coexpression
with GIT1 resulted in relocalization of HD169Q68 to membranous
structures and accumulation of protein aggregates. In wildtype mice,
Git1 distributed diffusely in neurons throughout the brain, but in a
mouse model of HD, Git1 immunoreactivity was also present in large
nuclear and cytoplasmic puncta containing Htt aggregates. In normal
human brain, GIT1 migrated at an apparent molecular mass of 95 kD.
However, in HD brains, expression of the 95-kD protein was reduced, and
prominent GIT1 C-terminal fragments of 25 to 50 kD were also detected.
Goehler et al. (2004) concluded that accumulation of C-terminal GIT1
fragments in HD may contribute to disease pathogenesis.

Using human embryonic kidney and mouse neuroblastoma cell lines, Bae et
al. (2006) showed that nuclear translocation and associated
neurotoxicity of mutant huntingtin was mediated by a ternary complex of
huntingtin, GAPDH, and SIAH1 (602212), a ubiquitin E3 ligase that
provided the nuclear translocation signal. Overexpression of GAPDH or
SIAH1 enhanced nuclear translocation of mutant huntingtin and
cytotoxicity, whereas GAPDH mutants unable to bind SIAH1 prevented
translocation. Depletion of GAPDH or SIAH1 by RNA interference
diminished nuclear translocation of mutant huntingtin.

Luo et al. (2008) identified PAK1 (116899) as an HTT-interacting protein
that bound both wildtype and mutant HTT proteins. Binding of PAK1
mediated soluble wildtype HTT-wildtype HTT, mutant HTT-wildtype HTT, and
mutant HTT-mutant-HH interactions and enhanced aggregation of mutant HTT
independent of PAK1 kinase activity. Overexpression of PAK1 enhanced HTT
toxicity in cell models and neurons that paralleled increased
aggregation, whereas PAK1 knockdown suppressed both aggregation and
toxicity. PAK1 colocalized with mutant HTT in human neuroblastoma cells
and rat cortical and striatal neurons and in human brains from HD
patients. Luo et al. (2008) suggested that pathology in HD may be at
least partly dependent on soluble mutant HTT-mutant HTT interaction.

- Apoptosis and Neurodegeneration

Portera-Cailliau et al. (1995) among others presented evidence that
apoptosis is a mode of cell death in Huntington disease. Apopain
(600636), a human counterpart of the nematode cysteine protease
death-gene product (CED-3), has a key role in proteolytic events leading
to apoptosis. Goldberg et al. (1996) showed that apoptotic extracts, and
apopain itself, specifically, cleave huntingtin. The rate of cleavage
increased with the length of the huntingtin polyglutamine tract,
providing an explanation for the gain of function associated with CAG
expansion. The results suggested to the investigators that HD may be a
disorder of inappropriate apoptosis.

Saudou et al. (1998) investigated the mechanisms by which mutant
huntingtin induces neurodegeneration by use of a cellular model that
recapitulates features of neurodegeneration seen in Huntington disease.
When transfected into cultured striatal neurons, mutant huntingtin
induced neurodegeneration by an apoptotic mechanism. Antiapoptotic
compounds or neurotrophic factors protected neurons against mutant
huntingtin. Blocking nuclear localization of mutant huntingtin
suppressed its ability to form intranuclear inclusions and to induce
neurodegeneration. However, the presence of inclusions did not correlate
with huntingtin-induced death. The exposure of mutant
huntingtin-transfected striatal neurons to conditions that suppress the
formation of inclusions resulted in an increase in mutant
huntingtin-induced death. These findings suggested that mutant
huntingtin acts within the nucleus to induce neurodegeneration. However,
intranuclear inclusions may reflect a cellular mechanism to protect
against huntingtin-induced cell death.

Clarke et al. (2000) studied the kinetics of neuronal death in 12 models
of photoreceptor degeneration, hippocampal neurons undergoing
excitotoxic cell death, a mouse model of cerebellar degeneration, and in
Parkinson (168600) and Huntington diseases. In all models the kinetics
of neuronal death were exponential and better explained by mathematical
models in which the risk of cell death remains constant or decreases
exponentially with age. These kinetics argue against the cumulative
damage hypothesis; instead, the time of death in any neuron is random.
Clarke et al. (2000) argued that their findings are most simply
accommodated by a '1-hit' biochemical model in which mutation imposes a
mutant steady state on the neuron and a single event randomly initiates
cell death. This model appears to be common to many forms of
neurodegeneration and has implications for therapeutic strategies in
that the likelihood that a mutant neuron can be rescued by treatment is
not diminished by age, and therefore treatment at any stage of illness
is likely to confer benefit.

Using a cellular model of HD, Wyttenbach et al. (2002) identified
heat-shock protein HSP27 (see 602195) as a suppressor of polyQ-mediated
cell death. In contrast to HSP40 and HSP70 chaperones, HSP27 suppressed
polyQ death without suppressing polyQ aggregation. While polyQ-induced
cell death was reduced by inhibiting cytochrome c release from
mitochondria, protection by HSP27 was regulated by its phosphorylation
status and was independent of its ability to bind to cytochrome c.
However, mutant huntingtin caused increased levels of reactive oxygen
species (ROS) in neuronal and nonneuronal cells. ROS contributed to cell
death because both N-acetyl-L-cysteine and glutathione in its reduced
form suppressed polyQ-mediated cell death. HSP27 decreased ROS in cells
expressing mutant huntingtin, suggesting that this chaperone may protect
cells against oxidative stress. The authors proposed that a polyQ
mutation may induce ROS that directly contribute to cell death, and that
HSP27 may be an antagonist of this process.

- Mitochondrial Dysfunction

Horton et al. (1995) used serial dilution PCR to demonstrate an 11-fold
increase of the common 4977 nucleotide mitochondrial DNA deletion in
temporal lobes of Huntington disease patients compared to normal
controls. Huntington disease frontal lobes have 5-fold greater levels,
whereas occipital lobe and putamen deletion levels were comparable with
control levels. The authors hypothesized that the increased rate of
mitochondrial DNA deletions could be caused by elevated oxygen radical
production by mitochondria in Huntington disease patients. Gu et al.
(1996) demonstrated marked deficiency of the mitochondrial respiratory
chain in the caudate nucleus but not the platelets from patients with
Huntington disease.

Relative to the mechanisms by which the mutant huntingtin protein cause
neurodegeneration, Panov et al. (2002) showed that lymphoblast
mitochondria from patients with HD have a lower membrane potential and
depolarize at lower calcium loads than do mitochondria from controls.
They found a similar defect in brain mitochondria from transgenic mice
expressing full-length mutant huntingtin, and this defect preceded the
onset of pathologic or behavioral abnormalities by months. By electron
microscopy, they identified N-terminal mutant huntingtin on neuronal
mitochondrial membranes, and by incubating normal mitochondria with a
fusion protein containing an abnormally long polyglutamine repeat, they
reproduced the mitochondrial calcium defect seen in human patients and
transgenic animals. Thus, mitochondrial calcium abnormalities occur
early in HD pathogenesis and may be a direct effect of mutant huntingtin
on the organelle.

Trushina et al. (2004) found that expression of full-length mutant Htt
impaired vesicular and mitochondrial trafficking in mouse neurons in
vitro and in whole mice in vivo. Particularly, mitochondria became
progressively immobilized and stopped more frequently in neurons from
transgenic animals. These defects occurred early in development, prior
to the onset of measurable neurologic or mitochondrial abnormalities.
Consistent with a progressive loss of function, wildtype Htt,
trafficking motors, and mitochondrial components were selectively
sequestered by mutant Htt in human HD-affected brain. Trushina et al.
(2004) concluded that mutant Htt aggregates sequester Htt and components
of trafficking machinery, leading to loss of mitochondrial motility and
eventually to mitochondrial dysfunction.

In STHdh(Q111) knockin striatal cells, Seong et al. (2005) found that a
juvenile-onset HD CAG repeat was associated with low mitochondrial ATP
and decreased mitochondrial ADP-uptake. This metabolic inhibition was
associated with enhanced Ca(2+)-influx through NMDA receptors, which
when blocked resulted in increased cellular ATP/ADP. In 40 human
lymphoblastoid cell lines bearing non-HD CAG lengths (9 to 34 units) or
HD-causing alleles (35 to 70 units), there was an inverse association of
ATP/ADP with the longer of the 2 allelic HD CAG repeats in both the
non-HD and HD ranges. Thus, the polyglutamine tract in huntingtin
appeared to regulate mitochondrial ADP-phosphorylation in a
Ca(2+)-dependent process, fulfilling the genetic criteria for the HD
trigger of pathogenesis. Seong et al. (2005) hypothesized that
aberration in cellular energy status may contribute to the exquisite
vulnerability of striatal neurons in HD.

Using striatal neuronal cell lines from wildtype mice and HD-knockin
mice, Cui et al. (2006) showed that mutant huntingtin disrupted
mitochondrial function by inhibiting expression of the transcriptional
coactivator Pgc1a (604517). Mutant huntingtin repressed Pgc1a
transcription by associating with the promoter and interfering with the
Creb (123810)/Taf4 (601796)-dependent transcriptional pathway critical
for regulation of Pgc1a expression. Crossbreeding of Pgc1a-knockout mice
with HD-knockin mice led to increased neurodegeneration of striatal
neurons and motor abnormalities in the HD mice. Expression of Pgc1a
partially reversed the toxic effects of mutant huntingtin in cultured
rat striatal neurons, and lentiviral-mediated delivery of Pgc1a in
striatum provided neuroprotection in transgenic HD mice. Cui et al.
(2006) concluded that PGC1A has a key role in controlling energy
metabolism in the early stages of HD pathogenesis.

Greenamyre (2007) reviewed the hypothesis that in patients with HD, gene
transcription regulated by PGC1A is defective, resulting in reduced
expression of mitochondrial and antioxidant genes regulated by PGC1A. In
this way, PGC1A provides a plausible link between what were previously
unrelated mechanisms: transcriptional dysregulation and mitochondrial
impairment. These studies underscored the role of PGC1A and
neurodegeneration and raised the possibility that increasing PGC1A
expression or function might be therapeutic in HD and other
neurodegenerative disorders.

- Other Disease Mechanisms

Schwarcz et al. (1988) demonstrated increased activity of quinolinate's
immediate biosynthetic enzyme, 3-hydroxyanthranilate oxygenase (EC
1.13.11.6), in HD brains as compared to control brains. The increment
was particularly pronounced in the striatum, which is known to exhibit
the most prominent nerve-cell loss in HD. Thus, the HD brain has a
disproportionately high capacity to produce the endogenous 'excitotoxin'
quinolinic acid, a tryptophan metabolite.

Miller et al. (2003) stated that rat Csp binds heterotrimeric G proteins
(see 139320) and promotes G protein inhibition of N-type calcium
channels (see 601012). They showed that an N-terminal fragment of human
huntingtin with an expanded polyglutamine tract blocked association of
Csp with G proteins and eliminated Csp's tonic G protein inhibition of
N-type calcium channels. In contrast, an N-terminal huntingtin fragment
without an expanded polyglutamine tract did not alter association of Csp
with G proteins and had no effect on channel inhibition by Csp.

Using quantitative single-cell analysis and time-lapse imaging, Trushina
et al. (2003) followed the subcellular location of mutant huntingtin. At
first, the mutant protein was localized to the cytoplasm. As affected
cells lost neurites and began to lose their morphology and prepare for
apoptosis, the mutant protein and its N-terminal fragments were
localized to the nucleus. However, neither blocking of nuclear
accumulation nor nuclear entry prevented cell death, suggesting that
nuclear entry was not the initiating event in toxicity. Further analysis
indicated that full-length mutant huntingtin bound to and disrupted
microtubules in the cytoplasm; stabilization of microtubules with taxol
resulted in increased cell survival. Trushina et al. (2003) postulated
that cytoplasmic dysfunction involving microtubules is a primary event
in neuronal toxicity in HD, resulting in the disruption of cellular
processes such as vesicle trafficking, disintegration of the nucleus,
and cell death.

Bezprozvanny and Hayden (2004) reviewed the role of disrupted calcium
signaling in the pathogenesis of HD. Postulated mechanisms have included
disrupted mitochondrial calcium homeostasis, potentiation of certain
NMDA receptors which cause calcium influx, and increased sensitization
of ITPR1. Calcium overload may trigger apoptosis in medium spiny
striatal neurons in HD.

Intracellular amyloid-like inclusions formed by mutant proteins result
from polyglutamine expansions in HD and polyalanine expansions in
polyadenylate binding protein-2 (PABP2; 602279) in oculopharyngeal
muscular dystrophy (OPMD; 164300). Bao et al. (2004) found further
parallels between these diseases: as had been observed in HD, they
demonstrated that HSP70 (601113) and HDJ1 colocalized with PABP2
aggregates in muscle tissue from patients with OPMD and overexpression
of HSP70 reduced mutant PABP2 aggregate formation.

Charvin et al. (2005) demonstrated that low doses of dopamine acted
synergistically with mutated huntingtin to activate the proapoptotic
c-Jun (165160)/JNK (see 601158) pathway in cultured mouse striatal
cells. Dopamine also increased aggregate formation of mutant huntingtin
via the D2 receptor (DRD2; 126450). These effects were blocked by a
selective inhibitor of the JNK pathway and a DRD2 antagonist,
respectively. Charvin et al. (2005) suggested that increased
autooxidation of dopamine with the resultant increase in reactive oxygen
species in the striatum during aging could potentiate mutant
huntingtin-induced activation of the c-Jun/JNK pathway that becomes
manifest in adulthood.

Petersen et al. (2005) described a dramatic atrophy and loss of orexin
(HCRT; 602358)-producing neurons in the lateral hypothalamus of R6/2
Huntington mice and in Huntington patients. Similar to animal models and
patients with impaired orexin function, the R6/2 mice were narcoleptic.
Both the number of orexin neurons in the lateral hypothalamus and the
levels of orexin in the cerebrospinal fluid were reduced by 72% in
end-stage R6/2 mice compared with wildtype littermates, suggesting that
orexin could be used as a biomarker reflecting neurodegeneration.

By neuropathologic study of human brain tissue from patients with HD,
Shelbourne et al. (2007) found greater somatic instability of the mutant
HTT allele in neurons compared to glial cells. Striatal neurons were
particularly affected. Greater somatic mutation length gains were
observed from patients with more advanced stage disease. Similar
findings were observed in a mouse model of HD. In mice, striatal
interneurons tended to have smaller mutation length gains than
pan-striatal neurons. The findings demonstrated that there are tissue-
and cell-type differences in vulnerability to repeat expansion length,
and that the somatic repeat expansions in brain tissue can be 2 to 3
times greater than the inherited allele. The evidence also supported the
hypothesis that somatic increases of mutation length may play a role in
the progressive nature of the disorder.

DIAGNOSIS

- Prenatal Diagnosis

Harper and Sarfarazi (1985) pointed out that predictive testing can be
done in prenatal diagnosis without determining the status of the at-risk
parent. For example, if the affected grandparent of the fetus is
deceased, the other grandparent is genotype BB, and the parent at risk
is AB married to a CC individual, the fetus is unlikely to have
inherited HD if it is BC, while the risk is 50% if the fetus is AC. The
likelihood of the BC fetus being affected is a function of
recombination. Bloch and Hayden (1987) pointed out that this 'no news'
or 'good news' option has some important consequences. The 'no news'
outcome increases the risk of the fetus's having inherited the gene for
HD from 25% to about 50%; thus, persons given this information may need
long-term support. Also, the implication of linking the status of an
at-risk child to that of the at-risk parent may be more serious than
realized.

Quarrell et al. (1987) suggested the usefulness of the G8 marker in
exclusion testing for HD. They cited studies of 52 families from various
parts of the world, indicating a maximum total lod score of 75.3 at a
recombination fraction of about 5 cM. The 95% confidence intervals were
2.4 and 6.5 cM, with no evidence of multilocus heterogeneity. The marker
could be applied either for presymptomatic predictive testing or for
exclusion testing in pregnancy, where the estimated risk to the parent
is not altered. The requirements for family structure were much less
stringent in the case of exclusion testing. In South Wales they found
that nearly 90% of couples have the minimum structure required for an
exclusion test, whereas for a presymptomatic predictive test only 15%
have the ideal 3-generation family structure and only 10% have a
suitably extended 2-generation family. The distribution of G8 haplotypes
presented the same difficulty whichever test was being considered; only
about two-thirds of couples would be informative. If the fetus acquired
the G8 haplotype of the affected grandparent, then the risk to the fetus
was the same as that of the parent, i.e., 50%. If the fetus has the G8
haplotype of the unaffected grandparent, then the risk to the fetus
became 2.5%. If termination of pregnancy was unacceptable despite an
adverse result of the test and HD subsequently developed in the parent
in generation 2, it would be immediately known that HD would also be
likely to arise in the offspring since their risks are the same (apart
from the possibility of recombination). To prevent this complication,
Quarrell et al. (1987) told couples that if termination of pregnancy was
unacceptable for whatever reason, then an exclusion test would be
inappropriate.

Millan et al. (1989) pointed out the importance of not acquiring more
information than necessary to exclude or include the diagnosis of HD in
a fetus. In a family they studied, the probability of the fetus being
affected, approaching 50%, could be deduced from the genotype of the
fetus, the 2 parents, and the unaffected paternal grandfather of the
conceptus. Genotyping of the unaffected maternal grandmother of the
father refined downward somewhat (from 47 to 42%) the risk of HD in the
conceptus; however, it ran the risk of making the diagnosis of HD in the
father and the information was really unnecessary for genetic
counseling. Information about the prenatal exclusion test for HD was
given to an unselected series of couples who attended a genetic
counseling clinic in Glasgow from 1986 onwards. Ten couples underwent 13
prenatal tests during this period with expressed intention of stopping a
pregnancy if the results indicated a high risk (almost 50%) that the
fetus carried the HD gene. Although 9 fetuses at nearly 50% risk of
carrying the HD gene were identified, only 6 such pregnancies were
terminated. In each of the 3 high-risk pregnancies that continued, the
mother made a 'final hour' decision not to undergo the scheduled,
first-trimester termination.

Bloch and Hayden (1990) opposed the testing of children at risk for
Huntington disease and questioned the usefulness of DNA tests to support
a diagnosis of HD in either adulthood or childhood. They opposed testing
in adoption cases because of the negative effects on the child's
upbringing and education as well as the necessity to adhere to the
principle of autonomy on the part of the individual tested. Prenatal
testing was undertaken in their practice only if the parents were
prepared to make a decision about continuing the pregnancy on the basis
of the outcome of the prenatal testing. The parents were given to
understand that prenatal testing is similar to testing a minor child. In
the program of Bloch and Hayden (1990), 8 exclusion prenatal tests had
been performed, with 5 resulting in an increased risk for the fetus. In
4 of these, the parents decided to terminate the pregnancy.

In the experience of Tolmie et al. (1995), late reversal of a previous
decision to undergo first-trimester pregnancy termination for a genetic
indication was frequent among couples who had undergone the prenatal
exclusion test for HD.

- Testing in Adults

Early results of predictive testing using D4S10 RFLPs were reported by
Meissen et al. (1988). MacDonald et al. (1989) characterized genetically
5 highly informative multiallele RFLPs of value in the presymptomatic
diagnosis of HD. Morris et al. (1989) and Craufurd et al. (1989)
outlined problems associated with programs for presymptomatic predictive
testing for HD.

Positron-emission tomography (PET scanning) demonstrating loss of uptake
of glucose in the caudate nuclei may be a valuable indication of
affection in the presymptomatic period (Hayden et al., 1986).
Hypometabolism of glucose precedes tissue loss and caudate nucleus
atrophy. Mazziotta et al. (1987) used PET studies of cerebral glucose
metabolism in 58 clinically asymptomatic persons at risk for HD, 10
symptomatic patients with HD, and 27 controls. They found that 31% of
the persons at risk showed metabolic abnormalities of the caudate
nuclei, qualitatively identical to those in the patients. Taking into
account the age of each at-risk subject and the sex of the affected
parent, they averaged individual risk estimates of the members of the
asymptomatic group and estimated the probability of having the
clinically unexpressed HD gene at 33.9% for the group--a remarkably good
agreement with the percentage of metabolic abnormalities found.

Wiggins et al. (1992) reported on the psychologic consequences of
predictive testing for HD on the basis of observations in 135
participants in the Canadian program of genetic testing. The
participants were in 3 groups according to their test results: the
increased-risk group (37 persons); the decreased-risk group (58
persons); and the group with no change in risk (40 persons). They showed
that predictive testing had benefits for the psychologic health of
persons who received results that indicated either an increase or a
decrease in the risk of inheriting the gene. In an accompanying
editorial, Catherine V. Hayes (1992), president of the Huntington's
Disease Society of America, described what it meant to grow up as an
'at-risk' person and to have genetic testing.

Read (1993) commented that the problems arising in connection with HD
testing resembled those of HIV testing. The 10 years during which
testing for HD required family studies have given clinical geneticists
an opportunity to work out proper procedures. A great deal of effort has
gone into ensuring that presymptomatic testing is always voluntary and
is undertaken only after due consideration by fully informed patients.
Testing of children has been firmly discouraged. It is vital that these
practices should be continued.

Kremer et al. (1994) reported a worldwide study assessing the
sensitivity and specificity of the CAG expansion as a diagnostic test.
The study covered 565 families from 43 national and ethnic groups
containing 1,007 patients with signs and symptoms compatible with the
diagnosis of HD. Of these, 995 had an expanded CAG repeat that included
from 36 to 121 repeats; sensitivity = 98.8%, with 95% confidence limits
= 97.7-99.4. Included among those contributing to the sensitivity
estimate were 12 patients with previously diagnosed HD in whom the
number of CAG repeats was in the normal range. Reevaluation of these
established that 11 had clinical features atypical of HD. In 1,581 of
1,595 control chromosomes (99.1%), the number of CAG repeats ranged from
10 to 29. The remaining 14 control chromosomes had 30 or more repeats,
with 2 of these chromosomes having expansions of 37 and 39 repeats. An
estimate of specificity was made from 113 subjects with other
neuropsychiatric disorders with which HD is frequently confused. The
number of repeats found in these disorders was similar to the number
found on normal human chromosomes and showed no overlap with HD;
specificity = 100%, with 95% CI = 95.5-100. The study confirmed that CAG
expansion is the molecular basis of HD worldwide.

Decruyenaere et al. (1996) examined the psychologic effects of HD
predictive testing on 53 patients after 1 year. The authors found that
the test result had a definite impact on reproductive decision making
and that the single best predictor of the patient's post-test ego
strength was the patient's pre-test ego strength. They concluded that
persons who opt for HD testing are themselves a self-selected group with
good ego strength and positive coping strategies.

