RBCC

Full text data of PSEN1

PSEN1 (AD3, PS1, PSNL1) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Presenilin-1; PS-1; 3.4.23.- (Protein S182; Presenilin-1 NTF subunit; Presenilin-1 CTF subunit; Presenilin-1 CTF12; PS1-CTF12)

UniProt P49768
ID PSN1_HUMAN Reviewed; 467 AA.
AC P49768; B2R6D3; O95465; Q14762; Q15719; Q15720; Q96P33; Q9UIF0;
read moreDT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 169.
DE RecName: Full=Presenilin-1;
DE Short=PS-1;
DE EC=3.4.23.-;
DE AltName: Full=Protein S182;
DE Contains:
DE RecName: Full=Presenilin-1 NTF subunit;
DE Contains:
DE RecName: Full=Presenilin-1 CTF subunit;
DE Contains:
DE RecName: Full=Presenilin-1 CTF12;
DE Short=PS1-CTF12;
GN Name=PSEN1; Synonyms=AD3, PS1, PSNL1;
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 [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), AND
RP VARIANTS AD3 LEU-146; ARG-163; GLU-246 AND VAL-286.
RC TISSUE=Brain;
RX PubMed=7596406; DOI=10.1038/375754a0;
RA Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G.,
RA Ikeda M., Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L.,
RA Foncin J.-F., Bruni A.C., Montesi M.P., Sorbi S., Rainero I.,
RA Pinessi L., Nee L., Chumakov I., Pollen D., Brookes A., Sanseau P.,
RA Polinsky R.J., Wasco W., da Silva H.A.R., Haines J.L.,
RA Pericak-Vance M.A., Tanzi R.E., Roses A.D., Fraser P.E., Rommens J.M.,
RA St George-Hyslop P.H.;
RT "Cloning of a gene bearing missense mutations in early-onset familial
RT Alzheimer's disease.";
RL Nature 375:754-760(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Blood, and Brain;
RX PubMed=8641442; DOI=10.1016/0014-5793(96)00054-3;
RA Sahara N., Yahagi Y., Takagi H., Kondo T., Okochi M., Usami M.,
RA Shirasawa T., Mori H.;
RT "Identification and characterization of presenilin I-467, I-463 and I-
RT 374.";
RL FEBS Lett. 381:7-11(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA Powell C.S., Gegg M.E., Palmer M.S.;
RT "Human presenilin 1 gene encodes an alternative protein-minilin.";
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Rowen L., Madan A., Qin S., Abbasi N., Dors M., Ratcliffe A.,
RA Madan A., Dickhoff R., Shaffer T., James R., Lasky S., Hood L.;
RT "Complete sequence of the gene for presenilin 1.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
RA Kang L., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B.;
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113.
RX PubMed=9070286; DOI=10.1006/bbrc.1996.6043;
RA Tsujimura A., Yasojima K., Hashimoto-Gotoh T.;
RT "Cloning of Xenopus presenilin-alpha and -beta cDNAs and their
RT differential expression in oogenesis and embryogenesis.";
RL Biochem. Biophys. Res. Commun. 231:392-396(1997).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 24-32, AND ALTERNATIVE SPLICING
RP (ISOFORMS 6 AND 7).
RC TISSUE=Megakaryocyte, and Platelet;
RX PubMed=8804415; DOI=10.1016/0014-5793(96)00845-9;
RA Vidal R., Ghiso J., Wisniewski T., Frangione B.;
RT "Alzheimer's presenilin 1 gene expression in platelets and
RT megakaryocytes. Identification of a novel splice variant.";
RL FEBS Lett. 393:19-23(1996).
RN [12]
RP PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320;
RP 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY,
RP AND CHARACTERIZATION OF GAMMA-SECRETASE COMPLEX.
RX PubMed=15274632; DOI=10.1021/bi0494976;
RA Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J.,
RA Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S.;
RT "Purification and characterization of the human gamma-secretase
RT complex.";
RL Biochemistry 43:9774-9789(2004).
RN [13]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=8574969; DOI=10.1038/nm0296-224;
RA Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D.,
RA Merriam D.E., Hollister R.D., Hallmark O.G., Mancini R.,
RA Felsenstein K.M., Hyman B.T., Tanzi R.E., Wasco W.;
RT "Alzheimer-associated presenilins 1 and 2: neuronal expression in
RT brain and localization to intracellular membranes in mammalian
RT cells.";
RL Nat. Med. 2:224-229(1996).
RN [14]
RP PROTEOLYTIC PROCESSING.
RX PubMed=9173929; DOI=10.1006/nbdi.1997.0129;
RA Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W.,
RA Zhang J., Diehl T., Levesque G., Fraser P., Haass C., Koo E.H.,
RA Seubert P., St George-Hyslop P.H., Teplow D.B., Selkoe D.J.;
RT "Presenilin proteins undergo heterogeneous endoproteolysis between
RT Thr291 and Ala299 and occur as stable N- and C-terminal fragments in
RT normal and Alzheimer brain tissue.";
RL Neurobiol. Dis. 3:325-337(1997).
RN [15]
RP PHOSPHORYLATION.
RX PubMed=9144240; DOI=10.1073/pnas.94.10.5349;
RA Walter J., Gruenberg J., Capell A., Pesold B., Schindzielorz A.,
RA Citron M., Mendla K., St George-Hyslop P.H., Multhaup G., Selkoe D.J.,
RA Haass C.;
RT "Proteolytic processing of the Alzheimer disease-associated
RT presenilin-1 generates an in vivo substrate for protein kinase C.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:5349-5354(1997).
RN [16]
RP CASPASE CLEAVAGE SITE, AND MUTAGENESIS OF ASP-345; ASP-373 AND
RP ASP-385.
RX PubMed=9485372; DOI=10.1021/bi972106l;
RA Gruenberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H.,
RA Haass C.;
RT "Alzheimer's disease associated presenilin-1 holoprotein and its 18-20
RT kDa C-terminal fragment are death substrates for proteases of the
RT caspase family.";
RL Biochemistry 37:2263-2270(1998).