Gellera et al. (1996) reported that ideally a series of 3 PCR reactions
should be performed to rule out Huntington disease. They reviewed the
evidence that the huntingtin gene contains an unstable
polyglutamine-encoding (CAG)n repeat which is located in the N-terminal
portion of the protein beginning 18 codons downstream of the first ATG
codon (613004.0001). The unstable (CAG)n repeat lies immediately
upstream from a moderately polymorphic polyproline encoding (CCG)n
repeat. Gellera et al. (1996) noted further that a number of reports in
the literature indicated that in normal subjects the number of (CAG)n
polyglutamine repeats ranges from 10 to 36, while in HD patients it
ranges from 37 to 100. The (CCG)n polyproline repeat may vary in size
between 7 and 12 repeats in both affected and normal individuals. They
reported the occurrence of a CAA trinucleotide deletion (nucleotides
433-435) in HD chromosomes in 2 families that, because of its position
within the conventional antisense primer hd447, hampered HD mutation
detection if only the (CAG)n tract were amplified. Therefore, Gellera et
al. (1996) stressed the importance of using a series of 3 diagnostic PCR
reactions: one that amplified the (CAG)n tract alone, one that amplified
the (CCG)n tract alone, and one that amplified the whole region.

The first predictive testing for HD was based on analysis of linked
polymorphic DNA markers. Limitations to accuracy included recombination
between the markers and the mutation, pedigree structure, and
availability of DNA samples from family members. With availability of
direct tests for the HD mutation, Almqvist et al. (1997) assessed the
accuracy of results obtained by linkage approaches when requested to do
so by the test individuals. For 6 such individuals, there was
significant disparity between the tests: 3 went from a decreased risk to
an increased risk, while in another 3 the risk was decreased.

Harper et al. (2000) reviewed data on presymptomatic testing over a
10-year period in the U.K. A total of 2,937 tests had been performed,
2,502 based on specific mutation testing: 93.1% of these individuals
were at 50% prior risk, with 58.3% of them female; 41.4% were abnormal
or high risk, including 29.4% in subjects aged 60 or over. Almost all of
the tests were performed in National Health Service genetic centers,
with a defined genetic counseling protocol.

Lindblad (2001) discussed some of the ethical issues that arise when an
adult child at 25% risk for HD wishes to have the test, but the
parent(s) at 50% risk refuses to have one. If the child tests positive,
the genetic status of the parent will also be disclosed. No matter what
course of action is chosen in this situation, the ethically legitimate
interests of either child or parent might be violated (the same dilemma
arises in connection with prenatal testing). Lindblad (2001) concluded
that in this situation one should start with an exclusion test by the
linkage principle. In this way, she believed, less harm would be caused
than by direct mutation analysis.

By analysis of diffusion tensor MRI data from 25 presymptomatic HD gene
carriers using a multivariate support vector machine, Kloppel et al.
(2008) identified a pattern of structural brain changes in the putamen
and anterior parts of the corpus callosum that differed significantly
from controls. The pattern enabled correct classification of 82% of
scans as that of either mutation carrier or control. In addition,
probabilistic fiber tracking detected changes in connections between the
frontal cortex and the caudate, a large proportion of which play a role
in the control of voluntary saccades. Voluntary saccades are
specifically impaired in presymptomatic mutation carriers and are an
early clinical sign of motor abnormalities. In 14 carriers, there was a
correlation between impairment of voluntary saccades and fewer fiber
tracking streamlines connecting the frontal cortex and caudate body,
suggesting selective vulnerability of these white matter tracts.

Kloppel et al. (2009) used T1-weighted MRI scans to evaluate whole brain
structural changes in 96 presymptomatic mutation carriers in whom the
estimated time to clinical manifestation was based on age and CAG repeat
length. Individuals with at least a 33% chance of developing signs of HD
in 5 years were correctly assigned to the mutation carrier group 69% of
the time. This accuracy was below that reported by Kloppel et al. (2008)
using diffusion-weighted analysis. However, accuracy in the study of
Kloppel et al. (2009) improved to 83% when regions affected by the
disease (i.e., the caudate head) were selected a priori for analysis.
The results were no better than chance when the probability of
developing symptoms in 5 years was less than 10%. Kloppel et al. (2009)
noted that T1-weighted MRI scans are more readily available than
diffusion-weighted imaging as used in the study by Kloppel et al.
(2008).

- Differential Diagnosis

Warner et al. (1994) searched for possible missed cases of Huntington
disease in a set of 368 patients with psychiatric disorders, including
schizophrenia, presenile dementia, and senile dementia. One
schizophrenic patient, who died at age 88, had a CAG repeat size of 36;
a 68-year-old patient, who died of presenile dementia of Alzheimer
disease type, had a CAG repeat size of 34. Neither patient had
neuropathologic or clinical evidence of Huntington disease.

CLINICAL MANAGEMENT

Peyser et al. (1995) found no beneficial effect in treatment with
d-alpha-tocopherol in a cohort of 73 patients with Huntington disease.
However, postoperative analysis suggested possible beneficial effect on
neurologic symptoms for patients early in the course of the disease.

Neural and stem cell transplantation is a potential treatment for
neurodegenerative diseases, e.g., transplantation of specific committed
neuroblasts (fetal neurons) to the adult brain. Encouraged by animal
studies, a clinical trial of human fetal striatal tissue transplantation
for the treatment of Huntington disease was initially undertaken at the
University of South Florida. In this series, 1 patient died 18 months
after transplantation from causes unrelated to surgery. Freeman et al.
(2000) reported postmortem findings indicating that grafts derived from
human fetal striatal tissue can survive, develop, and remain unaffected
by the underlying disease process, at least for 18 months, after
transplantation into a patient with Huntington disease. Selective
markers of both striatal projection and interneurons showed transplant
regions clearly innervated by host tyrosine hydroxylase fibers. There
was no histologic evidence of immune rejection including microglia and
macrophages. Notably, neuronal protein aggregates of mutated huntingtin,
which is typical of HD neuropathology, were not found within the
transplanted fetal tissue.

Friedlander (2003) discussed apoptosis and caspases in neurodegenerative
diseases. The fact that activation of mechanisms mediating cell death
may be involved in neurologic diseases makes these pathways attractive
therapeutic targets. They noted that clinical trials of an inhibitor of
apoptosis (minocycline) for neurodegenerative disorders (Huntington
disease and ALS) were in progress (Fink et al., 1999; Chen et al.,
2000).

A variety of growth factors had been shown to induce cell proliferation
and neurogenesis. It was suggested by Curtis et al. (2003) that, if the
potential for endogenous neural replacement can be augmented
pharmacologically with the use of exogenous growth factors or
pharmaceuticals that increase the rate of neural progenitor formation,
neural migration, and neural maturation, then the rate of cell loss may
be slowed, and clinical improvements observed.

Ravikumar et al. (2003) showed that the protective effect of GLUT1
overexpression is associated with decreased huntingtin exon 1
aggregation in cell models. Reduced aggregation and enhanced clearance
of mutant huntingtin was observed when cells were cultured in raised
glucose concentrations (8 g/l). These effects were mimicked by 8 g/l
2-deoxyglucose (2DOG), but not with 8 g/l 3-O-methyl glucose, suggesting
that the biochemical mediator may be glucose-6-phosphate. Increased
clearance of mutant huntingtin by raised glucose (8 g/l) and 2DOG
correlated with increased autophagy and reduced phosphorylation of MTOR
(FRAP1; 601231), S6K1 (608938), and AKT. Ravikumar et al. (2003)
concluded that raised intracellular glucose/glucose-6-phosphate levels
reduced mutant huntingtin toxicity by increasing autophagy via mTOR and
possibly AKT.

Both animal and human studies suggest that transplantation of embryonic
neurons or stem cells offers a potential treatment strategy for
neurodegenerative disorders such as Parkinson disease (168600),
Huntington disease, and Alzheimer disease. Curtis et al. (2003)
investigated whether neurogenesis occurs in the subependymal layer
adjacent to the caudate nucleus in the adult human brain in response to
neurodegeneration of the caudate nucleus in HD. Postmortem control and
HD human brain tissue were examined by using the cell cycle marker
proliferating cell nuclear antigen (PCNA; 176740), the neuronal marker
beta-III-tubulin, and the glial cell marker glial fibrillary acidic
protein (GFAP; 137780). They observed a significant increase in cell
proliferation in the subependymal layer and HD compared with control
brains. Within the HD group, the degree of cell proliferation increased
with pathologic severity and increasing CAG repeats in the HD gene. Most
importantly, PCNA+ cells were shown to coexpress beta-III-tubulin or
GFAP, demonstrating the generation of neurons and glial cells in the
subependymal layer of the diseased human brain. The results provided
evidence of increased progenitor cell proliferation and neurogenesis in
the diseased adult human brain and further indicated the regenerative
potential of the human brain.

Ravikumar et al. (2004) presented data that provided proof of principle
for the potential of inducing autophagy to treat HD. They showed that
mammalian target of rapamycin (MTOR; 601231) is sequestered in
polyglutamine aggregates in cell models, transgenic mice, and human
brains. Such sequestration impairs the kinase activity of mTOR and
induces autophagy, a key clearance pathway for mutant huntingtin
fragments. This protects against polyglutamine toxicity.

Cheng et al. (2013) reported the beneficial effects of miR196a (608632)
on HD in cell, transgenic mouse models, and human induced pluripotent
stem cells derived from 1 individual with HD (HD-iPSCs). In the in vitro
results, a reduction of mutant HTT (613004) and pathologic aggregates,
accompanying the overexpression of miR196a, was observed in HD models of
human embryonic kidney cells and mouse neuroblastoma cells. In the in
vivo model, HD transgenic mice overexpressing miR196a revealed the
suppression of mutant HTT in the brain and also showed improvements in
neuropathologic progression, such as decreases of nuclear, intranuclear,
and neuropil aggregates and late-stage behavioral phenotypes. Most
importantly, miR196a also decreased HTT expression and pathologic
aggregates when HD-iPSCs were differentiated into the neuronal stage.
Cheng et al. (2013) postulated that mechanisms of miR196a in HD might be
through the alteration of ubiquitin-proteasome systems, gliosis, CREB
protein pathways, and several neuronal regulatory pathways in vivo.

POPULATION GENETICS

Huntington disease has a frequency of 4 to 7 per 100,000 persons. Reed
and Chandler (1958) estimated the frequency of recognized Huntington
chorea in the Michigan lower peninsula to be about 4.12 x 10(-5) and the
total frequency of heterozygotes to be about 1.01 x 10(-4). Wright et
al. (1981) estimated the minimal prevalence of HD in blacks in South
Carolina to be 0.97 per 100,000 persons--about one-fifth the prevalence
for whites in that state. Clinical features seemed identical. Even lower
prevalence has been observed in blacks in Africa. The higher prevalence
in South Carolina blacks may be because of white admixture and longer
life expectancy in South Carolina blacks than in African blacks. Walker
et al. (1981) estimated a prevalence of 7.61 per 100,000 in South Wales.
Heterozygote frequency was estimated as about 1 in 5,000. Simpson and
Johnston (1989) found an unusually high prevalence of Huntington disease
in the Grampian region of Scotland; they arrived at an incidence of 9.94
per 100,000. There were 46 individuals ascertained from 98 pedigrees.

New mutations are probably rare. Bundey (1983) concluded 'that it is
incorrect to say that new mutations for Huntington's chorea occur in
less than 0.1% of sufferers. I believe the evidence shows that the true
figure is nearer 10%. I therefore consider that the absence of a known
affected relative should not deter a neurologist from diagnosing
Huntington's chorea in a patient who shows the characteristic clinical
features of the disease.' She based her conclusion particularly on
estimates of fitness and the Haldane formula for estimating proportion
of new mutation cases. However, Mastromauro et al. (1989) could find no
evidence of difference in fitness of HD-affected persons from their
unaffected sibs or from the general population of Massachusetts.

Palo et al. (1987) estimated the frequency of HD in Finland to be 5
cases per million as contrasted with frequencies of 30 to 70 per million
in most Western countries. The lowest frequencies have been found in
South African blacks (0.6), in Japan (3.8), and in North American blacks
(15). The findings in Finland are consistent with almost all cases
having originated from a single source and illustrate founder effect,
which is shown by so many other diseases in that country. For example,
PKU (261600) has been found in only 5 cases over all time, whereas
aspartylglycosaminuria (208400) has been identified in almost 200 living
cases in a population of 4.9 million. The part of Finland that is an
exception to the above statement is the Aland archipelago where the
frequency of HD is high, but this is an exception that proves the rule:
the islands have been exposed to other populations (including the
British) for centuries.

Quarrell et al. (1988) presented data suggesting that there has been a
steady decline in births at risk for HD in both North Wales and South
Wales in the period between 1973 and 1987. Lanska et al. (1988)
determined an overall mortality rate for HD in the U.S. of 2.27 per
million population per year. Age-specific mortality rates peaked around
age 60. Lanska et al. (1988) suggested from their experience that the
risk of suicide may have been overstated.

Stine and Smith (1990) studied the effects of mutation, migration,
random drift, and selection on the changes in the frequency of genes
associated with HD, porphyria variegata (176200), and lipoid proteinosis
(247100) in the Afrikaner population of South Africa. By limiting
analyses to pedigrees descendant from founding families, it was possible
to exclude migration and new mutation as major sources of change.
Calculations which overestimated the possible effect of random drift
demonstrated that drift did not account for the changes. Therefore,
these changes must have been caused by natural selection, and a
coefficient of selection was estimated for each trait. A value of 0.34
was obtained for the coefficient of selection demonstrated by the HD
gene, indicating a selective disadvantage rather than advantage
suggested by some other studies.

In Finland, Ikonen et al. (1992) reported further studies by RFLP
haplotype analysis in combination with genealogic study of all the
Finnish HD families. They found that a high percentage (28%) of the
families had foreign ancestors. Furthermore, most of the Finnish
ancestors were localized to border regions or trade centers of the
country, following the old postal routes. The observed high-risk
haplotypes formed with markers from the D4S10 and D4S43 loci were evenly
distributed among the HD families in different geographic locations.
Ikonen et al. (1992) concluded that the HD gene(s) probably arrived in
Finland on several occasions via foreign immigrants.

On the basis of a review of the epidemiology of Huntington disease,
Harper (1992) predicted that molecular studies in the future would show
that more than 1 mutation has occurred at the HD locus. A very small
number of mutations, possibly a single common one, will be found to
account for most HD cases in populations of European origin. Any
predominant mutation will probably have an extremely ancient origin,
possibly dating back millennia. No single focus in northern Europe will
be found as the point of origin of such a principal mutation. Phenotype
will correlate poorly with specific mutations.

Leung et al. (1992) stated that the prevalence of HD in Hong Kong
Chinese for the period 1984-1991 was 3.7 per million. They traced the
ancestral origin of the patients mainly to the coastal provinces and
proposed that Chinese HD had a European origin. They found a male
preponderance: 63 males to 26 females. They made no comment on the
provinces of origin of the Hong Kong Chinese population generally.

Almqvist et al. (1994) constructed haplotypes for 23 different HD
families, 10% of the 233 known HD families in the Swedish Huntington
disease register. Ten different haplotypes were observed. Analysis of 2
polymorphic markers within the HD gene indicated that there are at least
3 origins of the HD mutation in Sweden. One of the haplotypes accounted
for 89% of the families, suggesting descent from a single ancestor.

Rubinsztein et al. (1994) investigated the evolution of HD by typing CAG
alleles from 5 different human populations and 10 different species of
primates. Using computer simulations, they found that human alleles have
expanded from a shorter primate ancestor and exhibit unusual asymmetric
length distributions. Suggesting that the key element in HD evolution is
a simple length-dependent mutational bias toward longer alleles, they
predicted that, in the absence of interference, expansion of
trinucleotide repeats will continue and accelerate, leading to an
ever-increasing incidence of HD. Masuda et al. (1995) demonstrated that
the size of the CAG repeat in Japanese HD patients ranges from 37 to 95
repeats, as compared with a range from 7 to 29 in normal controls.
Whereas HD chromosomes in the west are strongly associated with the
(CCG)7 repeat, immediately 3-prime adjacent to the CAG repeat, Japanese
HD chromosomes were found to be in strong linkage disequilibrium with
the (CCG)10 repeat. The frequency of HD in Japan is less than one-tenth
of the prevalence in western countries. It had been suggested that the
low frequency reflected western European origin with spread to Japan by
immigration. The haplotype findings concerning the association of the
CAG repeat and the CCG repeat suggest a separate origin with founder
effect in the Japanese cases.

Morrison et al. (1995) achieved virtually complete ascertainment of HD
in Northern Ireland which, with a population of 1.5 million, showed a
1991 prevalence rate of 6.4/100,000. Estimates of heterozygote frequency
gave values between 10 and 11 x 10(-5). The direct and indirect mutation
rates were 0.32 x 10(-6) and 1.05 x 10(-6), respectively. Genetic
fitness was increased in the affected HD population but decreased in the
at-risk population. Fertility in HD was not reduced, but it appeared
that at-risk persons had actively limited their family size. Factors
responsible for this included, among others, the fear of developing HD
and genetic counseling of families.

Scrimgeour et al. (1995) described a case of apparently typical HD in a
40-year-old Sudanese man from Khartoum, in whom the HD gene showed 51
CAG repeats. It was suspected that his mother and his deceased
16-year-old son were also affected.

Silber et al. (1998) described Huntington disease with proven expansions
of the HD gene in 5 black South African families of different ethnic
origins.

Falush et al. (2001) described a new approach for analysis of the
epidemiology of progressive genetic disorders that quantifies the rate
of progression of the disease in the population by measuring mutational
flow. They applied the method to HD. The disease is 100% penetrant in
individuals with 42 or more repeats of the CAG trinucleotide sequence.
Measurement of the flow from disease alleles provided a minimum estimate
of the flow in the whole population and implied that the new mutation
rate for HD in each generation is 10% or more of currently known cases
(95% confidence limits 6-14%). Analysis of the pattern of flow
demonstrated systematic underascertainment for repeat lengths less than
44. Ascertainment fell to less than 50% for individuals with 40 repeats
and to less than 5% for individuals with 36 to 38 repeats. Falush et al.
(2001) stated that clinicians should not assume that HD is rare outside
of known pedigrees or that most cases have onset at less than 50 years
of age.

In a study of Huntington disease in British Columbia based on referrals
for testing the CAG expansion, Almqvist et al. (2001) found that of the
141 subjects with a CAG expansion of at least 36, almost one-quarter did
not have a family history of HD. An extensive chart review revealed that
11 patients had reliable information on both parents (who lived well
into old age) and therefore could possibly represent new mutations for
HD. This indicated a new mutation rate 3 to 4 times higher than
previously reported. The findings also showed that the yearly incidence
rate for HD was 6.9 per million, which was 2 times higher than previous
incidence studies performed before identification of the HD mutation.
They identified 5 persons with a clinical presentation of HD but without
CAG expansion, i.e., genocopies.

Garcia-Planells et al. (2005) analyzed the genetic history of the HD
mutation in 115 HD patients from 83 families from the Valencia region of
eastern Spain. They identified a haplotype H1 (based on allele A of
marker dbSNP rs1313770, allele 7 of the CCG triplet, and allele A of
marker dbSNP rs82334) that was found in 47 of 48 phase-known mutant
chromosomes and in 120 of 166 chromosomes constructed using the PHASE
program. By constructing extended haplotypes, Garcia-Planells et al.
(2005) determined that the H1-associated CAG expansion originated
between 4,700 and 10,000 years ago. They also observed a nonhomogeneous
distribution in different geographic regions associated with the
different extended haplotypes of the ancestral haplotype H1, suggesting
that local founder effects had occurred.

In a population-based study of 1,772 chromosomes covering all regions of
Portugal, do Carmo Costa et al. (2006) found that the most frequent HTT
allele was 17 CAG repeats (37.9%), intermediate class 2 alleles (27 to
35 repeats) represented 3.0% of the population, and there were 2
expanded alleles (36 and 40 repeats, 0.11%). There was no evidence for
geographic clustering. Among 140 Portuguese HD families, there were 3
different founder haplotypes associated with 7-, 9-, or 10-CCG repeats,
suggesting different origins for the HD mutation. The haplotype carrying
the 7-CCG repeat was the most frequent.

Warby et al. (2009) identified a haplogroup, haplogroup A, comprising 22
SNPs in the HTT region on chromosome 4p that was significantly
associated with HD disease chromosomes (greater than 35 CAG repeats)
among 65 European HD patients but not in controls. The data were
confirmed in a replication cohort of 203 HD patients. The same SNPs were
significantly associated with the disease chromosome, but some were not,
arguing against a founder effect. In addition, chromosomes with
increased CAG repeats of 27 to 35 were also associated with haplogroup
A. Chromosomes with a haplotype subgroup, haplogroup A1 comprising 10
SNPs, were 6.5 times more likely to carry a CAG expansion. The specific
haplogroup A variants at risk for CAG expansion were not present in the
general population in China, Japan, and Nigeria, where the prevalence of
HD is much lower than in Europe. The data supported a stepwise model for
CAG expansion and suggested that CAG expansions occur on haplotypes that
are predisposed for CAG instability, likely resulting from cis-acting
elements. Warby et al. (2009) noted that the strong association between
specific SNP alleles and CAG expansion may provide an opportunity for
personalized therapeutics by using allele-specific gene silencing.

In a response to the report by Warby et al. (2009), Falush (2009)
presented evolutionary modeling of the HD CAG repeat length distribution
within populations and argued that the distribution of CAG repeat length
and disease incidence in different haplotypes can be explained by
founder events. Each haplotype examined involved expansion of repeats to
lengths that are classified as normal by HD investigators (less than 28
repeats). The results were based on the assumptions that the HD CAG
repeat is upwardly based (increases in length are more common than
decreases) and length-dependent (longer repeats mutate more frequently
than short ones), and that there is natural selection against longer
disease alleles. Falush (2009) argued against a cis element having a
role in the evolution of HD chromosomes. In a reply, Warby et al. (2009)
found fault with some aspects of the modeling presented by Falush
(2009), and asserted that cis elements do play a role in the instability
of CAG repeats at the HD locus.

HISTORY

In 1872, George Huntington of Pomeroy, Ohio, wrote about a hereditary
form of chorea 'which exists, so far as I know, almost exclusively on
the east end of Long Island.' Osler (1893) wrote about this disorder as
follows: 'Twenty years have passed since Huntingdon (sic), in a
postscript to an every-day sort of article on chorea minor, sketched
most graphically, in 3 or 4 paragraphs, the characters of a chronic and
hereditary form which he, his father and grandfather had observed in
Long Island.' As with many other conditions, Osler's writings about them
brought the disorder to general attention. In a footnote, he stated:
'Several years ago I made an attempt to get information about the
original family which the Huntingdons (sic) described, but their
physician stated that, owing to extreme sensitiveness on the subject,
the patients could not be seen.' Vessie (1932) traced the ancestry of
the families studied by Huntington (1872). About 1,000 cases in 12
generations descendant from 2 brothers in Suffolk, England, could be
identified. Uncertainty concerning the usual interpretation (Critchley,
1973; Maltsberger, 1961; Vessie, 1932) of the precise origin of the
Huntington gene in England was voiced by Caro and Haines (1975).

Durbach and Hayden (1993) published a personal account of George
Huntington based on unpublished sources and communications from several
of his descendants. Their account provides insight into his role as a
general practitioner, literally a 'horse-and-buggy doctor' as
demonstrated by one of the figures, as well as indicating his avocations
of sketching, hunting, and fishing.

Van der Weiden (1989) gave a biographical account of George Huntington
(1850-1916) and of the American anatomist George Sumner Huntington
(1861-1927), and pointed out that biographical data on the 2 have been
confused repeatedly.

Huntington disease represents a classic ethical dilemma created by the
human genome project, i.e., that of the widened gap between what we know
how to diagnose and what we know how to do anything about. Wexler (1992)
referred to the dilemma as the Tiresias complex. The blind seer Tiresias
confronted Oedipus with the dilemma: 'It is but sorrow to be wise when
wisdom profits not' (from Oedipus the King by Sophocles). Wexler (1992)
stated the questions as follows: 'Do you want to know how and when you
are going to die, especially if you have no power to change the outcome?
Should such knowledge be made freely available? How does a person choose
to learn this momentous information? How does one cope with the answer?'

According to the tabulation of Parrish and Nelson (1993), HD was the
21st genetic disorder of previously unknown basic biochemical defect in
which the gene was isolated by positional cloning. They reviewed the
methods for finding genes and tabulated the methods used in each of the
21 disorders.

ANIMAL MODEL

- Animal Models of Huntington Disease

Goldberg et al. (1996) produced transgenic mice containing the
full-length human HD cDNA with 44 CAG repeats. By 1 year, these mice had
no behavioral abnormalities; morphometric analysis at 6 months in 1
animal and at 9 months in 2 animals revealed no changes. Despite high
levels of mRNA expression, there was no evidence of the HD gene product
in any of these transgenic mice. In vitro transfection studies indicated
that the inclusion of 120 bp of the 5-prime untranslated region into the
cDNA construct and the presence of a frameshift mutation at nucleotide
2349 prevented expression of the HD cDNA. Goldberg et al. (1996)
concluded that the pathogenesis of HD is not mediated through
DNA-protein interaction and that presence of the RNA transcript with an
expanded CAG repeat is insufficient to cause the disease. Rather,
translation of the CAG is crucial for the pathogenesis of HD. In
contrast to the situation in humans, the CAG repeat in these mice was
remarkably stable in 97 meioses. This suggested that other genomic
sequences may play a critical role in influencing repeat instability.

Mangiarini et al. (1996) generated mice transgenic for the 5-prime end
of the human HD gene, including promoter sequences and exon 1 carrying
(CAG)n expansions of approximately 130 residues. In 3 mouse lines, the
transgene was ubiquitously expressed at both the mRNA and protein
levels. Transgenic mice exhibited a progressive neurologic phenotype
with many of the features of HD, including choreiform movements,
involuntary stereotypic movements, tremor, and epileptic seizures, as
well as nonmovement disorder components.

Mangiarini et al. (1997) examined the behavior of the CAG repeat in mice
transgenic for the HD mutation. They noted that the trinucleotide repeat
is unstable during transmission and somatogenesis. Similar studies of
intergenerational and somatic cell instability were found with the
myotonic dystrophy (DM1; 160900) CTG repeat in transgenic mice. In
studies of both of these repeats, the mutability of the repeats was
high, although the instability (in terms of repeat length increases) was
modest, showing fluctuations of only a few repeats. The somatic
instability of the repeats increased with the age of the mice and
appeared to occur in different tissues (perhaps correlating with the
level of expression of the transgene in particular tissues or cells).
Both expansions and deletions were seen in transgenic repeats, with a
tendency toward expansion upon male transmission and contraction upon
female transmission.

Davies et al. (1997) observed that mice transgenic for exon 1 of the
human HD gene carrying (CAG)115 to (CAG)156 repeat expansions developed
pronounced neuronal intranuclear inclusions, containing the proteins
huntingtin and ubiquitin, before developing a neurologic phenotype. The
appearance in transgenic mice of these inclusions, followed by
characteristic morphologic changes within neuronal nuclei, was
strikingly similar to nuclear abnormalities observed in biopsy material
from HD patients. Related observations were made by Scherzinger et al.
(1997), who used exon 1 of the HD gene with expanded CAG repeats for the
production of glutathione S-transferase (GST)-HD fusion proteins in E.
coli. The recombinant proteins were purified by affinity chromatography.
Site-specific proteolysis of the GST-HD51 fusion protein with a
polyglutamine expansion in the pathologic range (51 glutamines) resulted
in the formation of high molecular weight protein aggregates with a
fibrillar or ribbon-like morphology. The filaments, which were not
produced by proteolysis of shorter fusion proteins (20 or 30
glutamines), were similar to scrapie prions and beta-amyloid-like
fibrils in Alzheimer disease, and also resembled those detected by
electron microscopy in the neuronal intranuclear inclusions of mice
transgenic for the HD mutation.

Ordway et al. (1997) introduced a 146-unit CAG repeat into the mouse
hypoxanthine phosphoribosyltransferase gene (Hprt; 308000). Mutant mice
expressed a form of the Hprt protein that contains a long polyglutamine
repeat. These mice developed a phenotype similar to the human translated
CAG repeat disorders. Repeat-containing mice showed a late-onset
neurologic phenotype that progressed to premature death and neuronal
intranuclear inclusions. The authors concluded that CAG repeats do not
need to be located within one of the classic repeat disorder genes to
have a neurotoxic effect.

Bates et al. (1997) reviewed transgenic models of Huntington disease.

Although the HD mRNA and protein product show widespread distribution,
the progressive neurodegeneration is selective in location, with
regional neuron loss and gliosis in striatum, cerebral cortex, thalamus,
subthalamus, and hippocampus. Reddy et al. (1998) created an
experimental animal model in transgenic mice that showed widespread
expression of full-length human HD cDNA with either 16, 48, or 89 CAG
repeats. Only mice with 48 or 89 CAG repeats manifested progressive
behavioral and motor dysfunction with neuron loss and gliosis in
striatum, cerebral cortex, thalamus, and hippocampus.

Sathasivam et al. (1999) extended their observations of polyglutamine
inclusions in specific brain regions prior to the onset of a clinical
phenotype and searched for polyglutamine inclusions in nonneuronal
tissues. In transgenic mice, inclusions were identified outside the CNS
in a variety of postmitotic cells. This was consistent with a
concentration-dependent nucleation and aggregation model of inclusion
formation, indicating that brain-specific factors are not necessary for
this process. A detailed analysis of the timing and progression of
inclusion formation in skeletal muscle showed that the formation of
inclusions in non-CNS tissues could be useful with respect to in vivo
monitoring of pharmaceutical agents selected for their ability to
prevent polyglutamine aggregation in vitro, without the requirement that
the agent can cross the blood-brain barrier in the first instance.

Schilling et al. (1999) generated transgenic mice that expressed a cDNA
encoding an N-terminal fragment (171 amino acids) of huntingtin with 82,
44, or 18 glutamines. Mice expressing relatively low steady-state levels
of N171 huntingtin with 82 glutamine repeats (N171-82Q) developed
behavioral abnormalities, including loss of coordination, tremors,
hypokinesis, and abnormal gait, before dying prematurely. In mice
exhibiting these abnormalities, diffuse nuclear labeling, intranuclear
inclusions, and neuritic aggregates, all immunoreactive with an antibody
to the N-terminus (17 amino acids) of huntingtin, were found in multiple
populations of neurons. None of these behavioral or pathologic
phenotypes were seen in mice expressing N171-18Q. The authors considered
these findings to be consistent with the idea that N-terminal fragments
of huntingtin with a repeat expansion are toxic to neurons, and that
N-terminal fragments are prone to form both intranuclear inclusions and
neuritic aggregates.

Shelbourne et al. (1999) introduced an HD-like mutation (an extended
stretch of 72-80 CAG repeats) into the endogenous mouse Hdh gene.
Analysis of the mutation in vivo showed significant levels of germline
instability, with expansions, contractions, and sex-of-origin effects in
evidence. Mice expressing full-length mutant protein displayed abnormal
social behavior in the absence of acute neurodegeneration. Given that
psychiatric changes, including irritability and aggression, are common
findings in HD patients, the findings were considered consistent with
the hypothesis that some clinical features of HD may be caused by
pathologic processes that precede gross neuronal cell death. This
implies that effective treatment of HD may require an understanding and
amelioration of these dysfunctional processes, rather than simply
preventing the premature death of neurons in the brain.

The mechanism through which the widely expressed mutant HD gene mediates
a slowly progressing striatal neurotoxicity is unknown. Glutamate
receptor-mediated excitotoxicity has been hypothesized to contribute to
HD pathogenesis. Hansson et al. (1999) showed that transgenic HD mice
expressing exon 1 of the human HD gene with an expanded number of CAG
repeats were strongly protected from acute striatal excitotoxic lesions.
Intrastriatal infusions of quinolinic acid, the agonist of the
N-methyl-D-aspartate (NMDA) receptor, caused massive striatal neuronal
death in wildtype mice, but no damage in transgenic HD littermates. The
remarkable neuroprotection in transgenic HD mice occurred at the stage
when they had not developed any neurologic symptoms caused by the mutant
HD gene. At this stage, there was no change in the number of striatal
neurons and astrocytes in untreated transgenic mice, although the
striatal volume was decreased by 17%. Hansson et al. (1999) proposed
that the presence of exon 1 of the mutant HD gene induces profound
changes in striatal neurons that render these cells resistant to
excessive NMDA receptor activation.

Hodgson et al. (1999) produced yeast artificial chromosome transgenic
mice expressing normal and mutant huntingtin in the developmental and
tissue-specific manner identical to that observed in Huntington disease.
The mutant mice showed early electrophysiologic abnormalities,
indicating cytoplasmic dysfunction prior to observed nuclear inclusions
or neurodegeneration. By 12 months of age, mice had a selective
degeneration of medium spiny neurons in the lateral striatum associated
with the translocation of N-terminal huntingtin fragments to the
nucleus. Neurodegeneration could be present in the absence of macro- or
microaggregates, clearly showing that aggregates are not essential to
initiation of neuronal death. These mice demonstrated that initial
neuronal cytoplasmic toxicity is followed by cleavage of huntingtin,
nuclear translocation of huntingtin N-terminal fragments, and selective
neurodegeneration.

Van Dellen et al. (2000) studied the effect of environment on the
progression of Huntington disease in the mouse model developed by
Mangiarini et al. (1996). They found that exposure of HD mice to a
stimulating enriched environment from an early age helped to prevent the
loss of cerebral volume and delayed the onset of motor disorders. Thirty
male HD mice were randomized to either a normal or a stimulating
environment. The normal environment was a large standard cage with
routine care, which included normal feeding and bedding, whereas the
cages of environmentally enriched groups also contained cardboard,
paper, and plastic objects which were changed every 2 days from the age
of 4 weeks. Motor coordination was tested every week by placing each
mouse at the end of a suspended horizontal wooden rod; failure was
defined as consistent falling or inability to turn around. At the end of
testing at 22 weeks, only 1 mouse from the environmentally enriched
group failed this test, whereas all of the mice from the standard
environment had failed by this point. Another early sign of disease in
HD mice is clasping of the rear paws when briefly suspended by the tail.
The appearance of this sign was significantly delayed in mice from the
environmentally enriched environment. In addition, HD mice in the
enriched environment had a larger peristriatal cerebral volume when
compared to those in the nonenriched environment.

Wheeler et al. (2000) studied the distribution of a mutant huntingtin
gene product in Hdh-Q92 and Hdh-Q111 knockin mice, which harbor alleles
with 92 and 111 glutamines, respectively. The authors observed nuclear
localization of a version of the full-length protein predominant in
medium spiny neurons, and subsequent formation of N-terminal inclusions
and insoluble aggregate. These changes showed glutamine length
dependence and dominant inheritance with recruitment of wildtype
protein, suggesting to the authors 2 alternative pathogenic scenarios:
the effect of the glutamine tract may act by altering interaction with a
critical cellular constituent, or by depleting a form of huntingtin
essential to medium spiny striatal neuron function and survival.

To understand gene expression changes mediated by polyglutamine repeat
expansion in the human huntingtin protein, Luthi-Carter et al. (2000)
used oligonucleotide DNA arrays to profile approximately 6,000 striatal
mRNAs in the R6/2 mouse, a transgenic HD model. They found diminished
levels of less than 2% of mRNAs tested; however, some encoded components
of neurotransmitter, calcium, and retinoid signaling pathways at both
early and late symptomatic time points (6 and 12 weeks of age). Similar
changes in gene expression were also seen in another HD mouse model
(N171-82Q). The authors concluded that mutant huntingtin directly or
indirectly reduces the expression of a distinct set of genes involved in
signaling pathways known to be critical to striatal neuron function.

Li et al. (2000) reported that in mutant mice expressing HD repeats, the
production and aggregation of N-terminal huntingtin fragments
preferentially occur in HD-affected neurons and their processes and
axonal terminals. N-terminal fragments of mutant huntingtin form
aggregates and induce neuritic degeneration in cultured striatal
neurons. N-terminal mutant huntingtin also binds to synaptic vesicles
and inhibits their glutamate uptake in vitro. Li et al. (2000) suggested
that the specific processing and accumulation of toxic fragments of
N-terminal huntingtin in HD-affected striatal neurons, especially in
their neuronal processes and axonal terminals, may contribute to the
selective neuropathology of HD.

Transgenic HD model mice that express a portion of the disease-causing
form of human huntingtin develop a behavioral phenotype suggesting
dysfunction of dopaminergic neurotransmission. Bibb et al. (2000) showed
that presymptomatic mice had severe deficiencies in dopamine signaling
in the striatum. The findings included selective reductions in total
levels of dopamine- and cAMP-regulated phosphoprotein DARPP32 (604399),
as well as other dopamine-regulated phosphoprotein markers of medium
spiny neurons. HD mice also showed defects in dopamine-regulated ion
channels and in the D1 dopamine (126449)/DARPP32 signaling cascade.
These presymptomatic defects may contribute to HD pathology.

Hilditch-Maguire et al. (2000) surveyed 19 classes of organelle in
Hdh(ex4/5)/Hdh(ex4/5) knockout compared with wildtype embryonic stem
cells to identify any that might be affected by huntingtin deficiency.
Although most did not differ, dramatic changes in 6 classes revealed
that huntingtin's function is essential for normal nuclear (nucleoli,
transcription factor-speckles) and perinuclear membrane (mitochondria,
endoplasmic reticulum, Golgi, and recycling endosomes) organelles and
for proper regulation of the iron pathway. Moreover, upmodulation by
deferoxamine mesylate implicated huntingtin as an iron-response protein.
However, excess huntingtin produced abnormal organelles that resembled
the deficiency phenotype, suggesting the importance of huntingtin level
to the protein's normal pathway. The authors proposed roles for the
protein in RNA biogenesis, trafficking, and iron homeostasis to be
explored in HD pathogenesis.

Trettel et al. (2000) compared striatal cell lines established from
wildtype and Hdh(Q111) knockin mouse embryos. Alternate versions of
full-length huntingtin, distinguished by epitope accessibility, were
localized to different sets of nuclear and perinuclear organelles
involved in RNA biogenesis and membrane trafficking. However, mutant
STHdh(Q111) cells also exhibited additional forms of the full-length
mutant protein and displayed dominant phenotypes that did not mirror
phenotypes caused by either huntingtin deficiency or excess. These
phenotypes reflected a disruption of striatal cell homeostasis by the
mutant protein, suggesting an additional mechanism that is separate from
its normal activity. The authors hypothesized that specific stress
pathways, including elevated p53, endoplasmic reticulum stress response,
and hypoxia, may be pathophysiologic processes in HD.

Transgenic mice expressing N-terminal mutant huntingtin show
intranuclear huntingtin accumulation and develop progressive neurologic
symptoms. Inhibiting caspase-1 (147678) can prolong the survival of
these HD mice. Li et al. (2000) reported that intranuclear huntingtin
induces the activation of caspase-3 (600636) and the release of
cytochrome c from mitochondria in cultured cells. As a result, cells
expressing intranuclear huntingtin underwent apoptosis. Intranuclear
huntingtin increased the expression of caspase-1, which may in turn
activate caspase-3 and trigger apoptosis. The authors proposed that the
increased level of caspase-1 induced by intranuclear huntingtin may
contribute to HD-associated cell death.

By quantifying the CAG repeat sizes of individual mutant alleles in
tissues derived from an accurate genetic mouse model of HD, Kennedy and
Shelbourne (2000) showed that the mutation became very unstable in
striatal tissue. The expansion-biased changes increased with age, such
that some striatal cells from old HD mice contained mutations that had
tripled in size. The authors hypothesized that this pattern of repeat
instability and the concomitant increased polyglutamine load may
contribute to the patterns of selective neuronal cell death in HD, and
that the expansion may increase by mechanisms that are not
replication-based.

Leavitt et al. (2001) demonstrated that mutant human huntingtin causes
apoptotic cell death in the testes of transgenic mice expressing no
endogenous Htt. This proapoptotic effect of mutant Htt was completely
inhibited by increased levels of murine wildtype Htt, providing the
first evidence that wildtype Htt can reduce the toxicity of mutant Htt
in vivo.

Lin et al. (2001) used gene targeting to generate mice with 150 CAG
repeats in the Hdh gene. Such mice exhibited late-onset behavioral and
neuroanatomic abnormalities consistent with HD, including a motor task
deficit, gait abnormalities, reactive gliosis, and the formation of
neuronal intranuclear inclusions predominating in the striatum.
Inclusions exhibited increased glial fibrillary acidic protein
immunoreactivity, suggesting to the authors that these mice had neuronal
injury similar to that found early in the course of HD.

Kovtun and McMurray (2001) followed heritable changes in CAG length in
male transgenic mice generated by Mangiarini et al. (1996). In germ
cells, expansion was limited to the postmeiotic, haploid cell and
therefore did not involve mitotic replication or recombination between a
homologous chromosome or sister chromatid during meiosis. Kovtun and
McMurray (2001) suggested a model in which expansion in the germ cells
arises by gap repair and depends on a complex containing MSH2 (609309).
Expansion occurs during gap-filling synthesis when DNA loops comprising
the CAG trinucleotide repeats are sealed into the DNA strand. A shift in
the repeat sizes toward expansion was observed in epididymal sperm,
demonstrating that expansion is a postmeiotic event in the male germ
cell that occurs late in the maturation of spermatids to mature
spermatozoa. Somatic changes in expansion were age-dependent, began near
11 weeks of age, and continued throughout the lifetime of the animal.
Age-dependent expansion in somatic tissues at 30 weeks was abrogated in
the absence of Msh2, indicating that Msh2 is involved in the somatic
expansion mutation. Absence of MSH2 also completely abolished germline
expansion and age-dependent somatic expansion in transgenic cells.

Jana et al. (2001) used a mouse neuro2a cell line that expresses
truncated N-terminal huntingtin with different polyglutamine length,
along with mice transgenic for HD exon 1, to demonstrate that the
ubiquitin-proteasome pathway is involved in the pathogenesis of HD.
Proteasomal 20S core catalytic component (176843) was redistributed to
the polyglutamine aggregates in both the cellular and transgenic mouse
models. Proteasome inhibitor dramatically increased the rate of
aggregate formation caused by N-terminal huntingtin protein with 60
glutamine repeats, but had very little influence on aggregate formation
by N-terminal huntingtin protein with 150 glutamine repeats. Both normal
and polyglutamine-expanded N-terminal huntingtin proteins were degraded
by proteasome, but the rate of degradation was inversely proportional to
the repeat length. The shift of the proteasomal components from the
total cellular environment to the aggregates, as well as the
comparatively slower degradation of N-terminal huntingtin with longer
polyglutamine, decreased the proteasome's availability for degrading
other key target proteins, such as p53. This altered proteasomal
function was associated with disrupted mitochondrial membrane potential,
released cytochrome c from mitochondria into the cytosol, and activated
caspase-9- (602234) and caspase-3-like proteases. The authors concluded
that the impaired proteasomal function may play an important role in
polyglutamine protein-induced cell death.

Petersen et al. (2001) examined dissociated postnatally derived cultures
of striatal neurons from transgenic mice expressing exon 1 of the human
HD gene carrying a CAG repeat expansion. While there was no difference
in cell death between wildtype and mutant littermate-derived cultures,
the mutant striatal neurons exhibited elevated cell death following a
single exposure to a neurotoxic concentration of dopamine. The mutant
neurons exposed to dopamine also exhibited lysosome-associated responses
including induction of autophagic granules and electron-dense lysosomes.
The autophagic/lysosomal compartments colocalized with high levels of
oxygen radicals in living neurons and ubiquitin. The authors suggested
that the combination of mutant huntingtin and a source of oxyradical
stress (such as excessive dopamine) may induce autophagy and may
underlie the selective cell death characteristic of HD.

Sathasivam et al. (2001) observed that it was impossible to establish
fibroblast lines from R6/2 transgenic mice (Mangiarini et al., 1996) at
12 weeks of age, although this could be achieved without difficulty at 6
and 9 weeks. Cultures derived from mice at 12 weeks contained a high
frequency of dysmorphic cells, including cells with an aberrant nuclear
morphology and a high frequency of micronuclei and large vacuoles. All
of these features were also present in a line derived from a juvenile HD
patient. Fibroblast lines derived from R6/2 mice and from HD patients
were found to have a high frequency of multiple centrosomes which could
account for all of the observed phenotypes, including a reduced mitotic
index, high frequency of aneuploidy, and persistence of the midbody. The
authors were unable to detect large insoluble polyglutamine aggregates
in either the mouse or human fibroblast lines, in contrast to findings
in neuronal cells.

To elucidate the role of transglutaminase-2 (TGM2; 190196) in HD,
Mastroberardino et al. (2002) generated a transgenic HD mouse model
(R6/1) that was also null for TGM2 (Tgm2 -/-). Comparisons of
transglutaminase activity among different mouse lines showed that Tgm2
is the predominant transglutaminase active in the brain. The deletion of
Tgm2 led to significant ameliorations in generalized and brain weight
loss in the HD mice. Tgm2 ablation also led to a large reduction in
overall cell death and to an increased number of neuronal intranuclear
inclusions, suggesting that Tgm2 crosslinking is not directly involved
in the assembly of inclusions. Moreover, the findings suggested a
protective role for neuronal aggregates. Tgm2 -/- HD mice showed a
significant improvement in motor behavior and survival. The results
suggested that TGM2 plays a role in the regulation of neuronal cell
death in HD.

Muchowski et al. (2002) investigated the mechanism underlying the major
pathologic feature in Huntington disease neurons: the presence of
detergent-insoluble ubiquitinated inclusion bodies composed of the
huntingtin protein. They analyzed the effects of drugs or genetic
mutations that disrupt the microtubule cytoskeleton in an S. cerevisiae
model of the aggregation of an N-terminal polyglutamine-containing
fragment of huntingtin exon 1 (HtEx1). Treatment of yeast with drugs
that disrupt microtubules resulted in less than 2% of the inclusion
bodies observed in mock-treated cells and prevented the formation of
large juxtanuclear inclusion bodies. Disruption of microtubules also
unmasked a potent glutamine length-dependent toxicity of HtEx1 under
conditions where HtEx1 exists in an entirely detergent-soluble
nonaggregated form. These results suggested that active transport along
microtubules may be required for inclusion body formation by HtEx1 and
that inclusion body formation may have evolved as a cellular mechanism
to promote the sequestration or clearance of soluble species of HtEx1
that are otherwise toxic to cells.