RN [17]
RP INTERACTION WITH CTNNB1, AND SUBCELLULAR LOCATION.
RX PubMed=9738936; DOI=10.1016/S0014-5793(98)00886-2;
RA Murayama M., Tanaka S., Palacino J., Murayama O., Honda T., Sun X.,
RA Yasutake K., Nihonmatsu N., Wolozin B., Takashima A.;
RT "Direct association of presenilin-1 with beta-catenin.";
RL FEBS Lett. 433:73-77(1998).
RN [18]
RP INTERACTION WITH FLNA AND FLNB.
RX PubMed=9437013;
RA Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.;
RT "Interaction of presenilins with the filamin family of actin-binding
RT proteins.";
RL J. Neurosci. 18:914-922(1998).
RN [19]
RP FUNCTION, AND MUTAGENESIS OF MET-292.
RX PubMed=10545183; DOI=10.1021/bi9914210;
RA Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M.,
RA Loetscher H., Jacobsen H., Haass C.;
RT "Amyloidogenic function of the Alzheimer's disease-associated
RT presenilin 1 in the absence of endoproteolysis.";
RL Biochemistry 38:14600-14605(1999).
RN [20]
RP INTERACTION WITH MTCH1.
RX PubMed=10551805; DOI=10.1074/jbc.274.46.32543;
RA Xu X., Shi Y.-C., Wu X., Gambetti P., Sui D., Cui M.-Z.;
RT "Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein
RT interacting with the C terminus of presenilin-1.";
RL J. Biol. Chem. 274:32543-32546(1999).
RN [21]
RP FUNCTION.
RX PubMed=10593990; DOI=10.1074/jbc.274.51.36801;
RA Ray W.J., Yao M., Mumm J., Schroeter E.H., Saftig P., Wolfe M.,
RA Selkoe D.J., Kopan R., Goate A.M.;
RT "Cell surface presenilin-1 participates in the gamma-secretase-like
RT proteolysis of Notch.";
RL J. Biol. Chem. 274:36801-36807(1999).
RN [22]
RP INTERACTION WITH CTNND2.
RX PubMed=10037471; DOI=10.1046/j.1471-4159.1999.0720999.x;
RA Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H.,
RA Xu D., Liang Y., Rogaeva E.A., Ikeda M., Duthie M., Murgolo N.,
RA Wang L., VanderVere P., Bayne M.L., Strader C.D., Rommens J.M.,
RA Fraser P.E., St George-Hyslop P.H.;
RT "Presenilins interact with armadillo proteins including neural-
RT specific plakophilin-related protein and beta-catenin.";
RL J. Neurochem. 72:999-1008(1999).
RN [23]
RP FUNCTION, AND MUTAGENESIS OF ASP-257 AND ASP-385.
RX PubMed=10206644; DOI=10.1038/19077;
RA Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T.,
RA Selkoe D.J.;
RT "Two transmembrane aspartates in presenilin-1 required for presenilin
RT endoproteolysis and gamma-secretase activity.";
RL Nature 398:513-517(1999).
RN [24]
RP FUNCTION, AND MUTAGENESIS OF ASP-257 AND ASP-385.
RX PubMed=10899933; DOI=10.1046/j.1471-4159.2000.0750583.x;
RA Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W.,
RA Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T.;
RT "Aspartate mutations in presenilin and gamma-secretase inhibitors both
RT impair notch1 proteolysis and nuclear translocation with relative
RT preservation of notch1 signaling.";
RL J. Neurochem. 75:583-593(2000).
RN [25]
RP FUNCTION, AND MUTAGENESIS OF LEU-286.
RX PubMed=10811883; DOI=10.1073/pnas.100049897;
RA Kulic L., Walter J., Multhaup G., Teplow D.B., Baumeister R.,
RA Romig H., Capell A., Steiner H., Haass C.;
RT "Separation of presenilin function in amyloid beta-peptide generation
RT and endoproteolysis of Notch.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000).
RN [26]
RP FUNCTION, AND INTERACTION WITH CDH1.
RX PubMed=11226248; DOI=10.1073/pnas.041603398;
RA Baki L., Marambaud P., Efthimiopoulos S., Georgakopoulos A., Wen P.,
RA Cui W., Shioi J., Koo E., Ozawa M., Friedrich V.L., Robakis N.K.;
RT "Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits
RT cadherin/p120 association, and regulates stability and function of the
RT cadherin/catenin adhesion complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:2381-2386(2001).
RN [27]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=11987239; DOI=10.1006/bcmd.2002.0486;
RA Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L.,
RA Rothermund K., Sisodia S.S., Borregaard N., Corey S.J.;
RT "Identification of the presenilins in hematopoietic cells with
RT localization of presenilin 1 to neutrophil and platelet granules.";
RL Blood Cells Mol. Dis. 28:28-38(2002).
RN [28]
RP INTERACTION WITH HERPUD1.
RX PubMed=11799129; DOI=10.1074/jbc.M112372200;
RA Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R.,
RA Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B.,
RA Yanagisawa K., Komano H.;
RT "Endoplasmic reticulum stress-inducible protein, Herp, enhances
RT presenilin-mediated generation of amyloid beta-protein.";
RL J. Biol. Chem. 277:12915-12920(2002).
RN [29]
RP INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77;
RP 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, AND CHARACTERIZATION OF
RP VARIANTS AD3 VAL-79 AND LEU-82.
RX PubMed=12058025; DOI=10.1074/jbc.M112121200;
RA Nielsen A.L., Holm I.E., Johansen M., Bonven B., Jorgensen P.,
RA Jorgensen A.L.;
RT "A new splice variant of glial fibrillary acidic protein GFAPepsilon,
RT interacts with the presenilin proteins.";
RL J. Biol. Chem. 277:29983-29991(2002).
RN [30]
RP INTERACTION WITH CDH2, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP ASP-385.
RX PubMed=14515347; DOI=10.1002/jnr.10753;
RA Uemura K., Kitagawa N., Kohno R., Kuzuya A., Kageyama T.,
RA Chonabayashi K., Shibasaki H., Shimohama S.;
RT "Presenilin 1 is involved in maturation and trafficking of N-cadherin
RT to the plasma membrane.";
RL J. Neurosci. Res. 74:184-191(2003).
RN [31]
RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX.
RX PubMed=12679784; DOI=10.1038/ncb960;
RA Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.;
RT "Reconstitution of gamma-secretase activity.";
RL Nat. Cell Biol. 5:486-488(2003).
RN [32]
RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND
RP NCSTN.
RX PubMed=12740439; DOI=10.1073/pnas.1037392100;
RA Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S.,
RA Selkoe D.J.;
RT "Gamma-secretase is a membrane protein complex comprised of
RT presenilin, nicastrin, Aph-1, and Pen-2.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003).
RN [33]
RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8;
RA Hillman R.T., Green R.E., Brenner S.E.;
RT "An unappreciated role for RNA surveillance.";
RL Genome Biol. 5:R8.1-R8.16(2004).
RN [34]
RP PHOSPHORYLATION AT SER-310 AND SER-346, AND MUTAGENESIS OF SER-310 AND
RP SER-346.
RX PubMed=14576165; DOI=10.1074/jbc.M306653200;
RA Fluhrer R., Friedlein A., Haass C., Walter J.;
RT "Phosphorylation of presenilin 1 at the caspase recognition site
RT regulates its proteolytic processing and the progression of
RT apoptosis.";
RL J. Biol. Chem. 279:1585-1593(2004).
RN [35]
RP TOPOLOGY.
RX PubMed=15385547; DOI=10.1074/jbc.M407898200;
RA Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U.,
RA Rovelli G., Martoglio B.;
RT "Consensus analysis of signal peptide peptidase and homologous human
RT aspartic proteases reveals opposite topology of catalytic domains
RT compared with presenilins.";
RL J. Biol. Chem. 279:50790-50798(2004).
RN [36]
RP FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, AND MUTAGENESIS OF
RP TYR-256; ASP-257; ASP-385 AND TYR-389.
RX PubMed=15341515; DOI=10.1111/j.1471-4159.2004.02596.x;
RA Wrigley J.D., Nunn E.J., Nyabi O., Clarke E.E., Hunt P., Nadin A.,
RA De Strooper B., Shearman M.S., Beher D.;
RT "Conserved residues within the putative active site of gamma-secretase
RT differentially influence enzyme activity and inhibitor binding.";
RL J. Neurochem. 90:1312-1320(2004).
RN [37]
RP INTERACTION WITH CDH1 AND CTNNB1.
RX PubMed=16126725; DOI=10.1074/jbc.M507503200;
RA Serban G., Kouchi Z., Baki L., Georgakopoulos A., Litterst C.M.,
RA Shioi J., Robakis N.K.;
RT "Cadherins mediate both the association between PS1 and beta-catenin
RT and the effects of PS1 on beta-catenin stability.";
RL J. Biol. Chem. 280:36007-36012(2005).
RN [38]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [39]
RP FUNCTION OF PAL MOTIF, AND MUTAGENESIS OF PRO-433; ALA-434 AND
RP LEU-435.
RX PubMed=16305624; DOI=10.1111/j.1471-4159.2005.03548.x;
RA Wang J., Beher D., Nyborg A.C., Shearman M.S., Golde T.E., Goate A.;
RT "C-terminal PAL motif of presenilin and presenilin homologues required
RT for normal active site conformation.";
RL J. Neurochem. 96:218-227(2006).
RN [40]
RP REVIEW ON VARIANTS.
RX PubMed=8875251;
RA Cruts M., Hendriks L., Van Broeckhoven C.;
RT "The presenilin genes: a new gene family involved in Alzheimer disease
RT pathology.";
RL Hum. Mol. Genet. 5:1449-1455(1996).
RN [41]
RP REVIEW ON VARIANTS.
RX PubMed=9521418;
RX DOI=10.1002/(SICI)1098-1004(1998)11:3<183::AID-HUMU1>3.3.CO;2-M;
RA Cruts M., van Broeckhoven C.;
RT "Presenilin mutations in Alzheimer's disease.";
RL Hum. Mutat. 11:183-190(1998).
RN [42]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [43]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [44]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [45]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [46]
RP INVOLVEMENT IN ACNINV3.
RX PubMed=20929727; DOI=10.1126/science.1196284;
RA Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y.,
RA Qu T., Chen M., Sun M., Shen Y., Zhang X.;
RT "Gamma-secretase gene mutations in familial acne inversa.";
RL Science 330:1065-1065(2010).
RN [47]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND MASS
RP SPECTROMETRY.
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 [48]
RP VARIANTS AD3 THR-143 AND ALA-384.
RX PubMed=8634711; DOI=10.1093/hmg/4.12.2363;
RA Cruts M., Backhovens H., Wang S.-Y., van Gassen G., Theuns J.,
RA de Jonghe C., Wehnert A., de Voecht J., de Winter G., Cras P.,
RA Bruyland M., Datson N., Weissenbach J., den Dunnen J.T., Martin J.-J.,
RA Hendriks L., Van Broeckhoven C.;
RT "Molecular genetic analysis of familial early-onset Alzheimer's
RT disease linked to chromosome 14q24.3.";
RL Hum. Mol. Genet. 4:2363-2372(1995).
RN [49]
RP VARIANTS AD3 LEU-82; HIS-115; THR-139; ARG-163; THR-231; LEU-264;
RP VAL-392 AND TYR-410.
RX PubMed=8634712; DOI=10.1093/hmg/4.12.2373;
RA Campion D., Flaman J.-M., Brice A., Hannequin D., Dubois B.,
RA Martin C., Moreau V., Charbonnier F., Didierjean O., Tardieu S.,
RA Penet C., Puel M., Pasquier F., le Doze F., Bellis G., Calenda A.,
RA Heilig R., Martinez M., Mallet J., Bellis M., Clerget-Darpoux F.,
RA Agid Y., Frebourg T.;
RT "Mutations of the presenilin I gene in families with early-onset
RT Alzheimer's disease.";
RL Hum. Mol. Genet. 4:2373-2377(1995).