To assess the consequences of mutant protein when huntingtin is
limiting, Auerbach et al. (2001) studied 3 lines of compound
heterozygous mice in which both copies of the HD gene were altered,
resulting in greatly reduced levels of huntingtin with a normal human
polyglutamine length (Q20) and/or an expanded disease-associated segment
(Q111). All surviving mice in each of the 3 lines were small from birth
and had variable movement abnormalities. Magnetic resonance microimaging
and histologic evaluation showed enlarged ventricles in approximately
50% of the Q20/Q111 and Q20/null mice, revealing a developmental defect
that does not worsen with age. Only Q20/Q111 mice exhibited a rapidly
progressive movement disorder that, in the absence of striatal
pathology, began at 3 to 4 months of age, progressed to paralysis of the
limbs and tail and hypokinesis, and resulted in premature death, usually
by 12 months of age. The authors concluded that greatly reduced
huntingtin levels fail to support normal development in mice, resulting
in reduced body size, movement abnormalities, and a variable increase in
ventricle volume. On this sensitized background, mutant huntingtin
causes a rapid neurologic disease, distinct from the HD-pathogenic
process. The authors hypothesized that therapeutic elimination of
huntingtin in HD patients could lead to unintended neurologic and
developmental side effects.

Wheeler et al. (2002) reported late-onset neurodegeneration and gait
deficits in older Hdh(Q111) knockin mice. Using the early
nuclear-accumulation phenotypes as surrogate markers, the authors showed
that the disease process, initiated by full-length mutant protein, was
hastened by coexpression of mutant fragment; therefore, accrual of
insoluble product in already compromised neurons may exacerbate
pathogenesis. In contrast, timing of early disease events was not
altered by normal huntingtin or by mutant caspase-1, 2 proteins shown to
reduce inclusions and glutamine toxicity in other HD models.

Supporting the view that transcriptional dysregulation may contribute Yu
et al. (2002) examined the expression and localization of the
polyglutamine-containing or glutamine-rich transcription factors TBP
(600075), CBP, and SP1 in HD mouse models. All 3 transcription factors
were diffusely distributed in the nucleus, despite the presence of
abundant intranuclear inclusions. There were no differences in the
nuclear staining of these transcription factors between HD and wildtype
mouse brains. Western blots showed that these transcription factors were
not trapped in huntingtin inclusions. The authors suggested that altered
gene expression may result from the interactions of soluble mutant
huntingtin with nuclear transcription factors, rather than from the
depletion of transcription factors by nuclear inclusions.

Luthi-Carter et al. (2002) investigated gene expression in several brain
areas in the R6/2 HD mouse. They reported that although several genes
exhibited differential expression compared to wildtype mice, there was
no regional specificity, and comparable changes in gene expression were
also seen in skeletal muscle. In comparing transgenic mice bearing
either full-length atrophin-1 (DRPLA; 607462) or partial huntingtin
transproteins to wildtype, Luthi-Carter et al. (2002) reported that
there was considerable overlap in the alteration of gene expression
between the 2 models, at least in the cerebellum. The authors concluded
that polyglutamine-induced changes may be independent of their protein
context. However, in a study comparing mice harboring truncated or
full-length mutant huntingtin transcripts, Chan et al. (2002) reported
that the full-length mutant transcript had less of an effect on gene
expression than the truncated protein, suggesting that protein context
may indeed play a role. Sipione et al. (2002) limited their study to
cultured rat striatal cells bearing different length mutant huntingtin
transcripts and reported differences in expression among genes involved
in cell signaling, transcription, lipid metabolism, and vesicle
trafficking.

Fossale et al. (2002) compared the gene expression pattern of Hdh(Q111)
mice and wildtype mice striatal RNAs by microarray and quantitative
RT-PCR analysis. The authors observed a mutant-specific increase in
hybridization to Rrs1 (see Tsuno et al., 2000), which encodes a
ribosomal protein from as early as 3 weeks of age. Studies of the human
homolog revealed elevated Rrs1 mRNA in HD compared with control
postmortem brain.

Helmlinger et al. (2002) showed that R6 transgenic mice express mutant
huntingtin in the retina, leading to severe vision deficiencies and
retinal dystrophy. Comparable early and progressive retinal degeneration
and dysfunction have been described in R7E mice, which are transgenic
mice overexpressing the human SCA7 gene (ATXN1; 607640). These
abnormalities are reminiscent of other retinal degeneration phenotypes
(in particular rd7/rd7 mice) where photoreceptor cell loss occurs.
Helmlinger et al. (2002) suggested that the NRL (162080) pathway and
photoreceptor cell fate may be altered in R6 and R7E mice retina.

By examining brains from mice expressing 150 CAG repeats in the Htt
gene, Zhou et al. (2003) found evidence that accumulation of toxic Htt
fragments was associated with an age-dependent decrease in proteasome
activity and was exacerbated by inhibition of proteasome activity.

Wheeler et al. (2003) tested whether a genetic background deficient in
Msh2 (609309) would eliminate the unstable behavior of the CAG array in
Hdh(Q111) mice. Analyses of Hdh(Q111/+):Msh2(+/+) and
Hdh(Q111/+):Msh2(-/-) progeny revealed that, while inherited instability
involved Msh2-dependent and -independent mechanisms, lack of Msh2 was
sufficient to abrogate progressive HD CAG repeat expansion in striatum.
The absence of Msh2 also eliminated striatal mutant huntingtin with
somatically expanded glutamine tracts and caused an approximately
5-month delay in nuclear mutant protein accumulation, but did not alter
the striatal specificity of this early phenotype. The authors concluded
that somatic HD CAG instability appears to be a consequence of a
striatal-selective disease process that accelerates the timing of an
early disease phenotype, via expansion of the glutamine tract in mutant
huntingtin.

Gines et al. (2003) found that reduced cAMP-responsive element
(CRE)-mediated signaling in Hdh(Q111) mouse striatum, monitored by
brain-derived neurotrophic factor (113505) and phospho-CRE binding
protein (CREB; 123810), predated inclusion formation. Furthermore, cAMP
levels in Hdh(Q111) striatum declined from an early age (10 weeks), and
cAMP was significantly decreased in HD postmortem brain and
lymphoblastoid cells. Reduced CRE signaling in cultured STHdh(Q111)
striatal cells was associated with cytosolic CREB-binding protein
(600140) indicative of diminished cAMP synthesis. Mutant cells exhibited
mitochondrial respiratory chain impairment, evident by decreased ATP and
ATP/ADP ratio, impaired MTT conversion, and heightened sensitivity to
3-nitropropionic acid. The authors proposed that impaired ATP synthesis
and diminished cAMP levels may amplify the early HD disease cascade by
decreasing CRE-regulated gene transcription and altering
energy-dependent processes essential to neuronal cell survival.

In Drosophila, Gunawardena et al. (2003) showed that a reduction in
huntingtin expression caused axonal transport defects, suggesting a
normal role for the protein in axonal transport. Cytoplasmic expression
of pathogenic huntingtin with expanded polyQ repeats resulted in
titration of soluble motor proteins and defects in axonal transport,
while nuclear expression induced neuronal apoptosis. Gunawardena et al.
(2003) suggested that pathogenic polyQ proteins cause neurodegeneration
by 2 nonmutually exclusive mechanisms: one involving disruption of
axonal transport, and one involving nuclear accumulation and apoptosis.

Slow et al. (2003) established a YAC mouse model of HD with the entire
human HD gene containing 128 CAG repeats, designated YAC128. The strain
developed motor abnormalities and age-dependent brain atrophy, including
cortical and striatal atrophy associated with striatal neuronal loss.
YAC128 mice exhibited initial hyperactivity, followed by the onset of a
motor deficit and finally hypokinesis. The motor deficit in the YAC128
mice was highly correlated with striatal neuronal loss, providing a
structural correlate for the behavioral changes. Slow et al. (2003)
defined the natural history of HD-related changes in the YAC128 mice,
demonstrating the presence of huntingtin inclusions after the onset of
behavior and neuropathologic changes.

Marsh et al. (2003) reviewed Drosophila models of Huntington disease.

Lievens et al. (2005) targeted the expression of the polyQ-containing
domain of Htt or an extended polyQ peptide alone in a subset of
Drosophila glial cells, where the only fly glutamate transporter, Eaat1
(SLC1A3; 600111), is detected. This resulted in formation of nuclear
inclusions, progressive decrease in Eaat1 transcription and shortened
adult life span, but no significant glial cell death. Brain expression
of Eaat1 was normally sustained by the EGFR (131550)-Ras (190020)-ERK1
(601795) signaling pathway, suggesting that polyQ could act by
antagonizing this pathway. The presence of polyQ peptides abolished
Eaat1 upregulation by constitutively active Egfr and potently inhibited
Egfr-mediated Erk activation in fly glial cells. Long polyQ also limited
the effect of activated Egfr on Drosophila eye development. Lievens et
al. (2005) concluded that polyQ acts at an upstream step in the pathway,
situated between EGFR and ERK activation, and that disruption of EGFR
signaling and ensuing glial cell dysfunction could play a direct role in
the pathogenesis of HD and other polyQ diseases.

Von Horsten et al. (2003) generated a transgenic rat model of HD, which
carries a truncated huntingtin cDNA fragment with 51 CAG repeats under
control of the native rat huntingtin promoter. The rats exhibited
adult-onset neurologic phenotypes with reduced anxiety, cognitive
impairments, and slowly progressive motor dysfunction as well as typical
histopathologic alterations in the form of neuronal nuclear inclusions
in the brain. As in HD patients, MRI demonstrated striatal shrinkage,
and PET scan showed reduced brain glucose metabolism.

Li et al. (2003) reported that axonal terminals in HD mouse brains that
contained huntingtin aggregates often had fewer synaptic vesicles than
did normal axonal terminals. Subcellular fractionation and electron
microscopy revealed that mutant huntingtin colocalized with
huntingtin-associated protein-1 (HAP1; 600947) in HD mouse brain axonal
terminals. Mutant huntingtin bound more tightly to synaptic vesicles
than did wildtype huntingtin, and it decreased the association of HAP1
with synaptic vesicles in HD mouse brains. Brain slices from HD
transgenic mice that had axonal aggregates showed a significant decrease
in glutamate release, suggesting that neurotransmitter release from
synaptic vesicles was impaired. The authors suggested that mutant
huntingtin may have an abnormal association with synaptic vesicles that
may impair synaptic function.

Schilling et al. (2004) fused a nuclear localization signal (NLS)
derived from atrophin-1 (DRPLA; 607462) to the N terminus of an N171-82Q
construct. Two lines of mice that were identified expressed NLS-N171-82Q
at comparable levels and developed phenotypes identical to previously
described HD-N171-82Q mice. Western blot and immunohistochemical
analyses revealed that NLS-N171-82Q fragments accumulated in nuclear,
but not cytoplasmic, compartments. The authors suggested that disruption
of nuclear processes may account for many of the disease phenotypes
displayed in the mouse models generated by expressing mutant N-terminal
fragments of Htt.

By comparing previously reported genetic modifiers in 3 Drosophila
models of human neurodegenerative disease, Ghosh and Feany (2004)
confirmed that protein folding, histone acetylation, and apoptosis are
common features of neurotoxicity. Two novel genetic modifiers, the
Drosophila homolog of ATXN2 (601517) and CGI7231, were identified.
Cell-type specificity was demonstrated as many, but not all, retinal
modifiers also modified toxicity in postmitotic neurons.

In HD(+/-)/Msh2(+/+) and HD(+/-)/Msh2(-/-) mice, Kovtun et al. (2004)
showed that long CAG repeats were shortened during somatic replication
early in embryonic development. Deletions arose during replication, did
not depend on the presence of Msh2, and were largely restricted to early
development. In contrast, expansions depended on strand break repair,
required the presence of Msh2, and occurred later in development. Kovtun
et al. (2004) hypothesized that deletions in early development may serve
to safeguard the genome and protect against expansion of disease-range
repeats during parent-offspring transmission.

Diabetes frequently develops in HD patients and in transgenic mouse
models of HD such as the R6/2 mouse. Bjorkqvist et al. (2005) reported
that R6/2 mice (at week 12, corresponding to end-stage HD) were
hyperglycemic and hypoinsulinemic and failed to release insulin in an
intravenous glucose tolerance test. In vitro, basal and
glucose-stimulated insulin secretion was markedly reduced. Islet nuclear
huntingtin inclusions increased dramatically over time, predominantly in
beta cells, and beta-cell mass and pancreatic insulin content were 35%
and 16% of that in wildtype mice, respectively. Normally occurring
replicating cells were largely absent in R6/2 islets, while no abnormal
cell death could be detected. Exocytosis was virtually abolished in beta
cells but not in alpha cells. Bjorkqvist et al. (2005) concluded that
diabetes in R6/2 mice is caused by a combination of deficient beta-cell
mass and disrupted exocytosis.

Van Raamsdonk et al. (2005) generated YAC128 mice that lacked wildtype
Htt (YAC128 -/-) but expressed the same amount of mutant Htt as YAC128
mice with wildtype Htt (YAC128 +/+). YAC128 -/- mice performed worse
than YAC128 +/+ mice in the rotarod test of motor coordination and were
hypoactive compared with YAC128 +/+ mice at 2 months. There was no
significant effect of decreased wildtype Htt on striatal volume,
neuronal counts, or DARPP32 (604399) expression, but a modest worsening
of striatal neuronal atrophy was evident. Testes of YAC128 +/+ mice
showed atrophy and degeneration, which was markedly worsened in the
absence of wildtype Htt. YAC128 +/+ mice also showed a male-specific
deficit in survival compared with wildtype mice, which was exacerbated
by the loss of wildtype Htt. Overall, the loss of wildtype Htt
influenced motor dysfunction, hyperkinesia, testicular degeneration and
impaired life span in YAC128 mice.

Slow et al. (2005) reported the serendipitous development of the
'shortstop' mouse, which expresses a short human huntingtin fragment of
117 amino acids (only exons 1 and 2 of the HD gene) with an expanded
120-residue polyQ repeat. The mice showed early onset of frequent and
widespread huntingtin inclusions but had no clinical evidence of
neuronal dysfunction or neuronal degeneration. In contrast to YAC128
mice, which express full-length huntingtin and show enhanced toxicity to
NMDA-induced excitotoxic neuronal death, shortstop mice showed relative
protection from excitotoxicity. Slow et al. (2005) concluded that
huntingtin inclusions are not pathogenic and that neurodegeneration in
Huntington disease is mediated by excitotoxic mechanisms via the
full-length mutant protein.

To dissect the impact of nuclear and extranuclear mutant Htt on the
initiation and progression of disease, Benn et al. (2005) generated a
series of transgenic mouse lines in which nuclear localization or
nuclear export signal sequences were placed N-terminal to the Htt exon 1
protein carrying 144 glutamines. The exon 1 mutant protein was present
in the nucleus as part of an oligomeric or aggregation complex.
Increasing the concentration of the mutant transprotein in the nucleus
was sufficient for and dramatically accelerated the onset and
progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant
protein was sufficient to induce cytoplasmic neurodegeneration and
transcriptional dysregulation. Benn et al. (2005) further suggested that
cytoplasmic mutant exon 1 Htt, if present, also contributed to disease
progression.

Van Raamsdonk et al. (2005) demonstrated selective degeneration of the
striatum and cortex in the YAC128 mouse model of HD. At 12 months,
YAC128 mice showed significant atrophy in the striatum, globus pallidus,
and cortex with relative sparing of the hippocampus and cerebellum.
Similarly, neuronal loss at this age was present in the striatum and
cortex of YAC128 mice but was not detected in the hippocampus. Mutant
Htt expression levels were similar throughout the brain and thus failed
to explain the selective neuronal degeneration. However, nuclear
detection of mutant Htt occurred earliest and to the greatest extent in
the striatum. In contrast to YAC128 mice, the R6/1 mouse model of HD
(which expresses exon 1 of mutant Htt) exhibits nonselective, widespread
atrophy along with nonselective nuclear detection of mutant Htt at 10
months of age. The authors suggested that selective nuclear localization
of mutant Htt may contribute to the selective degeneration in HD.

In 2 mouse models of HD, Chiang et al. (2007) found increased blood
ammonia and citrulline levels due to a defect in activity of the urea
cycle. Liver samples showed low levels of Htt aggregates. A low-protein
diet resulted in neurologic improvement, suggesting that urea cycle
defects may contribute to the progression of HD. Further studies
indicated that the deficiency was due to suppression of Cebpa (116897),
a factor important for the transcription of urea cycle enzymes, such as
argininosuccinate lyase (ASL: 608310). Mutant Htt was found to interfere
with the ability of Cebpa to interact with its cofactor. Mutant Htt also
recruited Cebpa into aggregates and suppressed gene expression.

Yang et al. (2008) reported their progress in developing a transgenic
model for Huntington disease in a rhesus macaque that expresses
polyglutamine-expanded HTT. Hallmark features of HD, including nuclear
inclusions and neuropil aggregates, were observed in the brains of the
HD transgenic monkeys. Additionally, the transgenic monkeys showed
important clinical features of HD, including dystonia and chorea.

In a Drosophila model of HD with mutant human HTT, Mugat et al. (2008)
found that expression of engrailed (EN1; 131290), a transcription
activator, was able to prevent aggregation of polyQ-HTT by activating
transcription of endogenous wildtype htt. N-terminal fragments of both
wildtype human HTT and Drosophila wildtype htt were able to rescue
phenotypes induced by polyQ-HTT, confirming that human and Drosophila
HTT share biologic properties. The ratio between wildtype Drosophila htt
and mutant polyQ-HTT was important for the onset of corresponding
phenotypes, such as aggregation and eye toxicity. The protective role of
wildtype HTT N-terminal parts suggested that HD may be considered a
dominant-negative disease rather than solely dominant.

Crittenden et al. (2010) showed that CalDAG-GEFI (RASGRP2; 605577) was
severely downregulated in the striatum of mouse Huntington disease
models and was downregulated in HD individuals. In the R6/2 transgenic
mouse model of HD, striatal neurons with the largest aggregates of
mutant Htt had the lowest levels of CalDAG-GEFI. In a brain-slice
explant model of HD, knockdown of CalDAG-GEFI expression rescued
striatal neurons from pathology induced by transfection of
polyglutamine-expanded Htt exon 1. The authors suggested that the
striking downregulation of CalDAG-GEFI in HD could be a protective
mechanism that mitigates HTT-induced degeneration.

Faideau et al. (2010) developed a novel mouse model in which mutant
huntingtin was selectively expressed in striatal astrocytes. Astrocytes
expressing the mutant protein developed a progressive phenotype of
reactive astrocytes characterized by a marked decrease in expression of
the glutamate transporters GLAST (SLC1A3; 600111) and GLI1 (SLC1A2;
600300) and in glutamate uptake. These effects were associated with
neuronal dysfunction, as evidenced by the reduced expression of both
DARPP32 (PPP1R1B; 604399) and NR2B (GRIN2B; 138252). Parallel studies in
brain samples from HD subjects revealed early glial fibrillary acidic
protein (GFAP; 137780) expression in striatal astrocytes from grade 0 HD
cases. Astrogliosis was associated with morphologic changes that
increased with severity of disease, from grades 0 through 4, and was
more prominent in the putamen. Combined immunofluorescence of GFAP and
mutant Htt showed colocalization in all grades of HD severity.
Consistent with the findings from experimental mice, there was a
significant grade-dependent decrease in striatal SLC1A2 expression from
HD subjects. Faideau et al. (2010) suggested that the presence of mutant
Htt in astrocytes alters glial glutamate transport capacity early in the
disease process and may contribute to HD pathogenesis.

Pouladi et al. (2010) investigated the involvement of the insulin-like
growth factor-1 (IGF1; 147440) pathway in mediating the effect of HTT on
body weight. IGF1 expression was examined in transgenic mouse lines
expressing different levels of full-length wildtype Htt (YAC18 mice),
full-length mutant Htt (YAC128 and BACHD mice), and truncated mutant Htt
(shortstop mice). Htt influenced body weight by modulating the IGF1
pathway. Plasma IGF1 levels correlated with body weight and Htt levels
in the transgenic YAC mice expressing human HTT. The effect of Htt on
IGF1 expression was independent of CAG size. No effect on body weight
was observed in transgenic YAC mice expressing a truncated N-terminal
Htt fragment (shortstop), indicating that full-length Htt is required
for the modulation of IGF1 expression. Treatment with 17-beta-estradiol
(17B-ED) lowered the levels of circulating IGF1 in mammals. Treatment of
YAC128 with 17B-ED, but not placebo, reduced plasma IGF1 levels and
decreased the body weight of YAC128 animals to wildtype levels. Levels
of full-length Htt also influenced IGF1 expression in striatal tissues
of the brain.

Yamanaka et al. (2010) performed a comprehensive analysis of altered DNA
binding of multiple transcription factors using brains from R6/2 HD
mice, which express an N-terminal fragment of mutant huntingtin (Nhtt).
The authors observed a reduction of DNA binding of Brn2 (600494), a POU
domain transcription factor involved in differentiation and function of
hypothalamic neurosecretory neurons. Brn2 lost its function through 2
pathways, sequestration by mutant Nhtt and reduced transcription and
expression of hypothalamic neuropeptides, leading to reduced expression
of hypothalamic neuropeptides. In contrast, Brn1 (602480) was not
sequestered by mutant Nhtt, but was upregulated in R6/2 brain, except in
hypothalamus. Yamanaka et al. (2010) concluded that functional
suppression of Brn2, together with a region-specific lack of
compensation by Brn1, may mediate hypothalamic cell dysfunction by
mutant Nhtt.

Jacobsen et al. (2010) developed an HD transgenic ovine model.
Microinjection of a full-length human HTT cDNA containing 73
polyglutamine repeats under the control of the human promoter resulted
in 6 transgenic founders, varying in copy number, of the transgene.
Analysis of offspring (at 1 and 7 months of age) from 1 of the founders
showed robust expression of the full-length human HTT protein in both
CNS and non-CNS tissue. Immunohistochemical analysis demonstrated the
organization of the caudate nucleus and putamen and revealed decreased
expression of medium-sized spiny neuron marker DARPP-32 at 7 months of
age.

- Therapeutic Strategies

Ona et al. (1999) studied the effect of inhibition of caspase-1 (147678)
on the progression of Huntington disease in the mouse model developed by
Mangiarini et al. (1996), which they called R6/2 mice. Ona et al. (1999)
crossed R6/2 mice with a well-characterized transgenic mouse strain
expressing a dominant-negative mutant of caspase-1 in the brain (NSE
M17Z). The neuron-specific enolase promoter targets the expression of
mutant caspase-1 to neurons and glia within the central nervous system.
R6/2 and R6/2-NSE M17Z mice developed normally and were
indistinguishable from wildtype littermates until about 7 weeks of age.
Thereafter, the double mutant mice performed better on rotarod tests of
motor function and had a later onset and slower progression of
deterioration. Quantitative in situ hybridization of levels of mutant
huntingtin showed no differences between the R6/2 and the double mutant
mice. The double mutant mice also exhibited less weight loss than the
R6/2 mice. Mature IL1-beta (147720) levels are a sensitive and specific
indicator of caspase-1 activation. Mature IL1-beta levels in R6/2 mice
were elevated to 268% of those in wildtype controls. This increase was
significantly inhibited in the R6/2-NSE M17Z mice. IL1-beta levels in
the brains of human patients also exhibited significant increases, to
213% of those in normal controls. The protection conferred by M17Z
expression represented a 55% increase in disease duration and a 20%
prolongation of life. To rule out a strain-related epigenetic effect
mediating protection, Ona et al. (1999) treated 7-week-old R6/2 mice
with a caspase inhibitor by continuous intracerebroventricular infusion
for 4 weeks. Mice thus treated performed better on rotarod and lived 25%
longer than control mice who were treated with a vehicle drug. R6/2-NSE
M17Z mice had delayed onset of the appearance of neural inclusions and
neurotransmitter receptor alterations as well as of symptom onset. The
authors suggested that caspase-1 inhibitors may be applicable to human
Huntington disease.