RN [50]
RP VARIANTS AD3 VAL-260; VAL-285 AND VAL-392.
RX PubMed=7651536; DOI=10.1038/376775a0;
RA Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M.,
RA Liang Y., Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S.,
RA Nacmias B., Piacentini S., Amaducci L., Chumakov I., Cohen D.,
RA Lannfelt L., Fraser P.E., Rommens J.M., St George-Hyslop P.H.;
RT "Familial Alzheimer's disease in kindreds with missense mutations in a
RT gene on chromosome 1 related to the Alzheimer's disease type 3 gene.";
RL Nature 376:775-778(1995).
RN [51]
RP VARIANTS AD3 VAL-139; VAL-146; TYR-163; THR-267; ALA-280 AND GLY-280.
RX PubMed=7550356;
RA Clark R.F., Hutton M., Fuldner R.A., Froelich S., Karran E.,
RA Talbot C., Crook R., Lendon C.L., Prihar G., He C., Korenblat K.,
RA Martinez A., Wragg M., Busfield F., Behrens M.I., Myers A., Norton J.,
RA Morris J., Mehta N., Pearson C., Lincoln S., Baker M., Duff K.,
RA Zehr C., Perez-Tur J., Houlden H., Ruiz A., Ossa J., Lopera F.,
RA Arcos M., Madrigal L., Collinge J., Humphreys C., Asworth T.,
RA Sarner S., Fox N.C., Harvey R., Kennedy A., Roques P.K., Cline R.T.,
RA Phillips C.A., Venter J.C., Forsel L., Axelman K., Lilius L.,
RA Johnston J., Cowburn R., Viitanen M., Winblad B., Kosik K.S.,
RA Haltia M., Poyhonen M., Dickson D., Mann D., Neary D., Snowden J.,
RA Lantos P., Lannfelt L., Rossor M.N., Roberts G.W., Adams M.D.,
RA Hardy J., Goate A.M.;
RT "The structure of the presenilin 1 (S182) gene and identification of
RT six novel mutations in early onset AD families.";
RL Nat. Genet. 11:219-222(1995).
RN [52]
RP VARIANTS AD3 PHE-96; ARG-163 AND THR-213.
RX PubMed=8733303; DOI=10.1016/0304-3940(96)12587-8;
RA Kamino K., Sato S., Sakaki Y., Yoshiiwa A., Nishiwaki Y., Takeda H.,
RA Tanabe H., Nishimura T., Li K., St George-Hyslop P.H., Miki T.,
RA Ogihara T.;
RT "Three different mutations of presenilin 1 gene in early-onset
RT Alzheimer's disease families.";
RL Neurosci. Lett. 208:195-198(1996).
RN [53]
RP VARIANT AD3 ASP-135.
RX PubMed=9225696; DOI=10.1002/ana.410420121;
RA Crook R., Ellis R., Shanks M., Thal L.J., Perez-Tur J., Baker M.,
RA Hutton M., Haltia T., Hardy J., Galasko D.;
RT "Early-onset Alzheimer's disease with a presenilin-1 mutation at the
RT site corresponding to the Volga German presenilin-2 mutation.";
RL Ann. Neurol. 42:124-128(1997).
RN [54]
RP VARIANT AD3 ALA-280.
RX PubMed=9298817;
RX DOI=10.1002/(SICI)1098-1004(1997)10:3<186::AID-HUMU2>3.3.CO;2-K;
RA Lendon C.L., Martinez A., Behrens I.M., Kosik K.S., Madrigal L.,
RA Norton J., Neuman R., Myers A., Busfield F., Wragg M., Arcos M.,
RA Arango-Viana J.C., Ossa J., Ruiz A., Goate A.M., Lopera F.;
RT "E280A PS-1 mutation causes Alzheimer's disease but age of onset is
RT not modified by ApoE alleles.";
RL Hum. Mutat. 10:186-195(1997).
RN [55]
RP VARIANTS AD3 THR-233 AND THR-278.
RX PubMed=9172170;
RA Kwok J.B.J., Taddei K., Hallupp M., Fisher C., Brooks W.S., Broe G.A.,
RA Hardy J., Fulham M.J., Nicholson G.A., Stell R.,
RA St George-Hyslop P.H., Fraser P.E., Kakulas B., Clarnette R.,
RA Relkin N., Gandy S.E., Schofield P.R., Martins R.N.;
RT "Two novel (M233T and R278T) presenilin-1 mutations in early-onset
RT Alzheimer's disease pedigrees and preliminary evidence for association
RT of presenilin-1 mutations with a novel phenotype.";
RL NeuroReport 8:1537-1542(1997).
RN [56]
RP VARIANT AD3 PRO-171.
RX PubMed=9833068;
RA Ramirez-Duenas M.G., Rogaeva E.A., Leal C.A., Lin C.,
RA Ramirez-Casillas G.A., Hernandez-Romo J.A., St George-Hyslop P.H.,
RA Cantu J.M.;
RT "A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family
RT with early onset Alzheimer disease.";
RL Ann. Genet. 41:149-153(1998).
RN [57]
RP VARIANT GLY-318.
RX PubMed=9851443; DOI=10.1002/ana.410440617;
RA Mattila K.M., Forsell C., Pirttila T., Rinne J.O., Lehtimaki T.,
RA Roytta M., Lilius L., Eerola A., St George-Hyslop P.H., Frey H.,
RA Lannfelt L.;
RT "The Glu318Gly mutation of the presenilin-1 gene does not necessarily
RT cause Alzheimer's disease.";
RL Ann. Neurol. 44:965-967(1998).
RN [58]
RP VARIANT GLY-318.
RX PubMed=9851450; DOI=10.1002/ana.410440624;
RA Aldudo J., Bullido M.J., Frank A., Valdivieso F.;
RT "Missense mutation E318G of the presenilin-1 gene appears to be a
RT nonpathogenic polymorphism.";
RL Ann. Neurol. 44:985-986(1998).
RN [59]
RP VARIANTS AD3 VAL-79; CYS-115 AND VAL-231, AND VARIANT GLY-318.
RX PubMed=9384602; DOI=10.1093/hmg/7.1.43;
RA Cruts M., van Duijn C.M., Backhovens H., van den Broeck M.,
RA Wehnert A., Serneels S., Sherrington R., Hutton M., Hardy J.,
RA St George-Hyslop P.H., Hofman A., van Broeckhoven C.;
RT "Estimation of the genetic contribution of presenilin-1 and -2
RT mutations in a population-based study of presenile Alzheimer
RT disease.";
RL Hum. Mol. Genet. 7:43-51(1998).
RN [60]
RP VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND
RP PRO-426.
RX PubMed=9521423;
RX DOI=10.1002/(SICI)1098-1004(1998)11:3<216::AID-HUMU6>3.3.CO;2-O;
RA Poorkaj P., Sharma V., Anderson L., Nemens E., Alonso M.E., Orr H.,
RA White J., Heston L., Bird T.D., Schellenberg G.D.;
RT "Missense mutations in the chromosome 14 familial Alzheimer's disease
RT presenilin 1 gene.";
RL Hum. Mutat. 11:216-221(1998).
RN [61]
RP VARIANT AD3 GLU-378.
RX PubMed=10200054;
RX DOI=10.1002/(SICI)1098-1004(1998)11:6<481::AID-HUMU13>3.3.CO;2-E;
RA Besancon R., Lorenzi A., Cruts M., Radawiec S., Sturtz F.,
RA Broussolle E., Chazot G., van Broeckhoven C., Chamba G.,
RA Vandenberghe A.;
RT "Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in
RT a French family with early-onset Alzheimer's disease and transmission
RT study by mismatch enhanced allele specific amplification.";
RL Hum. Mutat. 11:481-481(1998).
RN [62]
RP VARIANT AD3 LYS-139.
RX PubMed=9719376;
RA Dumanchin C., Brice A., Campion D., Hannequin D., Martin C.,
RA Moreau V., Agid Y., Martinez M., Clerget-Darpoux F., Frebourg T.;
RT "De novo presenilin 1 mutations are rare in clinically sporadic, early
RT onset Alzheimer's disease cases.";
RL J. Med. Genet. 35:672-673(1998).
RN [63]
RP VARIANT AD3 LEU-117.
RX PubMed=9507958;
RA Wisniewski T., Dowjat W.K., Buxbaum J.D., Khorkova O.,
RA Efthimiopoulos S., Kulczycki J., Lojkowska W., Wegiel J.,
RA Wisniewski H.M., Frangione B.;
RT "A novel Polish presenilin-1 mutation (P117L) is associated with
RT familial Alzheimer's disease and leads to death as early as the age of
RT 28 years.";
RL NeuroReport 9:217-221(1998).
RN [64]
RP VARIANTS AD3 LEU-169 AND GLN-436.
RX PubMed=9831473;
RA Taddei K., Kwok J.B., Kril J.J., Halliday G.M., Creasey H.,
RA Hallupp M., Fisher C., Brooks W.S., Chung C., Andrews C.,
RA Masters C.L., Schofield P.R., Martins R.N.;
RT "Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated
RT with very early onset Alzheimer's disease.";
RL NeuroReport 9:3335-3339(1998).
RN [65]
RP VARIANT GLY-318.
RX PubMed=9915968; DOI=10.1086/302200;
RA Dermaut B., Cruts M., Slooter A.J.C., van Gestel S., de Jonghe C.,
RA Vanderstichele H., Vanmechelen E., Breteler M.M., Hofman A.,
RA van Duijn C.M., van Broeckhoven C.;
RT "The Glu318Gly substitution in presenilin 1 is not causally related to
RT Alzheimer disease.";
RL Am. J. Hum. Genet. 64:290-292(1999).
RN [66]
RP VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147;
RP ARG-163; CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264;
RP ILE-390; VAL-392 AND TYR-410, AND VARIANT GLY-318.
RX PubMed=10441572; DOI=10.1086/302553;
RA Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S.,
RA Puel M., Thomas-Anterion C., Michon A., Martin C., Charbonnier F.,
RA Raux G., Camuzat A., Penet C., Mesnage V., Martinez M.,
RA Clerget-Darpoux F., Brice A., Frebourg T.;
RT "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
RT heterogeneity, and mutation spectrum.";
RL Am. J. Hum. Genet. 65:664-670(1999).
RN [67]
RP VARIANTS AD3 PHE-143 AND SER-436.
RX PubMed=10090481;
RX DOI=10.1002/(SICI)1098-1004(1999)13:3<256::AID-HUMU11>3.0.CO;2-P;
RA Palmer M.S., Beck J.A., Campbell T.A., Humphries C.B., Roques P.K.,
RA Fox N.C., Harvey R., Rossor M.N., Collinge J.;
RT "Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset
RT Alzheimer's disease in the UK.";
RL Hum. Mutat. 13:256-256(1999).
RN [68]
RP VARIANT AD3 ARG-209.
RX PubMed=10447269;
RX DOI=10.1002/(SICI)1098-1004(1999)14:1<90::AID-HUMU19>3.0.CO;2-S;
RA Sugiyama N., Suzuki K., Matsumura T., Kawanishi C., Onishi H.,
RA Yamada Y., Iseki E., Kosaka K.;
RT "A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene
RT in a Japanese family with presenile familial Alzheimer's disease.";
RL Hum. Mutat. 14:90-90(1999).
RN [69]
RP VARIANTS AD3 LEU-233; ARG-282 AND THR-409, AND VARIANT GLY-318.