Kazemi-Esfarjani and Benzer (2000) used a Drosophila model for
Huntington and other polyglutamine diseases to screen for genetic
factors modifying the degeneration caused by expression of polyglutamine
in the eye. Among 7,000 P-element insertions, they isolated several
suppressor strains, 2 of which led to the discovery of suppressor genes.
The predicted product of one is HDJ1, which is homologous to human
heat-shock protein-40 (DNAJB2; 604139). That of the second, TPR2, is
homologous to the human tetratricopeptide repeat protein-2 (601964).
Each of these molecules contains a chaperone-related J domain. The
suppression of polyglutamine toxicity was verified in transgenic flies.

Data indicate that molecular chaperones can modulate polyglutamine
pathogenesis. To elucidate the basis of polyglutamine toxicity and the
mechanism by which chaperones suppress neurodegeneration, Chan et al.
(2000) studied transgenic Drosophila disease models of Machado-Joseph
disease (109150) and HD. They demonstrated that HSP70 (see 140559) and
Hdj1, the Drosophila homolog of human HSP40 (see 604139), showed
substrate specificity for polyglutamine proteins as well as synergy in
suppression of neurotoxicity, and altered the solubility properties of
the mutant polyglutamine protein.

Yamamoto et al. (2000) created a conditional model of HD by using the
tetracyclin-regulatable system. Mice expressing a mutated huntingtin
fragment (exon 1 of the Hd gene with a polyglutamine expansion of 94
repeats) demonstrated neuronal inclusions, characteristic
neuropathology, and progressive motor dysfunction. Blockade of
expression in symptomatic mice led to a disappearance of inclusions and
an amelioration of the behavioral phenotype. Yamamoto et al. (2000) thus
demonstrated that a continuous influx of the mutant protein is required
to maintain inclusions and symptoms, raising the possibility that HD may
be reversible. Orr and Zoghbi (2000) discussed potential therapeutic
strategies based on these conclusions.

Geldanamycin is a benzoquinone ansamycin that binds to the heat-shock
protein Hsp90 (see 140571) (Stebbins et al., 1997) and activates a
heat-shock response in mammalian cells. Sittler et al. (2001) showed
that treatment of mammalian cells with geldanamycin at nanomolar
concentrations induced the expression of Hsp40 (see 604572), Hsp70 (see
140550), and Hsp90 and inhibited HD exon 1 protein aggregation in a
dose-dependent manner. Similar results were obtained by overexpression
of Hsp70 and Hsp40 in a separate cell culture model of HD. The authors
proposed that this may provide the basis for the development of a novel
pharmacotherapy for HD and related glutamine repeat disorders.

On the hypothesis that transglutaminase may be critical to the
pathogenesis of Huntington disease via cross-linking huntingtin, Karpuj
et al. (2002) administered the transglutaminase (190195) competitive
inhibitor cystamine to transgenic mice expressing exon 1 of the
huntingtin gene containing an expanded polyglutamine repeat. Cystamine
given intraperitoneally entered the brain, where it inhibited
transglutaminase activity. When treatment began after the appearance of
abnormal movements, cystamine extended survival, reduced associated
tremor and abnormal movements, and ameliorated weight loss. Treatment
did not influence the appearance or frequency of neuronal nuclear
inclusions. Unexpectedly, cystamine treatment increased transcription of
1 of the 2 genes shown to be neuroprotective for polyglutamine toxicity
in Drosophila, DNAJ (DNAJB2; 604139).

Kazantsev et al. (2002) developed and tested suppressor polypeptides
that bind mutant huntingtin and interfere with the process of
aggregation in mammalian cell culture. In a Drosophila model, the most
potent suppressor inhibited both adult lethality and photoreceptor
neuron degeneration. The appearance of aggregates in photoreceptor
neurons correlated strongly with the occurrence of pathology, and
expression of suppressor polypeptides delayed and limited the appearance
of aggregates and protected photoreceptor neurons. Kazantsev et al.
(2002) concluded that targeting the protein interactions leading to
aggregate formation may be beneficial for the design and development of
therapeutic agents for Huntington disease.

Dunah et al. (2002) reported that huntingtin interacts with the
transcriptional activator SP1 (189906) and coactivator TAFII130 (TAF4;
601796). Coexpression of SP1 and TAFII130 in cultured striatal cells
from wildtype and HD transgenic mice reversed the transcriptional
inhibition of the dopamine D2 receptor gene caused by mutant huntingtin,
as well as protected neurons from huntingtin-induced cellular toxicity.
Furthermore, soluble mutant huntingtin inhibited SP1 binding to DNA in
postmortem brain tissues of both presymptomatic and affected HD
patients.

Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is
normally produced endogenously in humans at very low levels. Keene et
al. (2001) found that TUDCA prevented striatal degeneration and
ameliorated locomotor and cognitive deficits in the in vivo
nitropropionic acid rat model of HD. However, the transgenic mouse
models of HD result from genetic rather than chemical alterations,
involve chronic versus acute pathophysiology, and therefore may more
accurately reflect the true pathophysiology of HD. Keene et al. (2002)
examined the effects of TUDCA in the transgenic mouse model of HD,
containing a trinucleotide CAG expansion (approximately 150 repeats) of
the Htt exon 1. The mice exhibited severe neuropathophysiology and
associated neurodegeneration with concomitant sensorimotor deficits, and
typically died at approximately 14 weeks of age. The authors found that
TUDCA treatment led to a marked reduction in striatal cell apoptosis and
degeneration. In addition, intracellular inclusions were significantly
reduced, and the TUDCA-treated mice showed improved locomotor and
sensorimotor abilities. Keene et al. (2002) suggested, therefore, that
TUDCA may provide a novel and effective treatment for patients with HD.

Supporting the view that transcriptional dysregulation may contribute to
the molecular pathogenesis of HD, administration of HDAC inhibitors
rescued lethality and photoreceptor neurodegeneration in a Drosophila
model of polyglutamine disease (Steffan et al., 2001). To further
explore the therapeutic potential of HDAC inhibitors, Hockly et al.
(2003) conducted trials with a potent HDAC inhibitor, suberoylanilide
hydroxamic acid (SAHA), in the R6/2 HD mouse model. They found that the
inhibitor crosses the blood-brain barrier and increases histone
acetylation in the brain. It could be administered orally in drinking
water when complexed with cyclodextrins. SAHA dramatically improved the
motor impairment in the mouse model, clearly validating the pursuit of
this class of compounds as HD therapeutics.

Nagai et al. (2000) identified polyglutamine binding peptide-1 (QBP1)
from combinatorial peptide phage display libraries. Nagai et al. (2003)
showed that a tandem repeat of the inhibitor peptide QBP1, (QBP1)2,
significantly suppressed polyQ aggregation and polyQ-induced
neurodegeneration in the compound eye of Drosophila polyQ disease
models. In addition, (QBP1)2 expression rescued premature death of flies
expressing the expanded polyQ protein in the nervous system, increasing
the median life span from 5.5 to 52 days. The authors suggested that
QBP1 may prevent polyQ-induced neurodegeneration in vivo either by
altering the toxic conformation of the expanded polyQ stretch, or by
simply competing with the expanded polyQ stretches for binding to other
expanded polyQ proteins.

Ghosh and Feany (2004) identified nicotinamide, which has histone
deacetylase-inhibiting activity, as a potent suppressor of polyglutamine
toxicity.

The manipulation of chaperone levels has been shown to inhibit
aggregation and/or rescue cell death in S. cerevisiae, C. elegans, D.
melanogaster, and cell culture models of Huntington disease and other
polyglutamine (polyQ) disorders. Hay et al. (2004) showed that a
progressive decrease in Hdj1 (DNAJB2; 604139), Hdj2 (DNAJA1; 602837),
Hsp70 (HSPA1A; 140550), alpha-SGT (SGTA; 603419), and beta-SGT brain
levels likely contributes to disease pathogenesis in the R6/2 mouse
model of HD. Despite a predominantly extranuclear location, Hdj1, Hdj2,
Hsc70, alpha-SGT, and beta-SGT were found to colocalize with nuclear but
not with extranuclear aggregates. Hdj1 and alpha-SGT mRNA levels did not
change, suggesting the decrease in protein levels may be a consequence
of their sequestration to aggregates or an increase in protein turnover.
Ubiquitous overexpression of Hsp70 in the R6/2 mouse (as a result of
crossing to Hsp70 transgenics) delayed aggregate formation by 1 week,
had no effect on the detergent solubility of aggregates, and did not
alter the course of the neurologic phenotype. Radicicol and geldanamycin
could both maintain chaperone induction for at least 3 weeks and alter
the detergent solubility properties of polyQ aggregates over this time
course.

Ruan et al. (2004) treated immortalized striatal cells from HdhQ7
(wildtype) and HdhQ111 (mutant) mouse knockin embryos with
3-nitropropionic acid (3-NP), a mitochondrial complex II toxin. 3-NP
treatment caused significantly greater cell death in mutant striatal
cells compared with wildtype cells. In contrast, the extent of cell
death induced by rotenone, a complex I inhibitor, was similar in both
cell lines. Although evidence of apoptosis was present in 3-NP-treated
wildtype striatal cells, it was absent in 3-NP-treated mutant cells.
3-NP treatment caused a greater loss of mitochondrial membrane potential
in mutant striatal cells compared with wildtype cells. Cyclosporine A,
an inhibitor of mitochondrial permeability transition pore (PTP), and
ruthenium red, an inhibitor of the mitochondrial calcium uniporter, both
rescued mutant striatal cells from 3-NP-induced cell death and prevented
the loss of mitochondrial membrane potential. The authors concluded that
mutant Htt specifically increases cell vulnerability to mitochondrial
complex II inhibition, and may switch the type of cell death induced by
complex II inhibition from apoptosis to a nonapoptotic form.

Choo et al. (2004) examined mitochondria in human neuroblastoma cells
and clonal striatal cells established from Hdh(Q7) (wildtype) and
Hdh(Q111) mutant homozygote mouse knockin embryos. Huntingtin was
associated with the outer mitochondrial membrane, and recombinant mutant
huntingtin proteins decreased the Ca(2+) threshold necessary to trigger
mitochondrial permeability transition (MPT) pore opening. The mutant
huntingtin protein-induced MPT pore opening was accompanied by a
significant release of cytochrome c (CYCS; 123970), an effect completely
inhibited by cyclosporine A. The authors suggested that the development
of specific MPT inhibitors may be a therapeutic avenue to delay the
onset of HD.

Inhibition of polyglutamine-induced protein aggregation could provide
treatment options for polyglutamine diseases such as HD. Tanaka et al.
(2004) showed through in vitro screening studies that various
disaccharides can inhibit polyglutamine-mediated protein aggregation.
They also found that various disaccharides reduced polyglutamine
aggregates and increased survival in a cellular model of HD. Oral
administration of trehalose, the most effective of these disaccharides,
decreased polyglutamine aggregates in cerebrum and liver, improved motor
dysfunction, and extended life span in a transgenic mouse model of HD.
Tanaka et al. (2004) suggested that these beneficial effects are the
result of trehalose binding to expanded polyglutamines and stabilizing
the partially unfolded polyglutamine-containing protein. Lack of
toxicity and high solubility, coupled with efficacy upon oral
administration, made trehalose promising as a therapeutic drug or lead
component for the treatment of polyglutamine diseases. The
saccharide-polyglutamine interaction identified by Tanaka et al. (2004)
thus provided a possible new therapeutic strategy for polyglutamine
diseases.

Sang et al. (2005) reported that polyglutamine-induced cell death was
dramatically suppressed in flies lacking Dark, the fly homolog of human
APAF1 (602233). Dark appeared to play a role in the accumulation of
polyglutamine-containing aggregates. Suppression of cell death, caspase
activation, and aggregate formation were also observed when mutant
huntingtin exon 1 was expressed in homozygous Dark-mutant flies.
Expanded polyglutamine induced a marked increase in expression of Dark,
and Dark colocalized with ubiquitinated protein aggregates. APAF1
colocalized with huntingtin-containing aggregates in a murine model and
HD brain, suggesting a common role for Dark/APAF1 in polyglutamine
pathogenesis in invertebrates, mice, and man. These findings suggest
that limiting APAF1 activity may alleviate both pathologic protein
aggregation and neuronal cell death in HD.

Berger et al. (2005) demonstrated in Drosophila that lithium could
protect against the toxicity caused by aggregate-prone proteins with
either polyglutamine or polyalanine expansions. The protective effect
could be partly accounted for by lithium acting through the Wnt/Wg
(604663) pathway, as a GSK3B (605004)-specific inhibitor and
overexpression of Drosophila Tcf (153245) also mediated protective
effects. The authors suggested that lithium may deserve consideration as
a therapeutic for polyglutamine diseases.

In the R6/2 mouse model of Huntington disease, Chou et al. (2005) showed
that an agonist of the ADORA2A receptor (102776), CGS21680 (CGS),
attenuated neuronal symptoms of HD. Subsequently, Chiang et al. (2009)
showed that A2a receptors are present in liver and that CGS also
ameliorated a urea cycle deficiency by reducing mouse Htt aggregates in
the liver. By suppressing aggregate formation, CGS slowed the hijacking
of a crucial transcription factor (HSF1; 140580) and 2 protein
chaperones, Hsp27 (HSPB1; 602195) and Hsp70 (HSPA1A; 140550), into
hepatic Htt aggregates. The abnormally high levels of
high-molecular-mass ubiquitin conjugates in the liver of R6/2 mouse
model of HD were also ameliorated by CGS. The protective effect of CGS
against mouse Htt-induced aggregate formation was reproduced in 2 cell
lines and was prevented by an antagonist of the A2a receptor and a
protein kinase A (PKA) inhibitor. The mouse Htt-induced suppression of
proteasome activity was also normalized by CGS through PKA (PRKACA;
601639).

Borrell-Pages et al. (2006) found that Hsj1 (DNAJB2; 604139) proteins
protected rat striatal neurons from polyQ-huntingtin-induced cell death.
Hsj1a reduced intranuclear inclusions by acting as a typical chaperone
that unfolds misfolded proteins, whereas Hsj1b had a neuroprotective
effect by inhibiting cell death without any major effects in
polyQ-huntingtin aggregation. Hsj1b mediated its beneficial effects by
promoting release of BDNF (113505) from the Golgi apparatus in neuronal
cells. Postmortem brain tissue from patients with Huntington disease
showed significantly decreased levels of HSJ1b compared to controls.
Treatment with cystamine, a transglutaminase inhibitor, increased Hsj1b
levels and increased levels of BDNF in mouse neuronal cells and in a
mouse model of Huntington disease and showed a neuroprotective effect.
Treatment of rodent and primate models of HD with cystamine and
cysteamine resulted in a transient increase in peripheral blood levels
of BDNF in these animals.

Using two mouse models of HD, Phan et al. (2009) demonstrated that
adipose tissue dysfunction was detectable at early ages and became more
pronounced as the disease progressed. HD mice exhibited reduced levels
of leptin (LEP; 164160) and adiponectin (ADIPOQ; 605441), which are
adipose tissue-derived hormones that regulate food intake and glucose
metabolism. Impaired gene expression and lipid accumulation in
adipocytes could be recapitulated by expression of an inducible mutant
HTT transgene in an adipocyte cell line, and mutant HTT inhibited
transcriptional activity of the coactivator PPARGC1A (604517) in
adipocytes, which may contribute to aberrant gene expression. Phan et
al. (2009) concluded that mutant huntingtin may have a direct
detrimental effects in cell types other than neurons, and that
circulating adipose-tissue-derived hormones may be accessible markers
for HD prognosis and progression.

In neurons from a rat model of HD, Okamoto et al. (2009) found that
inhibition of synaptic NMDA receptor activity resulted in decreased
mutant Htt inclusions. Stimulation of synaptic NMDAR activity induced
mutant Htt inclusions via a TCP1 (186980) ring complex-dependent
mechanism, which rendered neurons more resistant to mutant Htt-mediated
cell death. In contrast, stimulation of extrasynaptic NMDARs increased
the vulnerability of mutant Htt-containing neurons to cell death by
impairing the neuroprotective CREB (123810)-PGC1A (604517) cascade and
increasing the level of the small guanine nucleotide-binding protein
Rhes (612842), which is known to sumoylate and disaggregate mutant Htt.
Treatment of transgenic mice expressing a mutant Htt protein with
low-dose memantine blocked extrasynaptic, but not synaptic, NMDARs and
ameliorated neuropathologic and behavioral manifestations. In contrast,
high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR
activity, decreased neuronal inclusions and worsened the outcome. The
findings helped explain the selective vulnerability of striatal and
cortical neurons in HD, and indicated that a balance between synaptic
versus extrasynaptic NMDA receptor activity influences inclusions and
neurotoxicity of mutant huntingtin.

Becanovic et al. (2010) performed genomewide expression profiling of the
YAC128 transgenic mouse model of HD at 12 and 24 months of age by use of
2 microarray platforms in parallel. The authors identified 13 genes that
were differentially expressed between YAC128 and controls and the
findings were validated by quantitative real-time PCR in independent
cohorts of animals. The RNA levels of Wt1 (607102), Pcdh20, and Actn2
(102573) changed as early as 3 months of age, whereas Gsg1l, Sfmbt2
(615392), Acy3 (614413), Polr2a (180660), and Ppp1r9a (602468)
expression levels were not affected until 12 to 24 months of age.
Between human HD and control brain, altered expression levels were
evident in SLC45A3 (605097), PCDH20 (614449), ACTN2, DDAH1 (604743), and
PPP1R9A.

Metabolites in the kynurenine pathway of tryptophan degradation in
mammals are thought to play an important role in neurodegenerative
disorders, including Huntington disease. Kynurenic acid (KYNA) had been
shown to reduce neuronal vulnerability in animal models by inhibiting
ionotropic excitatory amino acid receptors, and is neuroprotective in
animal models of brain ischemia. Zwilling et al. (2011) synthesized a
small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO;
603538), termed JM6, and found that oral administration of JM6 to rats
increased KYNA levels and reduced extracellular glutamate in the brain.
In a mouse model of Huntington disease, JM6 extended lifespan, prevented
synaptic loss, and decreased microglial activation. These findings
supported a critical link between tryptophan metabolism in the blood and
neurodegeneration.

*FIELD* SA
Barinaga (1996); Barkley et al. (1977); Bird et al. (1974); Brackenridge
(1974); Brackenridge (1971); Brackenridge et al. (1978); Byers and
Dodge (1967); Chase et al. (1979); Conneally (1984); Critchley (1984);
Farrer et al. (1984); Ferrante et al. (1985); Folstein et al. (1981);
Gilliam et al. (1987); Goldberg et al. (1993); Gusella et al. (1984);
Gusella et al. (1984); Gusella et al. (1983); Haines et al. (1986);
Harper (1984); Harper et al. (1979); Hayden (1981); Hayden and Beighton
(1982); Hayden et al. (1988); Hodge et al. (1980); Holmgren et al.
(1987); Khoshnan et al. (2002); Klawans et al. (1972); Ko et al. (2001);
Lazzarini et al. (1984); Lyon (1962); MacDonald et al. (1989); Martin
and Gusella (1986); Myrianthopoulos (1966); Pericak-Vance et al.
(1978); Perry et al. (1973); Roses (1996); Scrimgeour (1983); Tyler
et al. (1990); Volkers et al. (1980); Zabel et al. (1986); Zlotogora
(1997)
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357. Van Raamsdonk, J. M.; Pearson, J.; Rogers, D. A.; Bissada, N.;
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358. Vessie, P. R.: Original article on the transmission of Huntington's
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359. Volkers, W. S.; Went, L. N.; Vegter-van der Vlis, M.; Harper,
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360. von Horsten, S.; Schmitt, I.; Nguyen, H. P.; Holzmann, C.; Schmidt,
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361. Walker, D. A.; Harper, P. S.; Wells, C. E. C.; Tyler, A.; Davies,
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362. Walker, F. O.: Huntington's disease. Lancet 369: 218-228,
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363. Wallace, D. C.; Hall, A. C.: Evidence of genetic heterogeneity
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364. Wang, H. S.; Greenberg, C. R.; Hewitt, J.; Kalousek, D.; Hayden,
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365. Wang, H. S.; Greenberg, C. R.; Kalousek, D.; Gusella, J.; Horsman,
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366. Warby, S. C.; Montpetit, A.; Hayden, A. R.; Carroll, J. B.; Butland,
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367. Warby, S. C.; Visscher, H.; Butland, S.; Pearson, C. E.; Hayden,
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368. Warner, J.; Barron, L.; St Clair, D.; Brock, D.: Reliability
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369. Wasmuth, J. J.; Hewitt, J.; Smith, B.; Allard, D.; Haines, J.
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370. Went, L. N.; Vegter-van der Vlis, M.; Bruyn, G. W.: Parental
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371. Wexler, N. S.: The Tiresias complex: Huntington's disease as
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372. Wexler, N. S.; Bonilla, E.; Young, A. B.; Shoulson, I.; Gomez,
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376. Wheeler, V. C.; Lebel, L.-A.; Vrbanac, V.; Teed, A.; te Riele,
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377. Wheeler, V. C.; White, J. K.; Gutekunst, C.-A.; Vrbanac, V.;
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379. Willingham, S.; Outeiro, T. F.; DeVit, M. J.; Lindquist, S. L.;
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380. Wolff, G.; Deuschl, G.; Wienker, T. F.; Hummel, K.; Bender, K.;
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382. Wyttenbach, A.; Sauvageot, O.; Carmichael, J.; Diaz-Latoud, C.;
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383. Yamamoto, A.; Lucas, J. J.; Hen, R.: Reversal of neuropathology
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384. Yamanaka, T.; Tosaki, A.; Miyazaki, H.; Kurosawa, M.; Furukawa,
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385. Yang, S.-H.; Cheng, P.-H.; Banta, H.; Piotrowska-Nitsche, K.;
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388. Youngman, S.; Sarfarazi, M.; Quarrell, O. W. J.; Conneally, P.
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389. Yu, Z.-X.; Li, S.-H.; Nguyen, H.-P.; Li, X.-J.: Huntingtin inclusions
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394. Zuo, J.; Robbins, C.; Taillon-Miller, P.; Cox, D. R.; Myers,
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3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145:
863-874, 2011.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Oral motor dysfunction (juvenile form);
[Eyes];
Abnormal eye movement

NEUROLOGIC:
[Central nervous system];
Hyperreflexia;
Chorea;
Dementia;
Bradykinesia;
Abnormal eye movement;
Seizures (juvenile form);
Rigidity (juvenile form);
Ataxic gait (juvenile form);
Neuronal loss and gliosis in caudate and putamen;
Cerebellar atrophy (juvenile form);
[Behavioral/psychiatric manifestations];
Depression;
Personality change