RX PubMed=10533070;
RX DOI=10.1002/(SICI)1098-1004(199911)14:5<433::AID-HUMU10>3.0.CO;2-K;
RA Aldudo J., Bullido M.J., Valdivieso F.;
RT "DGGE method for the mutational analysis of the coding and proximal
RT promoter regions of the Alzheimer's disease presenilin-1 gene: two
RT novel mutations.";
RL Hum. Mutat. 14:433-439(1999).
RN [70]
RP VARIANT AD3 PRO-169.
RX PubMed=10025789;
RA Ezquerra M., Carnero C., Blesa R., Gelpi J.L., Ballesta F., Oliva R.;
RT "A presenilin 1 mutation (Ser169Pro) associated with early-onset AD
RT and myoclonic seizures.";
RL Neurology 52:566-570(1999).
RN [71]
RP VARIANT AD3 PRO-219.
RX PubMed=10208579;
RA Smith M.J., Gardner R.J., Knight M.A., Forrest S.M., Beyreuther K.,
RA Storey E., McLean C.A., Cotton R.G., Cappal R., Masters C.L.;
RT "Early-onset Alzheimer's disease caused by a novel mutation at codon
RT 219 of the presenilin-1 gene.";
RL NeuroReport 10:503-507(1999).
RN [72]
RP VARIANT AD3 ASN-116.
RX PubMed=10439444;
RA Romero I., Joergensen P., Bolwig G., Fraser P.E., Rogaeva E., Mann D.,
RA Havsager A.-M., Joergensen A.L.;
RT "A presenilin-1 Thr116Asn substitution in a family with early-onset
RT Alzheimer's disease.";
RL NeuroReport 10:2255-2260(1999).
RN [73]
RP VARIANTS AD3 VAL-79; LEU-105 AND VAL-139, AND VARIANT GLY-318.
RX PubMed=10631141; DOI=10.1086/302702;
RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J.,
RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.;
RT "High prevalence of pathogenic mutations in patients with early-onset
RT dementia detected by sequence analyses of four different genes.";
RL Am. J. Hum. Genet. 66:110-117(2000).
RN [74]
RP VARIANT AD3 SER-405.
RX PubMed=10644793; DOI=10.1136/jnnp.68.2.220;
RA Yasuda M., Maeda S., Kawamata T., Tamaoka A., Yamamoto Y., Kuroda S.,
RA Maeda K., Tanaka C.;
RT "Novel presenilin-1 mutation with widespread cortical amyloid
RT deposition but limited cerebral amyloid angiopathy.";
RL J. Neurol. Neurosurg. Psych. 68:220-223(2000).
RN [75]
RP VARIANT AD3 SER-92.
RX PubMed=11027672; DOI=10.1006/bbrc.2000.3646;
RA Lewis P.A., Perez-Tur J., Golde T.E., Hardy J.;
RT "The presenilin 1 C92S mutation increases abeta 42 production.";
RL Biochem. Biophys. Res. Commun. 277:261-263(2000).
RN [76]
RP VARIANT FRONTOTEMPORAL DEMENTIA PRO-113.
RX PubMed=11094121;
RA Raux G., Gantier R., Thomas-Anterion C., Boulliat J., Verpillat P.,
RA Hannequin D., Brice A., Frebourg T., Campion D.;
RT "Dementia with prominent frontotemporal features associated with L113P
RT presenilin 1 mutation.";
RL Neurology 55:1577-1578(2000).
RN [77]
RP ERRATUM, AND VARIANT AD3 GLU-431.
RA Ringman J.M., Jain V., Murrell J., Ghetti B., Cochran E.J.;
RL Hum. Genet. 109:242-242(2001).
RN [78]
RP VARIANT AD3 ALA-206.
RX PubMed=11710891; DOI=10.1001/jama.286.18.2257;
RA Athan E.S., Williamson J., Ciappa A., Santana V., Romas S.N.,
RA Lee J.H., Rondon H., Lantigua R.A., Medrano M., Torres M., Arawaka S.,
RA Rogaeva E., Song Y.-Q., Sato C., Kawarai T., Fafel K.C., Boss M.A.,
RA Seltzer W.K., Stern Y., St George-Hyslop P.H., Tycko B., Mayeux R.;
RT "A founder mutation in presenilin 1 causing early-onset Alzheimer
RT disease in unrelated Caribbean Hispanic families.";
RL JAMA 286:2257-2263(2001).
RN [79]
RP VARIANT AD3 SER-266.
RX PubMed=11920851; DOI=10.1002/ajmg.10250;
RA Matsubara-Tsutsui M., Yasuda M., Yamagata H., Nomura T., Taguchi K.,
RA Kohara K., Miyoshi K., Miki T.;
RT "Molecular evidence of presenilin 1 mutation in familial early onset
RT dementia.";
RL Am. J. Med. Genet. 114:292-298(2002).
RN [80]
RP VARIANT AD3 PRO-166.
RX PubMed=12048239; DOI=10.1073/pnas.112686799;
RA Moehlmann T., Winkler E., Xia X., Edbauer D., Murrell J., Capell A.,
RA Kaether C., Zheng H., Ghetti B., Haass C., Steiner H.;
RT "Presenilin-1 mutations of leucine 166 equally affect the generation
RT of the Notch and APP intracellular domains independent of their effect
RT on Abeta 42 production.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002).
RN [81]
RP VARIANT AD3 MET-174.
RX PubMed=12484344; DOI=10.1007/s10048-002-0136-6;
RA Bertoli-Avella A.M., Marcheco Teruel B., Llibre Rodriguez J.J.,
RA Gomez Viera N., Borrajero-Martinez I., Severijnen E.A., Joosse M.,
RA van Duijn C.M., Heredero Baute L., Heutink P.;
RT "A novel presenilin 1 mutation (L174 M) in a large Cuban family with
RT early onset Alzheimer disease.";
RL Neurogenetics 4:97-104(2002).
RN [82]
RP VARIANT AD3 VAL-271.