MISCELLANEOUS:
Onset first to seventh decade with 30 to 40 year mode;
Prevalence much higher in whites than blacks;
Juvenile rigid early-onset form more often paternally inherited;
Normal range of expanded repeats 9-29, HD range 36-121;
Complete penetrance

MOLECULAR BASIS:
Caused by a trinucleotide repeat expansion (CAG)n in the huntingtin
gene (HTT, 613004.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 4/16/2010
Michael J. Wright - revised: 6/17/1999
Ada Hamosh - revised: 6/17/1999

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 10/22/2013
ckniffin: 4/16/2010
joanna: 9/18/2009
joanna: 2/18/2009
joanna: 5/2/2002
joanna: 5/1/2002
root: 6/24/1999
kayiaros: 6/17/1999
carol: 6/17/1999

*FIELD* CN
Ada Hamosh - updated: 01/17/2014
George E. Tiller - updated: 8/30/2013
George E. Tiller - updated: 8/20/2013
George E. Tiller - updated: 8/13/2013
Cassandra L. Kniffin - updated: 4/23/2013
Cassandra L. Kniffin - updated: 10/17/2012
George E. Tiller - updated: 12/1/2011
George E. Tiller - updated: 11/21/2011
Cassandra L. Kniffin - updated: 1/25/2011
Cassandra L. Kniffin - updated: 7/30/2010
George E. Tiller - updated: 6/25/2010
Cassandra L. Kniffin - updated: 6/8/2010
Cassandra L. Kniffin - updated: 4/16/2010
Cassandra L. Kniffin - updated: 2/19/2010
Cassandra L. Kniffin - updated: 1/4/2010
Cassandra L. Kniffin - updated: 12/17/2009
George E. Tiller - updated: 11/10/2009
Cassandra L. Kniffin - updated: 11/5/2009
Cassandra L. Kniffin - updated: 10/9/2009
Cassandra L. Kniffin - reorganized: 9/15/2009
Patricia A. Hartz - updated: 7/22/2009
George E. Tiller - updated: 7/6/2009
George E. Tiller - updated: 5/13/2009
Patricia A. Hartz - updated: 5/12/2009
Cassandra L. Kniffin - updated: 5/8/2009
Matthew B. Gross - updated: 5/7/2009
George E. Tiller - updated: 4/22/2009
Cassandra L. Kniffin - updated: 4/3/2009
Cassandra L. Kniffin - updated: 3/18/2009
Ada Hamosh - updated: 7/11/2008
George E. Tiller - updated: 6/5/2008
George E. Tiller - updated: 5/30/2008
Cassandra L. Kniffin - updated: 5/28/2008
George E. Tiller - updated: 4/25/2008
Cassandra L. Kniffin - updated: 4/3/2008
George E. Tiller - updated: 2/5/2008
Cassandra L. Kniffin - updated: 1/8/2008
George E. Tiller - updated: 12/12/2007
George E. Tiller - updated: 10/31/2007
Cassandra L. Kniffin - updated: 9/28/2007
Ada Hamosh - updated: 8/28/2007
Patricia A. Hartz - updated: 8/24/2007
Cassandra L. Kniffin - updated: 8/2/2007
Patricia A. Hartz - updated: 7/16/2007
Ada Hamosh - updated: 6/28/2007
George E. Tiller - updated: 5/21/2007
George E. Tiller - updated: 3/22/2007
Victor A. McKusick - updated: 2/26/2007
Victor A. McKusick - updated: 2/21/2007
George E. Tiller - updated: 1/16/2007
George E. Tiller - updated: 10/5/2006
George E. Tiller - updated: 9/21/2006
George E. Tiller - updated: 9/12/2006
Patricia A. Hartz - updated: 6/12/2006
John Logan Black, III - updated: 5/17/2006
Cassandra L. Kniffin - updated: 4/28/2006
Ada Hamosh - updated: 4/19/2006
Cassandra L. Kniffin - updated: 4/10/2006
Patricia A. Hartz - updated: 3/23/2006
George E. Tiller - updated: 1/10/2006
Victor A. McKusick - updated: 11/17/2005
George E. Tiller - updated: 10/21/2005
Marla J. F. O'Neill - updated: 10/20/2005
Cassandra L. Kniffin - updated: 10/17/2005
Cassandra L. Kniffin - updated: 9/20/2005
Patricia A. Hartz - updated: 9/8/2005
Cassandra L. Kniffin - updated: 8/16/2005
John Logan Black, III - updated: 7/26/2005
Patricia A. Hartz - updated: 7/25/2005
Marla J. F. O'Neill - updated: 6/24/2005
George E. Tiller - updated: 6/3/2005
George E. Tiller - updated: 4/25/2005
George E. Tiller - updated: 3/15/2005
Cassandra L. Kniffin - updated: 3/1/2005
George E. Tiller - updated: 2/15/2005
Victor A. McKusick - updated: 2/8/2005
George E. Tiller - updated: 1/28/2005
Victor A. McKusick - updated: 12/29/2004
George E. Tiller - updated: 12/29/2004
George E. Tiller - updated: 12/17/2004
Cassandra L. Kniffin - updated: 12/8/2004
Victor A. McKusick - updated: 11/23/2004
Victor A. McKusick - updated: 11/9/2004
George E. Tiller - updated: 10/26/2004
Cassandra L. Kniffin - updated: 10/11/2004
Patricia A. Hartz - updated: 10/6/2004
Stylianos E. Antonarakis - updated: 8/3/2004
Victor A. McKusick - updated: 5/18/2004
Victor A. McKusick - updated: 5/3/2004
George E. Tiller - updated: 4/1/2004
George E. Tiller - updated: 2/3/2004
Victor A. McKusick - updated: 1/22/2004
Ada Hamosh - updated: 12/30/2003
Cassandra L. Kniffin - updated: 11/24/2003
George E. Tiller - updated: 10/30/2003
George E. Tiller - updated: 10/22/2003
Victor A. McKusick - updated: 10/13/2003
George E. Tiller - updated: 10/10/2003
Victor A. McKusick - updated: 8/28/2003
Victor A. McKusick - updated: 8/26/2003
Victor A. McKusick - updated: 8/15/2003
Victor A. McKusick - updated: 7/18/2003
Victor A. McKusick - updated: 6/26/2003
Cassandra L. Kniffin - updated: 6/25/2003
George E. Tiller - updated: 5/19/2003
Victor A. McKusick - updated: 4/9/2003
Victor A. McKusick - updated: 3/28/2003
Cassandra L. Kniffin - updated: 2/12/2003
Cassandra L. Kniffin - updated: 1/21/2003
George E. Tiller - updated: 12/17/2002
George E. Tiller - updated: 12/16/2002
George E. Tiller - updated: 12/4/2002
Victor A. McKusick - updated: 10/11/2002
George E. Tiller - updated: 10/10/2002
Victor A. McKusick - updated: 9/27/2002
Stylianos E. Antonarakis - updated: 9/11/2002
Ada Hamosh - updated: 7/12/2002
Victor A. McKusick - updated: 7/8/2002
George E. Tiller - updated: 5/8/2002
George E. Tiller - updated: 5/1/2002
Ada Hamosh - updated: 3/29/2002
Victor A. McKusick - updated: 2/12/2002
Victor A. McKusick - updated: 2/6/2002
Ada Hamosh - updated: 1/30/2002
Ada Hamosh - updated: 1/25/2002
Victor A. McKusick - updated: 1/10/2002
George E. Tiller - updated: 12/14/2001
George E. Tiller - updated: 11/9/2001
Ada Hamosh - updated: 10/16/2001
Ada Hamosh - updated: 10/15/2001
George E. Tiller - updated: 10/9/2001
Victor A. McKusick - updated: 9/4/2001
Ada Hamosh - updated: 8/27/2001
Michael J. Wright - updated: 8/7/2001
Ada Hamosh - updated: 3/28/2001
George E. Tiller - updated: 3/27/2001
Victor A. McKusick - updated: 3/8/2001
George E. Tiller - updated: 2/5/2001
George E. Tiller - updated: 1/29/2001
George E. Tiller - updated: 1/23/2001
Victor A. McKusick - updated: 1/16/2001
Victor A. McKusick - updated: 1/3/2001
Victor A. McKusick - updated: 8/7/2000
Ada Hamosh - updated: 8/1/2000
Ada Hamosh - updated: 7/13/2000
George E. Tiller - updated: 6/28/2000
Stylianos E. Antonarakis - updated: 4/24/2000
Ada Hamosh - updated: 4/18/2000
George E. Tiller - updated: 4/14/2000
Ada Hamosh - updated: 4/12/2000
Victor A. McKusick - updated: 4/10/2000
Victor A. McKusick - updated: 3/7/2000
Ada Hamosh - updated: 2/1/2000
Michael J. Wright - updated: 1/6/2000
Orest Hurko - updated: 12/21/1999
Victor A. McKusick - updated: 10/26/1999
Victor A. McKusick - updated: 9/15/1999
Michael J. Wright - updated: 8/16/1999
Victor A. McKusick - updated: 6/2/1999
Ada Hamosh - updated: 5/19/1999
Victor A. McKusick - updated: 5/17/1999
Victor A. McKusick - updated: 5/3/1999
Ada Hamosh - updated: 4/7/1999
Victor A. McKusick - updated: 3/18/1999
Victor A. McKusick - updated: 2/19/1999
Victor A. McKusick - updated: 11/10/1998
Victor A. McKusick - updated: 10/26/1998
Stylianos E. Antonarakis - updated: 10/8/1998
Victor A. McKusick - updated: 9/25/1998
Victor A. McKusick - updated: 9/17/1998
Victor A. McKusick - updated: 2/11/1998
Stylianos E. Antonarakis - updated: 1/23/1998
Victor A. McKusick - updated: 1/13/1998
Victor A. McKusick - updated: 10/17/1997
Victor A. McKusick - updated: 9/23/1997
Victor A. McKusick - updated: 9/3/1997
Michael J. Wright - updated: 8/6/1997
Jennifer P. Macke - updated: 7/29/1997
Victor A. McKusick - updated: 6/16/1997
Victor A. McKusick - updated: 4/15/1997
Victor A. McKusick - updated: 3/31/1997
Victor A. McKusick - updated: 2/3/1997
Moyra Smith - updated: 1/24/1997
Cynthia K. Ewing - updated: 10/22/1996
Moyra Smith - updated: 10/7/1996
Moyra Smith - updated: 9/16/1996
Moyra Smith - updated: 9/6/1996
Iosif W. Lurie - updated: 7/15/1996
Moyra Smith - updated: 7/9/1996
Iosif W. Lurie - updated: 7/4/1996
Orest Hurko - updated: 5/6/1996
Orest Hurko - updated: 3/27/1996
Moyra Smith - updated: 3/26/1996
Moyra Smith - updated: 3/19/1996
Orest Hurko - updated: 3/6/1996
Orest Hurko - updated: 11/16/1995

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 01/17/2014
carol: 10/8/2013
carol: 10/1/2013
carol: 8/30/2013
tpirozzi: 8/30/2013
mgross: 8/29/2013
carol: 8/20/2013
tpirozzi: 8/20/2013
tpirozzi: 8/14/2013
tpirozzi: 8/13/2013
alopez: 5/8/2013
ckniffin: 4/23/2013
alopez: 3/21/2013
carol: 10/18/2012
ckniffin: 10/17/2012
terry: 8/9/2012
alopez: 8/7/2012
terry: 7/5/2012
alopez: 4/17/2012
mgross: 1/26/2012
mgross: 1/4/2012
alopez: 12/5/2011
terry: 12/1/2011
carol: 11/21/2011
terry: 11/21/2011
wwang: 4/29/2011
ckniffin: 4/14/2011
alopez: 3/11/2011
wwang: 2/17/2011
ckniffin: 1/25/2011
wwang: 11/18/2010
terry: 11/12/2010
terry: 11/3/2010
wwang: 10/6/2010
wwang: 9/1/2010
terry: 8/10/2010
wwang: 8/2/2010
ckniffin: 7/30/2010
wwang: 7/15/2010
terry: 6/25/2010
wwang: 6/15/2010
ckniffin: 6/8/2010
terry: 5/11/2010
wwang: 4/29/2010
ckniffin: 4/16/2010
wwang: 2/23/2010
ckniffin: 2/19/2010
carol: 2/4/2010
terry: 1/21/2010
wwang: 1/4/2010
ckniffin: 1/4/2010
wwang: 1/4/2010
ckniffin: 12/17/2009
terry: 12/3/2009
wwang: 11/10/2009
ckniffin: 11/5/2009
wwang: 11/4/2009
ckniffin: 10/9/2009
carol: 9/16/2009
carol: 9/15/2009
ckniffin: 9/10/2009
mgross: 7/29/2009
terry: 7/22/2009
alopez: 7/7/2009
terry: 7/6/2009
wwang: 6/25/2009
terry: 5/14/2009
terry: 5/13/2009
mgross: 5/12/2009
wwang: 5/12/2009
wwang: 5/11/2009
ckniffin: 5/8/2009
mgross: 5/7/2009
wwang: 5/7/2009
terry: 4/22/2009
wwang: 4/8/2009
ckniffin: 4/3/2009
carol: 3/26/2009
wwang: 3/25/2009
ckniffin: 3/18/2009
joanna: 2/10/2009
joanna: 2/2/2009
terry: 1/27/2009
terry: 1/21/2009
terry: 1/15/2009
terry: 1/14/2009
wwang: 10/6/2008
alopez: 7/15/2008
terry: 7/11/2008
wwang: 6/12/2008
terry: 6/5/2008
wwang: 6/5/2008
terry: 5/30/2008
wwang: 5/29/2008
ckniffin: 5/28/2008
wwang: 4/29/2008
terry: 4/25/2008
wwang: 4/15/2008
ckniffin: 4/3/2008
wwang: 3/19/2008
wwang: 2/6/2008
terry: 2/5/2008
wwang: 1/23/2008
ckniffin: 1/8/2008
wwang: 12/28/2007
terry: 12/12/2007
alopez: 11/2/2007
terry: 10/31/2007
wwang: 10/4/2007
ckniffin: 9/28/2007
alopez: 9/5/2007
terry: 8/28/2007
mgross: 8/28/2007
terry: 8/24/2007
wwang: 8/17/2007
ckniffin: 8/2/2007
mgross: 7/16/2007
alopez: 6/28/2007
wwang: 6/1/2007
terry: 5/21/2007
wwang: 3/22/2007
alopez: 3/22/2007
ckniffin: 3/8/2007
terry: 2/26/2007
alopez: 2/23/2007
terry: 2/21/2007
alopez: 1/17/2007
terry: 1/16/2007
carol: 11/27/2006
alopez: 10/5/2006
alopez: 9/21/2006
alopez: 9/12/2006
mgross: 6/12/2006
wwang: 5/24/2006
wwang: 5/22/2006
terry: 5/17/2006
wwang: 5/4/2006
ckniffin: 4/28/2006
alopez: 4/21/2006
terry: 4/19/2006
wwang: 4/18/2006
ckniffin: 4/10/2006
mgross: 3/29/2006
terry: 3/23/2006
wwang: 1/31/2006
terry: 1/10/2006
alopez: 11/28/2005
terry: 11/17/2005
alopez: 10/21/2005
wwang: 10/20/2005
ckniffin: 10/17/2005
terry: 10/12/2005
ckniffin: 9/20/2005
mgross: 9/8/2005
wwang: 8/31/2005
wwang: 8/23/2005
ckniffin: 8/16/2005
carol: 7/26/2005
terry: 7/26/2005
mgross: 7/25/2005
wwang: 6/27/2005
terry: 6/24/2005
alopez: 6/3/2005
tkritzer: 4/25/2005
mgross: 4/14/2005
alopez: 3/15/2005
tkritzer: 3/9/2005
ckniffin: 3/1/2005
wwang: 2/21/2005
wwang: 2/17/2005
terry: 2/15/2005
tkritzer: 2/9/2005
terry: 2/8/2005
alopez: 1/28/2005
tkritzer: 1/27/2005
tkritzer: 12/30/2004
terry: 12/29/2004
alopez: 12/29/2004
tkritzer: 12/17/2004
tkritzer: 12/15/2004
ckniffin: 12/8/2004
tkritzer: 11/30/2004
terry: 11/23/2004
tkritzer: 11/10/2004
terry: 11/9/2004
terry: 11/3/2004
tkritzer: 10/26/2004
alopez: 10/13/2004
ckniffin: 10/11/2004
mgross: 10/6/2004
tkritzer: 9/10/2004
mgross: 8/3/2004
tkritzer: 6/21/2004
alopez: 5/28/2004
alopez: 5/19/2004
terry: 5/18/2004
carol: 5/12/2004
terry: 5/3/2004
tkritzer: 4/21/2004
terry: 4/1/2004
carol: 3/17/2004
alopez: 2/17/2004
cwells: 2/3/2004
alopez: 1/23/2004
terry: 1/22/2004
alopez: 12/30/2003
terry: 12/30/2003
carol: 12/5/2003
ckniffin: 11/24/2003
cwells: 10/30/2003
cwells: 10/22/2003
tkritzer: 10/16/2003
terry: 10/13/2003
cwells: 10/10/2003
alopez: 9/11/2003
cwells: 9/3/2003
terry: 8/28/2003
cwells: 8/27/2003
terry: 8/26/2003
alopez: 8/19/2003
terry: 8/15/2003
cwells: 7/30/2003
terry: 7/18/2003
tkritzer: 7/17/2003
terry: 6/26/2003
carol: 6/26/2003
ckniffin: 6/25/2003
cwells: 5/19/2003
tkritzer: 5/15/2003
carol: 4/9/2003
terry: 4/9/2003
cwells: 4/3/2003
terry: 3/28/2003
cwells: 2/28/2003
ckniffin: 2/12/2003
carol: 1/24/2003
carol: 1/22/2003
ckniffin: 1/21/2003
cwells: 12/17/2002
cwells: 12/16/2002
carol: 12/16/2002
tkritzer: 12/12/2002
ckniffin: 12/9/2002
cwells: 12/4/2002
tkritzer: 10/28/2002
tkritzer: 10/16/2002
terry: 10/11/2002
cwells: 10/10/2002
cwells: 10/2/2002
carol: 9/27/2002
mgross: 9/17/2002
mgross: 9/11/2002
alopez: 8/6/2002
alopez: 7/16/2002
terry: 7/12/2002
alopez: 7/9/2002
terry: 7/8/2002
cwells: 5/17/2002
cwells: 5/14/2002
cwells: 5/8/2002
cwells: 5/1/2002
carol: 4/17/2002
alopez: 4/2/2002
terry: 3/29/2002
ckniffin: 3/12/2002
carol: 3/11/2002
terry: 3/8/2002
alopez: 2/14/2002
terry: 2/12/2002
mgross: 2/11/2002
terry: 2/6/2002
alopez: 2/5/2002
alopez: 1/31/2002
terry: 1/30/2002
alopez: 1/25/2002
cwells: 1/25/2002
cwells: 1/16/2002
terry: 1/10/2002
alopez: 1/3/2002
cwells: 12/28/2001
cwells: 12/14/2001
cwells: 11/21/2001
cwells: 11/9/2001
alopez: 10/17/2001
terry: 10/16/2001
alopez: 10/15/2001
cwells: 10/15/2001
cwells: 10/9/2001
alopez: 9/7/2001
terry: 9/4/2001
alopez: 8/30/2001
terry: 8/27/2001
cwells: 8/16/2001
cwells: 8/8/2001
terry: 8/7/2001
alopez: 3/29/2001
terry: 3/28/2001
cwells: 3/27/2001
mcapotos: 3/20/2001
mcapotos: 3/14/2001
terry: 3/8/2001
cwells: 2/6/2001
cwells: 2/5/2001
mcapotos: 2/1/2001
mcapotos: 1/29/2001
mcapotos: 1/25/2001
mcapotos: 1/23/2001
terry: 1/16/2001
carol: 1/3/2001
terry: 1/3/2001
mcapotos: 8/28/2000
mcapotos: 8/11/2000
terry: 8/7/2000
alopez: 8/2/2000
terry: 8/1/2000
alopez: 7/13/2000
alopez: 6/28/2000
mgross: 4/24/2000
alopez: 4/18/2000
terry: 4/14/2000
alopez: 4/12/2000
carol: 4/12/2000
terry: 4/10/2000
mcapotos: 4/3/2000
mcapotos: 3/17/2000
terry: 3/7/2000
alopez: 2/2/2000
terry: 2/1/2000
carol: 1/31/2000
alopez: 1/6/2000
carol: 12/21/1999
alopez: 11/15/1999
carol: 11/3/1999
terry: 10/26/1999
terry: 10/25/1999
carol: 9/30/1999
jlewis: 9/28/1999
terry: 9/15/1999
alopez: 8/18/1999
terry: 8/16/1999
jlewis: 6/9/1999
terry: 6/2/1999
alopez: 5/19/1999
terry: 5/19/1999
carol: 5/19/1999
terry: 5/17/1999
mgross: 5/11/1999
mgross: 5/10/1999
terry: 5/3/1999
terry: 4/30/1999
alopez: 4/7/1999
mgross: 3/29/1999
mgross: 3/25/1999
terry: 3/18/1999
carol: 2/22/1999
terry: 2/19/1999
dkim: 12/15/1998
terry: 11/18/1998
terry: 11/16/1998
terry: 11/10/1998
terry: 10/27/1998
terry: 10/26/1998
carol: 10/12/1998
carol: 10/8/1998
alopez: 9/29/1998
carol: 9/25/1998
carol: 9/21/1998
terry: 9/17/1998
dkim: 7/24/1998
carol: 7/2/1998
alopez: 2/11/1998
dholmes: 2/6/1998
carol: 1/26/1998
carol: 1/23/1998
alopez: 1/13/1998
dholmes: 1/8/1998
terry: 11/10/1997
terry: 10/17/1997
terry: 10/14/1997
mark: 10/1/1997
terry: 9/26/1997
terry: 9/23/1997
mark: 9/10/1997
alopez: 9/9/1997
terry: 9/3/1997
alopez: 8/27/1997
alopez: 8/8/1997
terry: 8/6/1997
terry: 7/29/1997
terry: 7/10/1997
alopez: 7/10/1997
terry: 7/7/1997
terry: 6/23/1997
terry: 6/16/1997
mark: 6/9/1997
mark: 5/27/1997
alopez: 5/5/1997
jenny: 4/15/1997
terry: 4/9/1997
jenny: 3/31/1997
terry: 3/20/1997
mark: 2/3/1997
terry: 1/30/1997
mark: 1/25/1997
terry: 1/24/1997
mark: 1/24/1997
terry: 11/21/1996
jamie: 11/20/1996
jamie: 10/16/1996
mark: 10/7/1996
mark: 9/16/1996
mark: 9/6/1996
terry: 8/9/1996
terry: 8/5/1996
carol: 7/15/1996
carol: 7/9/1996
carol: 7/4/1996
terry: 7/1/1996
mark: 6/7/1996
terry: 6/6/1996
joanna: 5/10/1996
mark: 5/6/1996
terry: 4/30/1996
terry: 4/15/1996
mark: 4/3/1996
terry: 3/29/1996
mark: 3/27/1996
terry: 3/26/1996
mark: 3/26/1996
mark: 3/25/1996
terry: 3/22/1996
mark: 3/19/1996
terry: 3/19/1996
mark: 3/19/1996
mark: 3/15/1996
terry: 3/12/1996
mark: 3/6/1996
mimman: 3/4/1996
terry: 2/29/1996
mark: 1/28/1996
terry: 1/24/1996
mark: 1/14/1996
mark: 12/11/1995
terry: 10/20/1995
mark: 10/10/1995
pfoster: 4/7/1995
davew: 8/1/1994
warfield: 3/28/1994

MIM 613004
*RECORD*
*FIELD* NO
613004
*FIELD* TI
*613004 HUNTINGTIN; HTT
;;IT15;;
HD GENE
*FIELD* TX

DESCRIPTION

The HTT gene encodes huntingtin, a ubiquitously expressed nuclear
read moreprotein that binds to a number of transcription factors to regulate
transcription. Abnormal expansion of a polyglutamine tract in the N
terminus of huntingtin causes Huntington disease (143100), a devastating
autosomal dominant neurodegenerative disease characterized by motor,
psychiatric, and cognitive dysfunction (summary by Futter et al., 2009).