RX PubMed=12493737; DOI=10.1074/jbc.M211827200;
RA Kwok J.B.J., Halliday G.M., Brooks W.S., Dolios G., Laudon H.,
RA Murayama O., Hallupp M., Badenhop R.F., Vickers J., Wang R.,
RA Naslund J., Takashima A., Gandy S.E., Schofield P.R.;
RT "Presenilin-1 mutation L271V results in altered exon 8 splicing and
RT Alzheimer's disease with non-cored plaques and no neuritic
RT dystrophy.";
RL J. Biol. Chem. 278:6748-6754(2003).
RN [83]
RP VARIANT CMD1U GLY-333.
RX PubMed=17186461; DOI=10.1086/509900;
RA Li D., Parks S.B., Kushner J.D., Nauman D., Burgess D., Ludwigsen S.,
RA Partain J., Nixon R.R., Allen C.N., Irwin R.P., Jakobs P.M., Litt M.,
RA Hershberger R.E.;
RT "Mutations of presenilin genes in dilated cardiomyopathy and heart
RT failure.";
RL Am. J. Hum. Genet. 79:1030-1039(2006).
RN [84]
RP VARIANT GLY-318.
RX PubMed=18485326; DOI=10.1016/j.ajhg.2008.04.014;
RA Cornier A.S., Staehling-Hampton K., Delventhal K.M., Saga Y.,
RA Caubet J.-F., Sasaki N., Ellard S., Young E., Ramirez N., Carlo S.E.,
RA Torres J., Emans J.B., Turnpenny P.D., Pourquie O.;
RT "Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-
RT Levin syndrome.";
RL Am. J. Hum. Genet. 82:1334-1341(2008).
RN [85]
RP VARIANT CYS-315.
RX PubMed=21248752; DOI=10.1038/nature09639;
RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P.,
RA Davies H., Jones D., Lin M.L., Teague J., Bignell G., Butler A.,
RA Cho J., Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C.,
RA Jia M., Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A.,
RA Mudie L., Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S.,
RA Kahnoski R.J., Anema J., Tuveson D.A., Perez-Mancera P.A.,
RA Mustonen V., Fischer A., Adams D.J., Rust A., Chan-On W., Subimerb C.,
RA Dykema K., Furge K., Campbell P.J., Teh B.T., Stratton M.R.,
RA Futreal P.A.;
RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex
RT gene PBRM1 in renal carcinoma.";
RL Nature 469:539-542(2011).
RN [86]
RP VARIANTS AD3 ARG-134; ARG-163 AND VAL-262, AND VARIANT TYR-214.
RX PubMed=22503161; DOI=10.1016/j.neurobiolaging.2012.02.020;
RA Lohmann E., Guerreiro R.J., Erginel-Unaltuna N., Gurunlian N.,
RA Bilgic B., Gurvit H., Hanagasi H.A., Luu N., Emre M., Singleton A.;
RT "Identification of PSEN1 and PSEN2 gene mutations and variants in
RT Turkish dementia patients.";
RL Neurobiol. Aging 33:1850.E17-1850.E27(2012).
CC -!- FUNCTION: Probable catalytic subunit of the gamma-secretase
CC complex, an endoprotease complex that catalyzes the intramembrane
CC cleavage of integral membrane proteins such as Notch receptors and
CC APP (beta-amyloid precursor protein). Requires the other members
CC of the gamma-secretase complex to have a protease activity. May
CC play a role in intracellular signaling and gene expression or in
CC linking chromatin to the nuclear membrane. Stimulates cell-cell
CC adhesion though its association with the E-cadherin/catenin
CC complex. Under conditions of apoptosis or calcium influx, cleaves
CC E-cadherin promoting the disassembly of the E-cadherin/catenin
CC complex and increasing the pool of cytoplasmic beta-catenin, thus
CC negatively regulating Wnt signaling. May also play a role in
CC hematopoiesis.
CC -!- SUBUNIT: Homodimer. Component of the gamma-secretase complex, a
CC complex composed of a presenilin homodimer (PSEN1 or PSEN2),
CC nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal
CC complex is sufficient for secretase activity. Other components
CC which are associated with the complex include SLC25A64, SLC5A7,
CC PHB and PSEN1 isoform 3. Predominantly heterodimer of a N-terminal
CC (NTF) and a C-terminal (CTF) endoproteolytical fragment.
CC Associates with proteolytic processed C-terminal fragments C83 and
CC C99 of the amyloid precursor protein (APP). Associates with
CC NOTCH1. Associates with cadherin/catenin adhesion complexes
CC through direct binding to CDH1 or CDH2. Interaction with CDH1
CC stabilizes the complex and stimulates cell-cell aggregation.
CC Interaction with CDH2 is essential for trafficking of CDH2 from
CC the endoplasmic reticulum to the plasma membrane. Interacts with
CC CTNND2, CTNNB1, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL.
CC Interacts through its N-terminus with isoform 3 of GFAP. Interacts
CC with DOCK3 (By similarity).
CC -!- INTERACTION:
CC Q02410:APBA1; NbExp=4; IntAct=EBI-297277, EBI-368690;
CC P98084:Apba2 (xeno); NbExp=2; IntAct=EBI-297277, EBI-81669;
CC P05067:APP; NbExp=6; IntAct=EBI-297277, EBI-77613;
CC P05067-4:APP; NbExp=3; IntAct=EBI-297277, EBI-302641;
CC Q63053:Arc (xeno); NbExp=3; IntAct=EBI-2606326, EBI-5275794;
CC Q16543:CDC37; NbExp=3; IntAct=EBI-297277, EBI-295634;
CC P35222:CTNNB1; NbExp=2; IntAct=EBI-297277, EBI-491549;
CC Q9BQ95:ECSIT; NbExp=4; IntAct=EBI-297277, EBI-712452;
CC P14923:JUP; NbExp=4; IntAct=EBI-297277, EBI-702484;
CC Q92542:NCSTN; NbExp=3; IntAct=EBI-297277, EBI-998440;
CC P50502:ST13; NbExp=3; IntAct=EBI-297277, EBI-357285;
CC P49755:TMED10; NbExp=3; IntAct=EBI-297277, EBI-998422;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass
CC membrane protein. Golgi apparatus membrane; Multi-pass membrane
CC protein. Cell surface. Note=Bound to NOTCH1 also at the cell
CC surface. Colocalizes with CDH1/2 at sites of cell-cell contact.