CLONING

By positional cloning and exon amplification of the Huntington disease
(HD; 143100) locus on chromosome 4p16.3, the Huntington's Disease
Collaborative Research Group (1993) identified a novel transcript,
designated IT15 (important transcript 15), from human retinal and
frontal cortex cDNA libraries. The corresponding gene was predicted to
encode a 3,144-residue protein with a molecular mass of 348 kD. The
protein was called 'huntingtin' (HTT) (Hoogeveen et al., 1993). Northern
blot analysis detected a 10 to 11-kb transcript in a variety of human
tissues. The reading frame was found to contain a polymorphic
trinucleotide repeat varying from 11 to 34 CAG copies in normal
individuals. This repeat was expanded to a range of 42 to over 66 copies
(613004.0001) in 1 allele from patients with Huntington disease.

Lee et al. (2002) identified an upstream open reading frame (uORF)
encoding a 21-amino acid peptide within the 5-prime UTR of the
huntingtin gene. This upstream ORF negatively influenced expression from
the huntingtin mRNA, perhaps by limiting ribosomal access to downstream
initiation sites.

Barnes et al. (1994) found that mouse Htt (It15, Hdh) shares 86% and 91%
sequence identity with human HTT DNA and protein, respectively. Despite
the overall high level of conservation, the murine gene possesses an
imperfect CAG repeat encoding only 7 consecutive glutamines, compared to
the 13 to 36 residues that are normal in the human. Although no evidence
for polymorphic variation of the CAG repeat was seen in mice, a nearby
CCG repeat differed in length by 1 unit between several strains of
laboratory mouse and Mus spretus. The absence of a long CAG repeat in
the mouse was consistent with the lack of a spontaneous mouse model of
HD.

Baxendale et al. (1995) cloned and sequenced the homolog of the HTT gene
in the pufferfish, Fugu rubripes.

GENE STRUCTURE

Ambrose et al. (1994) found that the HTT gene spans 180 kb and contains
67 exons ranging in size from 48 bp to 341 bp with an average of 138 bp.

Lin et al. (1995) presented a detailed comparison of the sequence of the
putative promoter and the organization of the 5-prime genomic region
encompassing the first 5 exons of the mouse Htt and human HTT genes.
They found 2 dinucleotide (CT) and 1 trinucleotide intronic polymorphism
in Htt and an intronic CA polymorphism in HTT. A comparison of 940-bp
sequence 5-prime to the putative translation start site revealed a
highly conserved region (78.8% nucleotide identity) between the Htt and
the HTT gene from mouse nucleotide -56 to -206.

Baxendale et al. (1995) found that the Fugu HTT homolog spans only 23 kb
of genomic DNA, compared to the 170-kb human gene, and yet all 67 exons
are conserved. The first exon, the site of the disease-causing triplet
repeat in the human, is highly conserved. However, the glutamine repeat
in Fugu consists of only 4 residues. Baxendale et al. (1995) also showed
that synteny may be conserved over longer stretches of the 2 genomes.
The work described a detailed example of sequence comparison between
human and Fugu and illustrated the power of the pufferfish genome as a
model system in the analysis of human genes.

MAPPING

The human HTT gene maps to chromosome 4p16.3 (Huntington's Disease
Collaborative Research Group, 1993).

- Mouse Gene

Using DNA markers near the Huntington disease gene on 4p, Cheng et al.
(1989) defined a conserved linkage group on mouse chromosome 5. By
linkage analyses using recombinant inbred strains, a standard outcross,
and an interspecific backcross, they assigned homologs of 4 anonymous
DNA segments and the QDPR gene (612676) to mouse chromosome 5 and
determined their relationship to previously mapped markers on that
autosome. The findings suggested that the murine counterpart of the HD
gene may lie between Hx and Emv1. Hx stands for hemimelia-extra toes;
the gene lies 6 cM distal to Emv1, an endogenous ecotropic provirus.

From studies of the comparative mapping of the 4p16.3 region in man and
mouse, Altherr et al. (1992) concluded that the homolog of the HD gene
should be located on mouse chromosome 5. Nasir et al. (1994) confirmed
this conclusion by using an interspecific backcross to map the murine
homolog of IT15 (Hdh) to an area of mouse chromosome 5 that is within
the region of conserved synteny with human chromosome 4p16.3. Near the
unstable CAG repeat encoding a stretch of polyglutamine that is involved
in the pathogenesis of HD, there is a polyproline-encoding CCG repeat
that shows more limited allelic variation. Barnes et al. (1994) used the
mouse homolog, Hdh, to map the gene to mouse chromosome 5 in a region
devoid of mutations causing any comparable phenotype.

Grosson et al. (1994) localized the mouse homologs of the HD gene and 17
other human chromosome 4 loci, including 6 previously unmapped genes, by
use of an interspecific cross. All loci mapped in a continuous linkage
group on mouse chromosome 5, distal to En2 (engrailed-2; 131310) and Il6
(interleukin-6; 147620), the human counterparts of which are located on
chromosome 7. The relative order of the loci on human chromosome 4 and
mouse chromosome 5 was maintained for the most part. Grosson et al.
(1994) knew of no phenotypic correspondence between human and mouse
mutations mapping to this region of syntenic conservation. The gene that
is mutant in achondroplasia (100800), namely, fibroblast growth factor
receptor-3 (FGFR3; 134934), was not among the genes mapped.

Lin et al. (1995) cloned the mouse Htt gene and showed that it maps to
mouse chromosome 5 within a region of conserved synteny with human
4p16.3.

GENE FUNCTION

Hoogeveen et al. (1993) synthesized oligopeptides corresponding to the
C-terminal end of the predicted HD gene product. Immunobiochemical
studies with polyclonal antibodies directed against this synthetic
peptide revealed the presence of a protein, called huntingtin by them,
with a molecular mass of approximately 330 kD in lymphoblastoid cells
from normal individuals and patients with Huntington disease.
Immunocytochemical studies showed a cytoplasmic localization in various
cell types, including neurons. In most of the neuronal cells, the
protein was also present in the nucleus. No difference in molecular mass
or intracellular localization was found between normal and mutant cells.

Dure et al. (1994) examined the in situ hybridization of riboprobes
specific for the IT15 gene against normal human fetal and adult brains.
In both types of specimen, the autoradiographic signal correlated
strongly with cell number except in the germinal matrix and white matter
where there is a significant proportion of glial cells. This suggested
that IT15 expression is predominantly neuronal. However, there was no
predominance of IT15 expression in the striatum of the fetal brain.

The wide expression of the HTT transcript does not correlate with the
pattern of neuropathology in the disease. To study the huntingtin
protein, Trottier et al. (1995) generated monoclonal antibodies against
4 different regions of the protein. On Western blots, these monoclonals
detected the huntingtin protein of approximately 350 kD in various human
cell lines and in neural and nonneural rodent tissues. A doublet protein
was detected in cell lines from HD patients, corresponding to the mutant
and normal huntingtin. Immunohistochemical studies in the human brain,
using 2 of these antibodies, detected huntingtin in perikarya of some
neurons, neuropils, and varicosities. Huntingtin was also visualized as
punctate staining likely to represent nerve endings.

Gutekunst et al. (1995) used both polyclonal and monoclonal antifusion
protein antibodies to identify native huntingtin in rat, monkey, and
human. Western blots revealed a protein with the expected molecular
weight that is present in the soluble fraction of rat and monkey brain
tissues and lymphoblastoid cell lines from control cases.
Immunocytochemistry indicated that huntingtin is located in neurons
throughout the brain, with the highest levels evident in larger neurons.
In the human striatum, huntingtin was enriched in a patch-like
distribution, potentially corresponding to the first areas affected in
HD. Subcellular localization of huntingtin was consistent with a
cytosolic protein primarily found in somatodendritic regions. Huntingtin
appears to be associated particularly with microtubules, although some
is also associated with synaptic vesicles. On the basis of the
localization of huntingtin in association with microtubules, Gutekunst
et al. (1995) speculated that the mutation impairs the cytoskeletal
anchoring or transport of mitochondria, vesicles, or other organelles or
molecules. Lymphoblastoid cell lines from juvenile-onset heterozygote HD
cases showed expression of both normal and mutant huntingtin; increasing
repeat expansion leads to lower levels of the mutant protein.

Li et al. (1995) described a huntingtin-associated protein (HAP1;
600947), which is enriched in brain. The authors found that binding of
HAP1 to huntingtin was enhanced by an expanded polyglutamine repeat.

De Rooij et al. (1996) used affinity-purified antibodies to analyze the
subcellular location of huntingtin. In mouse embryonic fibroblasts,
human skin fibroblasts, and mouse neuroblastoma cells, they detected
huntingtin in the cytoplasm and the nucleus.

Burke et al. (1996) described the isolation of a protein present in
brain homogenates that bound to a synthetic 60-glutamine peptide (such
as that found in huntingtin). Eighteen amino acids of this protein were
found to be identical to the N terminus of glyceraldehyde-3-phosphate
dehydrogenase (GAPD, or GAPDH; 138400). GAPD was also found to bind to
another protein with a polyglutamine tract, namely the DRPLA protein,
atrophin-1 (607462). Burke et al. (1996) demonstrated that synthetic
polyglutamine peptides, DRPLA protein, and huntingtin from unaffected
individuals with normal-sized polyglutamine tracts bind to GAPD. GAPD
had also been shown to bind to RNA, ATP, calcyclin (114110), actin (see
102610), tubulin (see 191130) and amyloid precursor protein (104760). On
the basis of their findings, the authors postulated that disease
characterized by the presence of an expanded CAG repeat, which share a
common mode of heritability, may also share a common metabolic
pathogenesis involving GAPD as a functional component. Both Roses (1996)
and Barinaga (1996) reviewed these findings.

In human lymphoblastoid cells, Kahlem et al. (1998) showed that
huntingtin is a substrate of transglutaminase (see, e.g., TGM1; 190195)
in vitro and that the rate constant of the reaction increases with
length of the polyglutamine over a range of an order of magnitude. As a
result, huntingtin with expanded polyglutamine is preferentially
incorporated into polymers. Both disappearance of huntingtin with
expanded polyglutamine and its replacement by polymeric forms are
prevented by inhibitors of transglutaminase. The effect of
transglutaminase therefore duplicates the changes in the affected parts
of the brain. In the presence of either tissue or brain
transglutaminase, monomeric huntingtin bearing a polyglutamine expansion
formed polymers much more rapidly than one with a short polyglutamine
sequence.

Zuccato et al. (2001) demonstrated that wildtype huntingtin upregulates
transcription of brain-derived neurotrophic factor (BDNF; 113505), a
prosurvival factor produced by cortical neurons that is necessary for
survival of striatal neurons in the brain. Zuccato et al. (2001) showed
that this beneficial activity of huntingtin is lost when the protein
becomes mutated, resulting in decreased production of cortical BDNF.
This leads to insufficient neurotrophic support for striatal neurons,
which then die. Zuccato et al. (2001) suggested that restoring wildtype
huntingtin activity and increasing BDNF production may be therapeutic
approaches for treating HD.

Kegel et al. (2002) demonstrated localization of huntingtin to
subnuclear compartments, including speckles, promyelocytic leukemia
protein bodies, and nucleoli, in normal and HD human fibroblasts and in
mouse neurons. Western blot analysis showed that purified nuclei had low
levels of full-length huntingtin compared with the cytoplasm, but
contained high levels of N- and C-terminal huntingtin fragments, which
tightly bound to the nuclear matrix. Full-length huntingtin
coimmunoprecipitated with the transcriptional CTBP1 (602618) protein,
and polyglutamine expansion in huntingtin reduced this interaction.
Full-length wildtype and mutant huntingtin repressed transcription when
targeted to DNA, but truncated N-terminal wildtype huntingtin did not,
suggesting that proteolysis of huntingtin in the nucleus may normally
occur in cells to terminate or modulate huntingtin function. However,
truncated N-terminal mutant huntingtin retained the ability to repress
transcription, suggesting an abnormal gain of function. Kegel et al.
(2002) suggested that wildtype huntingtin may function in the nucleus in
the assembly of nuclear matrix-bound protein complexes involved with
transcriptional repression and RNA processing. Proteolysis of mutant
huntingtin may disrupt nuclear functions by altering protein complex
interactions and inappropriately repressing transcription in HD.

By live-cell time-lapse video microscopy, Xia et al. (2003) visualized
polyglutamine-mediated aggregation and transient nuclear localization of
huntingtin over time in a striatal cell line. A classic nuclear
localization signal could not be detected in the huntingtin amino acid
sequence, but a nuclear export signal (NES) in the carboxy terminus of
huntingtin was discovered. Leptomycin B treatment of clonal striatal
cells enhanced the nuclear localization of huntingtin, and a mutant NES
huntingtin displayed increased nuclear localization, indicating that
huntingtin can shuttle to and from the nucleus. The huntingtin NES is
strictly conserved among all huntingtin proteins from diverse species.
This export signal may be important in Huntington disease because this
fragment of huntingtin is proteolytically cleaved during HD.

Zuccato et al. (2003) showed that the neuron-restrictive silencer
element (NRSE) is the target of wildtype huntingtin activity on BDNF
promoter II. Wildtype huntingtin inhibits the silencing activity of the
NRSE, increasing transcription of BDNF. Zuccato et al. (2003) showed
that this effect occurs through cytoplasmic sequestering of repressor
element-1 transcription factor/neuron-restrictive silencer factor
(REST/NRSF; 600571), the transcription factor that binds to NRSE. In
contrast, aberrant accumulation of REST/NRSF in the nucleus is present
in Huntington disease. Wildtype huntingtin coimmunoprecipitates with
REST/NRSF, and less immunoprecipitated material is found in brain tissue
with Huntington disease. Zuccato et al. (2003) also reported that
wildtype huntingtin acts as a positive transcriptional regulator for
other NRSE-containing genes involved in the maintenance of the neuronal
phenotype. Consistently, loss of expression of NRSE-controlled neuronal
genes was shown in cells, mice, and human brain with Huntington disease.
Zuccato et al. (2003) concluded that wildtype huntingtin acts in the
cytoplasm of neurons to regulate the availability of REST/NRSF to its
nuclear NRSE-binding site and that this control is lost in the pathology
of Huntington disease. The findings indicated a novel mechanism by which
mutation of huntingtin causes loss of transcription of neuronal genes.

Gauthier et al. (2004) showed that huntingtin specifically enhances
vesicular transport of BDNF along microtubules. They determined that
huntingtin-mediated transport involves HAP1 and the p150(Glued) (601143)
subunit of dynactin, an essential component of molecular motors. BDNF
transport was attenuated both in the disease context and by reducing the
levels of wildtype huntingtin. The alteration of the
huntingtin/HAP1/p150(Glued) complex correlated with reduced association
of motor proteins with microtubules. The
polyglutamine-huntingtin-induced transport deficit resulted in the loss
of neurotrophic support and neuronal toxicity. Gauthier et al. (2004)
concluded that a key role of huntingtin is to promote BDNF transport and
suggested that loss of this function might contribute to pathogenesis.

By yeast 1-hybrid and DNase footprint analyses, Tanaka et al. (2004)
identified 2 proteins, HDBP1 (SLC2A4RG; 609493) and HDBP2 (ZNF395;
609494), that bound a 7-bp consensus sequence (GCCGGCG) in the HTT
promoter. Mutation of the 7-bp consensus sequence abolished HTT promoter
function in a human neuronal cell line.

Using an antibody specific for HTT phosphorylated on ser421, Warby et
al. (2005) demonstrated that HTT phosphorylation was present at
significant levels under normal physiologic conditions in human and
mouse brain. Htt phosphorylation showed a regional distribution with
highest levels in the cerebellum, less in the cortex, and least in the
striatum. In cell cultures and in YAC transgenic mice, endogenous
phosphorylation of polyglutamine-expanded HTT was significantly reduced
relative to wildtype HTT. The presence and pattern of significant HTT
phosphorylation in the brain suggested to the authors that this dynamic
posttranslational modification may be important for the regulation of
HTT and may contribute to the selective neurodegeneration seen in HD.

Ralser et al. (2005) demonstrated that ataxin-2 (601517) interacted with
endophilin-A1 (SH3GL2; 604465) and endophilin-A3 (SH3GL3; 603362). In a
yeast model system, expression of ataxin-2 as well as both endophilin
proteins was toxic for yeast lacking Sac6, which encodes fimbrin (PLS3;
300131), a protein involved in actin filament organization and
endocytotic processes. Expression of huntingtin was also toxic in
Sac6-null yeast. These effects could be suppressed by simultaneous
expression of 1 of the 2 human fimbrin orthologs, L-plastin (LCP1;
153430) or T-plastin (PLS3). Ataxin-2 associated with L- and T-plastin,
and overexpression of ataxin-2 led to accumulation of T-plastin in
mammalian cells. Ralser et al. (2005) suggested an interplay between
ataxin-2, endophilin proteins, and huntingtin in plastin-associated
cellular pathways.

Cornett et al. (2005) studied the mechanism by which mutant HTT
accumulates in the nucleus; wildtype HTT is normally found in the
cytoplasm. They reported that N-terminal HTT shuttles between the
cytoplasm and nucleus and that small N-terminal HTT fragments interact
with the nuclear pore protein translocated promoter region (TPR;
189940), which is involved in nuclear export. PolyQ expansion and
aggregation decrease this interaction and increase the nuclear
accumulation of HTT. Reducing the expression of TPR by RNA interference
or deletion of 10 amino acids of N-terminal HTT, which are essential for
the interaction of HTT with TPR, increased the nuclear accumulation of
HTT. Cornett et al. (2005) concluded that TPR has a role in the nuclear
export of N-terminal HTT and that polyQ expansion reduces this nuclear
export to cause the nuclear accumulation of HTT.

Using yeast 2-hybrid analysis of a human brain cDNA library and affinity
chromatography assays with mouse brain cytosol, Caviston et al. (2007)
demonstrated that Htt and dynein intermediate chain (see DYNC1I1;
603772) interacted directly. HTT RNA interference in HeLa cells resulted
in Golgi disruption similar to the effects of compromised
dynein/dynactin function. In vitro studies revealed that Htt and dynein
were both present on vesicles purified from mouse brain. Antibodies to
Htt inhibited vesicular transport along microtubules, suggesting that
Htt facilitates dynein-mediated vesicle motility. In vivo inhibition of
dynein function resulted in a significant redistribution of Htt to the
cell periphery, suggesting that dynein transports Htt-associated
vesicles toward the cell center.

Argonaute proteins, such as AGO1 (EIF2C1; 606228) and AGO2 (EIF2C2;
606229), are components of a ribonucleoprotein complex that regulates
mRNA translation via small interfering RNA. Savas et al. (2008) found
that an N-terminal fragment of Htt with 25 or 97 glutamines
immunoprecipitated AGO1 and AGO2 from transfected HeLa cells. AGO2 also
immunoprecipitated endogenous HTT from HeLa cells. A portion of
endogenous HTT colocalized with AGO2 in P bodies in human and mouse cell
lines and in primary rat hippocampal neurons, but not all HTT foci
colocalized with AGO2 and a P-body marker. Small interfering RNA,
reporter gene assays, and FRAP analysis suggested that HTT may have a
role in gene silencing through the RNA interference pathway, and that
mutant HTT may reduce incorporation of AGO2 into P bodies and P
body-associated gene silencing.

Futter et al. (2009) found that wildtype huntingtin could bind to a
number of nuclear receptors, including LXR-alpha (NR1H3; 602423), PPARG
(601487), VDR (601769), and THRA1 (190120). Overexpression of huntingtin
activated, whereas knockout of huntingtin decreased, LXR-mediated
transcription of a reporter gene. Loss of huntingtin also decreased
expression of the LXR target gene, ABCA1 (600046). In vivo,
huntingtin-deficient zebrafish had a severe phenotype with reduction of
cartilage in the jaw and reduced expression of LXR-regulated genes. An
LXR agonist was able to partially rescue the phenotype and the
expression of LXR target genes in huntingtin-deficient zebrafish during
early development. The data suggested a novel function for wildtype
huntingtin as a cofactor of LXR. However, this activity was lost by
mutant polyQ huntingtin, which only interacted weakly with LXR.

Smith et al. (2009) showed that mutant huntingtin disrupted
intracellular transport and insulin secretion by direct interference
with microtubular beta-tubulin (TUBB; 191130). Mutant huntingtin
impaired glucose-stimulated insulin secretion in insulin-producing beta
cells, without altering stored levels of insulin. Mutant huntingtin also
retarded post-Golgi transport, and the speed of insulin vesicle
trafficking was reduced. There was an enhanced and aberrant interaction
between mutant huntingtin and beta-tubulin, implying the underlying
mechanism of impaired intracellular transport. Smith et al. (2009)
proposed a novel pathogenetic process by which mutant huntingtin may
disrupt hormone exocytosis from beta cells and possibly impair vesicular
transport in any cell that expresses the pathogenic protein.

Seong et al. (2010) investigated huntingtin's domain structure and
potential intersection with epigenetic silencer polycomb repressive
complex-2 (PRC2, see EZH1; 601674), suggested by shared embryonic
deficiency phenotypes. Analysis of a set of full-length recombinant
huntingtins, with different polyglutamine regions, demonstrated dramatic
conformational flexibility, with an accessible hinge separating 2 large
alpha-helical domains. Mouse embryos lacking huntingtin exhibited
impaired PRC2 regulation of Hox gene expression, trophoblast giant cell
differentiation, paternal X-chromosome inactivation, and histone H3K27
trimethylation, while full-length endogenous nuclear huntingtin in
wildtype embryoid bodies was associated with PRC2 subunits and was
detected with trimethylated histone H3K27 at Hoxb9 (142964). Supporting
a direct stimulatory role, full-length recombinant huntingtin
significantly increased the histone H3K27 trimethylase activity of
reconstituted PRC2 in vitro, and structure-function analysis
demonstrated that the polyglutamine region augmented full-length
huntingtin PRC2 stimulation, both in Hdh(Q111) embryoid bodies and in
vitro, with reconstituted PRC2. Seong et al. (2010) implicated a role
for the multisubunit PRC2 complex in neurodegenerative disorders such as
Huntington disease.

Song et al. (2011) found fragmented mitochondria in fibroblasts from a
patient with HD and in rat cortical neurons expressing human HTT with a
polyQ expansion. Neurons expressing mutant HTT also showed arrest in
mitochondrial movement and ultrastructural changes in mitochondrial
cristae. Mitochondrial changes were observed in a mouse model of HD
prior to emergence of neurologic deficits, neuronal cell death, and HTT
aggregate formation. Immunoprecipitation of normal and HD human or mouse
brain indicated that mutant, but not normal, huntingtin interacted with
Drp1 (DNM1; 603850), a protein involved in mitochondria and peroxisome
fission. In vitro assays with liposomes that mimicked the mitochondrial
outer membrane revealed that mutant huntingtin stimulated Drp1 GTPase
activity. Expression of a dominant-negative Drp1 mutant rescued mutant
huntingtin-mediated mitochondrial fragmentation, defects in
mitochondrial transport, and neuronal cell death. Electron microscopy
showed that the normal ring- and spiral-like organization of DRP1
oligomers had an additional layer of density with the addition of
mutant, but not normal, huntingtin.

Neurodegeneration in HD is thought to be due to proteolytic release of
toxic peptide fragments from mutant HTT. By transfecting small
interfering RNAs directed against 514 human proteases into polyQ
HTT-expressing HEK293 cells, Miller et al. (2010) identified 11
proteases, including MMP10 (185260), MMP14 (600754), and MMP23B
(603321), as putative polyQ HTT-processing proteases. Further
characterization revealed that MMP10 was the only metalloprotease in
this group that directly processed polyQ HTT; MMP14 and MMP23B appeared
to cause polyQ HTT degradation indirectly. MMP10 cleaved polyQ HTT at a
conserved site near the N terminus with the consensus sequence
(S/T)xxGG(I/L). Both Mmp10 and Mmp14 were upregulated in mouse striatal
cells expressing polyQ HTT, and knockdown of either Mmp10 or Mmp14
reduced cell death and caspase activation. Htt and Mmp10 colocalized in
cells undergoing apoptosis.

Godin et al. (2010) noted that HTT expression is associated with the
centrosomal region and microtubules of dividing cells. They found that
HTT localized to the spindle poles during mitosis from prophase to
anaphase in both HeLa cells and dividing mouse cortical neurons.
Knockdown of HTT expression in either cell model resulted in a spindle
orientation defect. The defect could be reversed in mouse cortical
neurons by expression of a 1,301-amino acid N-terminal fragment of mouse
Htt or a 620-amino acid N-terminal fragment of Drosophila Htt. Depletion
of Htt in mouse cells caused partial mislocalization of p150(Glued),
dispersal of dynein and Numa (NUMA1; 164009), and asynchronous cell
division. In day-14.5 mouse embryos, asynchronous division due to Htt
depletion led to premature neuronal differentiation at the expense of
proliferation and maintenance of progenitors in the neocortex. Godin et
al. (2010) concluded that HTT functions as a scaffold protein for the
dynein/dynactin complex in dividing cells.

MOLECULAR GENETICS

The Huntington's Disease Collaborative Research Group (1993) identified
an expanded (CAG)n repeat on 1 allele of the HTT gene (613004.0001) in
affected members from all of 75 HD families examined. The families came
from a variety of ethnic backgrounds and demonstrated a variety of
4p16.3 haplotypes. The findings indicated that the HD mutation involves
an unstable DNA segment similar to those previously observed in several
disorders, including the fragile X syndrome (300624), Kennedy syndrome
(313200), and myotonic dystrophy. The fact that the phenotype of HD is
completely dominant suggested that the disorder results from a
gain-of-function mutation in which either the mRNA product or the
protein product of the disease allele has some new property or is
expressed inappropriately (Myers et al., 1989).

Duyao et al. (1993), Snell et al. (1993), and Andrew et al. (1993)
analyzed the number of CAG repeats in a total of about 1,200 HTT genes
and in over 2,000 normal controls. Read (1993) summarized and collated
the results. In all 3 studies, the normal range of repeat numbers was
9-11 at the low and 34-37 at the high end, with a mean ranging from
18.29 to 19.71. Duyao et al. (1993) found a range of 37-86 in HD
patients, with a mean of 46.42.

Rubinsztein et al. (1996) studied a large cohort of individuals who
carried between 30 and 40 CAG repeats in the HTT gene. They used a PCR
method that allowed the examination of CAG repeats only, thereby
excluding the CCG repeats, which represent a polymorphism, as a
confounding factor. No individual with 35 or fewer CAG repeats had
clinical manifestations of HD. Most individuals with 36 to 39 CAG
repeats were clinically affected, but 10 persons (aged 67-95 years) had
no apparent symptoms of HD. The authors concluded that the HD mutation
is not fully penetrant in individuals with a borderline number of CAG
repeats.

Gusella et al. (1996) gave a comprehensive review of the molecular
genetic aspects of Huntington disease.

- Mechanism of Repeat Expansion

Zuhlke et al. (1993) studied the length variation of the repeat in 513
non-HD chromosomes from normal individuals and HD patients; the group
comprised 23 alleles with 11 to 33 repeats. In an analysis of the
inheritance of the (CAG)n stretch, they found meiotic instability for HD
alleles, (CAG)40 to (CAG)75, with a mutation frequency of approximately
70%; following the HD allele in 38 pedigrees during 54 meioses, they
found a ratio of stable to altered copy number of 15:39. On the other
hand, in 431 meioses of normal alleles, only 2 expansions were
identified. They found that the risk of expansion during spermatogenesis
was enhanced compared to oogenesis, explaining juvenile onset by
transmission from affected fathers. No mosaicism or differences in
repeat lengths were observed in the DNA from different tissues,
including brain and lymphocytes of 2 HD patients, indicating mitotic
stability of the mutation. Thus, the determination of the repeat number
in the DNA of blood lymphocytes is probably representative of all
tissues in a patient.

Telenius et al. (1994) found somatic mosaicism for the CAG repeat in
different tissues from 12 HD patients. Mosaicism for the highest numbers
of CAG repeats was found in the brain, particularly in the basal ganglia
and cortex, with lesser changes in the cerebellum. Sperm samples from 4
males also showed high levels of somatic mosaicism. Blood and other
tissues showed lower levels of mosaicism. Telenius et al. (1994)
suggested that expanded HTT gene CAG repeats are associated with
tissue-specific mitotic and meiotic instability.

MacDonald et al. (1993) found that unlike the similar CCG repeat in the
fragile X syndrome, the expanded HD repeat shows no evidence of somatic
instability in a comparison of blood, lymphoblast, and brain DNA from
the same persons. Furthermore, 4 pairs of monozygotic HD twins displayed
identical CAG repeat lengths, suggesting that repeat size is determined
in gametogenesis. However, in contrast to the fragile X syndrome and
with HD somatic tissue, mosaicism was readily detected as a diffuse
spread of repeat lengths in DNA from HD sperm samples. Thus, the
developmental timing of repeat instability appears to differ between HD
and fragile X syndrome, indicating perhaps that the fundamental
mechanisms leading to repeat expansion are distinct.

Leeflang et al. (1995) amplified the CAG triplet repeat region of the HD
gene in 923 single sperm from 3 affected and 2 normal individuals.
Average-sized alleles (15-18 repeats) showed only 3 contraction
mutations among 475 sperm (0.6%). A 30-repeat normal allele showed an
11% mutation frequency. The mutation frequency of a 36-repeat
intermediate allele was 53% with 8% of all gametes having expansions
that brought the allele size into the HD disease range (38 repeats or
more). Disease alleles (38-51 repeats) showed a very high mutation
frequency (92-99%). As repeat number increased, the authors found a
marked elevation in the frequency of expansions, in the mean number of
repeats added per expansion, and in the size of the largest observed
expansion. Contraction frequencies also appeared to increase with allele
size but decreased as repeat number exceeded 36. Since the sperm typing
data were of a discrete nature rather than consisting of smears of PCR
products from pooled sperm, Leeflang et al. (1995) could compare the
observed mutation frequency spectra to the distribution calculated using
discrete stochastic models based on current molecular ideas of the
expansion process. An excellent fit was found when the model specified
that a random number of repeats are added during the progression of the
DNA polymerase through the repeated region.

All mutations for Huntington disease arise from so-called intermediate
alleles (IAs) containing between 29 and 35 CAG repeats. The CAG repeats
expand on transmission through the paternal germline to 36 or more
repeats. Intermediate alleles are present on approximately 1% of normal
chromosomes of Caucasian descent. Affected individuals have an expanded
allele of between 36 to 121 CAGs, but incomplete penetrance has been
found for repeat lengths of 36 to 40 CAGs. Using single sperm analysis,
Chong et al. (1997) assessed CAG mutation frequencies of 4 IAs in
families with sporadic HD and IAs ascertained from the general
population by analyzing 1161 single sperm from 3 persons. They showed
that the intermediate alleles of the former group were more unstable
than those in the general population with identical size and sequence.
Furthermore, comparison of different sized IAs and IAs with different
sequences between the CAG and the adjacent CCG tracts indicated that DNA
sequence is a major influence on CAG stability. These studies provided
estimates of the likelihood of expansion to 36 or more CAG repeats for
individuals in the 2 groups. For an IA with (CAG)35 in the family with
sporadic HD, the likelihood for sibs to inherit a recurrent mutation
equal to or more than (CAG)36 was approximately 10%. For intermediate
alleles of a similar size in the general population, the risk of
inheriting an expanded allele of 36 or more CAGs through the paternal
germline was approximately 6%.

By typing greater than 3,500 sperm, Leeflang et al. (1999) determined
the size distribution of HD germline mutations produced by 26 men in the
Venezuelan cohort with CAG/CTG repeat numbers ranging from 37 to 62.
Both the mutation frequency and mean change in allele size increased
with increasing somatic repeat number. The mutation frequencies averaged
82%, and for individuals with at least 50 repeats, 98%. The
extraordinarily high mutation frequency levels are most consistent with
a process that occurs throughout germline mitotic divisions, rather than
resulting from a single meiotic event. A statistical model based on
incomplete processing of Okazaki fragments during DNA replication was
found to provide an excellent fit to the data, but variation in
parameter values among individuals suggests that the molecular mechanism
might be more complex.

Large intergenerational repeat expansions of the CAG trinucleotide
repeat in the HD gene are well documented for the male germline. Laccone
and Christian (2000) described a recurrent large expansion of a maternal
allele with 36 CAG repeats (to 66 and 57 repeats, respectively, in 2
daughters) associated with onset of Huntington disease in the second and
third decade in a family without history of HD. The findings gave
evidence of gonadal mosaicism in the unaffected mother. Laccone and
Christian (2000) hypothesized that large expansions also occur in the
female germline and that a negative selection of oocytes with long
repeats may explain the different instability behavior of the male and
female germlines.

Kovtun et al. (2000) followed the fate of the CAG trinucleotide repeat,
during transmission, in a transgene containing the exon 1 portion of the
human Huntington disease gene. Similar to humans, the mouse transmits
expansions predominantly through the male germline. However, the CAG
repeat size of the mutant human HD gene is different in male and female
progeny from identical fathers. Males predominantly expanded the repeat,
whereas females predominantly contracted the repeat. In contrast to the
classic definition of imprinting, CAG expansion is influenced by the
gender of the embryo. The authors hypothesized that there may be X- or
Y-encoded factors that influence repair or replication of DNA in the
embryo, and that gender dependence in the embryo may explain why
expansion in HD from premutation to disease primarily occurs through the
paternal line.

Yoon et al. (2003) performed single-molecule DNA analysis of testicular
germ cells isolated by laser capture microdissection from 2 HD patients,
showing that trinucleotide repeat expansion mutations were present
before the end of the first present meiotic division, and some mutations
were present even before meiosis began. Most of the larger Huntington
disease mutations were found in the postmeiotic cell population,
suggesting that expansions may continue to occur during meiosis and/or
after meiosis is complete.

Kennedy et al. (2003) showed dramatic mutation length increases (gains
of 16 to 1,000 CAG repeats) in human striatal cells early in the disease
course, most likely before the onset of pathologic cell loss. Studies of
knockin HD mice indicated that the size of the initial CAG repeat
mutation may influence both onset and tissue-specific patterns of
age-dependent, expansion-biased mutation length variability. Given that
CAG repeat length strongly correlates with clinical severity, Kennedy et
al. (2003) suggested that somatic increases of mutation length may play
a major role in the progressive nature and cell-selective aspects of
both adult-onset and juvenile-onset HD pathogenesis.

Cannella et al. (2005) reported a triplet size increase in an
intermediate-sized allele (34 CAG) of the huntingtin gene carried by a
lymphoblast cell culture after 30 passages. This finding demonstrated
that the huntingtin gene shows somatic as well as germline instability
and has a propensity for somatic CAG variation in human cells even with
repeat numbers under the expanded edge (i.e., intermediate alleles being
defined as containing between 29 and 35 CAG repeats). Factors
potentially cis acting with this particular mutation included a CCG
polymorphic stretch, deletion of the glutamic acid residue at position
2642, and the 4-codon segment between CAG and CCG polymorphisms.

Kovtun et al. (2007) demonstrated that the age-dependent somatic CAG
expansion associated with Huntington disease (Kennedy et al., 2003)
occurs in the process of removing oxidized base lesions, and is
remarkably dependent on the single-base excision repair enzyme
7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1; 601982). Both in vivo
and in vitro results supported a 'toxic oxidation' model in which OGG1
initiates an escalating oxidation-excision cycle that leads to
progressive age-dependent expansion. Kovtun et al. (2007) concluded that
age-dependent CAG expansion provides a direct molecular link between
oxidative damage and toxicity in postmitotic neurons through a DNA
damage response, and error-prone repair of single-strand breaks.

ANIMAL MODEL

Nasir et al. (1995) created a targeted disruption in exon 5 of Hdh, the
murine homolog of the HTT gene, using homologous recombination. They
found that homozygotes died before embryonic day 8.5 and initiated
gastrulation, but did not proceed to the formation of somites or to
organogenesis. Mice heterozygous for the mutation displayed increased
motor activity and cognitive deficits. Neuropathologic assessment of 2
heterozygous mice showed a significant neuronal loss in the subthalamic
nucleus. These studies showed that the HD gene is essential for
postimplantation development and that it may play an important role in
normal functioning of the basal ganglia.

To distinguish between 'loss-of-function' and 'gain-of-function' models
of HD, Duyao et al. (1995) inactivated the mouse Hdh by gene targeting.
Mice heterozygous for Hdh inactivation were phenotypically normal,
whereas homozygosity resulted in embryonic death. Homozygotes displayed
abnormal gastrulation at embryonic day 7.5 and were resorbing by day
8.5. The authors concluded that huntingtin is critical early in
embryonic development, before the emergence of the nervous system. That
Hdh inactivation did not mimic adult HD neuropathology suggested to the
authors that the human disease involves a gain of function.

Zeitlin et al. (1995) also used targeted gene disruption of Hdh and
found that mice nullizygous for the Hdh gene showed developmental
retardation and disorganization as embryos and died between days 8.5 and
10.5 of gestation. Based on the observation that the level of the
regionalized apoptotic cell death in the embryonic ectoderm, a layer
expressing the Hdh gene, was much higher than normal in the null
mutants, Zeitlin et al. (1995) proposed that huntingtin is involved in
processes counterbalancing the operation of an apoptotic pathway.

Hodgson et al. (1996) reported results of their studies designed to
rescue the embryonic lethality phenotype that results from targeted
disruption of the murine HD gene. They generated viable offspring that
were homozygous for the disrupted murine HD gene and that expressed
human huntingtin derived from a YAC transgene. These results indicated
that the YAC transgene was expressed prior to 7.5 days' gestation and
that the human huntingtin protein was functional in a murine background.

MacDonald et al. (1996) reviewed the work with targeted inactivation of
the mouse Hdh gene.

It is known that huntingtin plays a fundamental role in development,
since gene targeted Hd -/- mouse embryos died shortly after
gastrulation. Metzler et al. (2000) analyzed expression of huntingtin in
a variety of hematopoietic cell types, and in vitro hematopoiesis was
assessed using an Hd +/- and several Hd -/- embryonic stem (ES) cell
lines. Although wildtype and the 2 mutant cell lines formed primary
embryoid bodies (EBs) with similar efficiency, the number of
hematopoietic progenitors detected at various stages of the in vitro
differentiation were reduced in both of the heterozygous and the
homozygous ES cell lines examined. Expression analyses of hematopoietic
markers within the EBs revealed that primitive and definitive
hematopoiesis occurs in the absence of huntingtin. However, further
analysis using a suspension culture in the presence of hematopoietic
cytokines demonstrated a highly significant gene dosage-dependent
decrease in proliferation and/or survival of Hd +/- and Hd -/- cells.
Enrichment for the CD34+ (142230) cells within the EB confirmed that the
impairment is intrinsic to the hematopoietic cells. These observations
suggested that huntingtin expression is required for the generation and
expansion of hematopoietic cells and provides an alternative system in
which to assess the function of huntingtin.

Clabough and Zeitlin (2006) found that mice with targeted deletion of
the short CAG triplet repeat (7Q) in the Htt gene showed no gross
phenotypic differences compared to control littermates. However, adult
mice showed mild learning and memory deficits and slightly better motor
coordination compared to wildtype mice. Fibroblast cultures derived from
the 7Q-deletion mice had increased levels of ATP and senesced earlier
compared to wildtype fibroblasts. The findings indicated that the polyQ
stretch is not required for an essential function of HTT, but may be
required for modulating longevity in culture or modulating a function
involved in regulating energy homeostasis.

To determine whether caspase cleavage of HTT is a key event in the
neuronal dysfunction and selective neurodegeneration in HD, Graham et
al. (2006) generated YAC mice expressing caspase-3 (CASP3; 600636)- and
caspase-6 (CASP6; 601532)-resistant mutant human HTT. Mice expressing
mutant HTT resistant to cleavage by caspase-6, but not by caspase-3,
maintained normal neuronal function and did not develop
neurodegeneration. Furthermore, caspase-6-resistant mutant HTT mice were
protected against neurotoxicity induced by multiple stressors, including
NMDA, quinolinic acid, and staurosporine. Graham et al. (2006) concluded
that proteolysis of HTT at the caspase-6 cleavage site is a crucial and
rate-limiting step in the pathogenesis of HD.

Dietrich et al. (2009) inactivated the mouse Hdh gene in Wnt1 (164820)
cell lineages, which contribute to development of the midbrain,
hindbrain, granular cells of the cerebellum, and dorsal midline-derived
ependymal secretory structures, using the Cre-loxP system of
recombination. Conditional inactivation of the Hdh gene in Wnt1 cell
lineages resulted in congenital hydrocephalus, which was associated with
increase in CSF production by the choroid plexus, and abnormal
subcommissural organ.

Using synthetic antisense morpholinos to inhibit the translation of
huntingtin mRNA during early zebrafish development, Henshall et al.
(2009) determined the effects of huntingtin loss of function on the
developing nervous system, observing distinct defects in morphology of
neuromasts, olfactory placode, and branchial arches. There was impaired
formation of the anterior-most region of the neural plate as indicated
by reduced pre-placodal and telencephalic gene expression, with no
effect on mid- or hindbrain formation. The authors suggested a specific
'rate-limiting' role for huntingtin in formation of the telencephalon
and the pre-placodal region, and differing levels of requirement for
huntingtin function in specific nerve cell types.

Yamanaka et al. (2010) performed a comprehensive analysis of altered DNA
binding of multiple transcription factors using brains from R6/2 HD
mice, which express an N-terminal fragment of mutant huntingtin (Nhtt).
The authors observed a reduction of DNA binding of Brn2 (600494), a POU
domain transcription factor involved in differentiation and function of
hypothalamic neurosecretory neurons. Brn2 lost its function through 2
pathways, sequestration by mutant Nhtt and reduced transcription,
leading to reduced expression of hypothalamic neuropeptides. In
contrast, Brn1 (602480) was not sequestered by mutant Nhtt but was
upregulated in R6/2 brain, except in hypothalamus. Yamanaka et al.
(2010) concluded that functional suppression of Brn2 together with a
region-specific lack of compensation by Brn1 may mediate hypothalamic
cell dysfunction by mutant Nhtt.

Jiang et al. (2012) found that mutant Htt interacted with Sirt1 (604479)
and interfered with Sirt1 deacetylase activity in a mouse model of HD.
Overexpression of Sirt1 reversed neurodegeneration and molecular changes
observed in HD mice. Independently, Jeong et al. (2012) presented
similar findings, including interaction of Htt with Sirt1. They found
that interaction between Torc1 (CRTC1; 607536) and Creb (123810) had a
crucial role in Sirt1-mediated reversal of mutant Htt effects.

For a discussion of animal models of Huntington disease, see ANIMAL
MODEL section in 143100.

*FIELD* AV
.0001
HUNTINGTON DISEASE
HTT, (CAG)n EXPANSION

Huntington disease (HD; 143100) is caused by expansion of a polymorphic
trinucleotide repeat (CAG)n, encoding glutamine, located in the
N-terminal coding region of the HTT gene. In normal individuals, the
range of repeat numbers is 9 to 36. In those with HD, the repeat number
is above 37 (Duyao et al., 1993).

The trinucleotide repeat expansion was identified in affected members of
75 families with HD by the Huntington's Disease Collaborative Research
Group (1993). The families came from a variety of ethnic backgrounds and
demonstrated a variety of 4p16.3 haplotypes.

Gellera et al. (1996) noted that the unstable (CAG)n repeat lies
immediately upstream from a moderately polymorphic polyproline-encoding
(CCG)n repeat. They noted further that a number of reports in the
literature indicated that in normal subjects the number of (CAG)n
repeats ranges from 9 to 36, while in HD patients it ranges from 37 to
100. The downstream (CCG)n repeat may vary in size between 7 and 12
repeats in both affected and normal individuals. They reported the
occurrence of a CAA trinucleotide deletion (nucleotides 433-435) in HD
chromosomes in 2 families that, because of its position within the
conventional antisense primer hd447, hampered HD mutation detection if
only the (CAG)n tract were amplified. Therefore, Gellera et al. (1996)
stressed the importance of using a series of 3 diagnostic PCR reactions:
one that amplified the (CAG)n tract alone, one that amplified the (CCG)n
tract alone, and one that amplified the whole region.

*FIELD* SA
Bates et al. (1992); Gilliam et al. (1987); Zuo et al. (1992)
*FIELD* RF
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*FIELD* CN
George E. Tiller - updated: 8/16/2013
Patricia A. Hartz - updated: 4/6/2012
Patricia A. Hartz - updated: 11/15/2011
Patricia A. Hartz - updated: 8/22/2011
George E. Tiller - updated: 2/8/2011
George E. Tiller - updated: 11/1/2010
George E. Tiller - updated: 8/6/2010
Matthew B. Gross - updated: 4/28/2010
George E. Tiller - updated: 11/4/2009
Cassandra L. Kniffin - updated: 11/2/2009

*FIELD* CD
Cassandra L. Kniffin: 9/8/2009

*FIELD* ED
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terry: 4/6/2012
mgross: 2/1/2012
terry: 11/15/2011
mgross: 8/24/2011
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