CC Colocalizes with CTNNB1 in the endoplasmic reticulum and the
CC proximity of the plasma membrane. Also present in azurophil
CC granules of neutrophils.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=1; Synonyms=I-467;
CC IsoId=P49768-1; Sequence=Displayed;
CC Name=2; Synonyms=I-463;
CC IsoId=P49768-2; Sequence=VSP_005191;
CC Name=3; Synonyms=I-374;
CC IsoId=P49768-3; Sequence=VSP_005191, VSP_005192;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=4; Synonyms=Minilin;
CC IsoId=P49768-4; Sequence=VSP_007986, VSP_007987;
CC Name=5;
CC IsoId=P49768-5; Sequence=VSP_005192;
CC Name=6;
CC IsoId=P49768-6; Sequence=VSP_012288;
CC Name=7;
CC IsoId=P49768-7; Sequence=VSP_041440;
CC -!- TISSUE SPECIFICITY: Expressed in a wide range of tissues including
CC various regions of the brain, liver, spleen and lymph nodes.
CC -!- DOMAIN: The PAL motif is required for normal active site
CC conformation.
CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal
CC (NTF) and C-terminal (CTF) fragments of approximately 35 and 20
CC kDa, respectively. During apoptosis, the C-terminal fragment (CTF)
CC is further cleaved by caspase-3 to produce the fragment, PS1-
CC CTF12.
CC -!- PTM: After endoproteolysis, the C-terminal fragment (CTF) is
CC phosphorylated on serine residues by PKA and/or PKC.
CC Phosphorylation on Ser-346 inhibits endoproteolysis.
CC -!- DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-
CC onset form of Alzheimer disease. Alzheimer disease is a
CC neurodegenerative disorder characterized by progressive dementia,
CC loss of cognitive abilities, and deposition of fibrillar amyloid
CC proteins as intraneuronal neurofibrillary tangles, extracellular
CC amyloid plaques and vascular amyloid deposits. The major
CC constituent of these plaques is the neurotoxic amyloid-beta-APP
CC 40-42 peptide (s), derived proteolytically from the transmembrane
CC precursor protein APP by sequential secretase processing. The
CC cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved
CC products such as C31 derived from APP, are also implicated in
CC neuronal death. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Frontotemporal dementia (FTD) [MIM:600274]: A form of
CC dementia characterized by pathologic finding of frontotemporal
CC lobar degeneration, presenile dementia with behavioral changes,
CC deterioration of cognitive capacities and loss of memory. In some
CC cases, parkinsonian symptoms are prominent. Neuropathological
CC changes include frontotemporal atrophy often associated with
CC atrophy of the basal ganglia, substantia nigra, amygdala. In most
CC cases, protein tau deposits are found in glial cells and/or
CC neurons. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Cardiomyopathy, dilated 1U (CMD1U) [MIM:613694]: A
CC disorder characterized by ventricular dilation and impaired
CC systolic function, resulting in congestive heart failure and
CC arrhythmia. Patients are at risk of premature death. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A
CC chronic relapsing inflammatory disease of the hair follicles
CC characterized by recurrent draining sinuses, painful skin
CC abscesses, and disfiguring scars. Manifestations typically appear
CC after puberty. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase A22A family.
CC -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins
CC mutations;
CC URL="http://www.alzforum.org/res/com/mut/pre/default.asp";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PSEN1";
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DR EMBL; L42110; AAB46416.1; -; mRNA.
DR EMBL; L76517; AAB46370.1; -; mRNA.
DR EMBL; L76528; AAB46371.1; -; Genomic_DNA.
DR EMBL; L76519; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76520; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76521; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76522; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76523; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76524; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76525; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76526; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76527; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; U40379; AAB05894.1; -; mRNA.
DR EMBL; U40380; AAB05895.1; -; mRNA.
DR EMBL; AJ008005; CAA07825.1; -; mRNA.
DR EMBL; AF109907; AAC97960.1; -; Genomic_DNA.
DR EMBL; AF416717; AAL16811.1; -; mRNA.
DR EMBL; AK312531; BAG35430.1; -; mRNA.
DR EMBL; AC004858; AAF19253.1; -; Genomic_DNA.
DR EMBL; AC004858; AAF19254.1; -; Genomic_DNA.
DR EMBL; CH471061; EAW81092.1; -; Genomic_DNA.
DR EMBL; BC011729; AAH11729.1; -; mRNA.
DR EMBL; D84149; BAA20883.1; -; Genomic_DNA.
DR PIR; S58396; S58396.
DR PIR; S63683; S63683.
DR PIR; S63684; S63684.
DR RefSeq; NP_000012.1; NM_000021.3.
DR RefSeq; NP_015557.2; NM_007318.2.
DR RefSeq; XP_005267921.1; XM_005267864.1.
DR RefSeq; XP_005267922.1; XM_005267865.1.
DR RefSeq; XP_005267923.1; XM_005267866.1.
DR RefSeq; XP_005267924.1; XM_005267867.1.
DR UniGene; Hs.3260; -.
DR PDB; 2KR6; NMR; -; A=292-467.
DR PDBsum; 2KR6; -.
DR ProteinModelPortal; P49768; -.
DR SMR; P49768; 292-467.
DR DIP; DIP-1134N; -.
DR IntAct; P49768; 42.
DR MINT; MINT-88325; -.
DR STRING; 9606.ENSP00000326366; -.
DR BindingDB; P49768; -.
DR ChEMBL; CHEMBL2094135; -.
DR GuidetoPHARMACOLOGY; 2402; -.
DR MEROPS; A22.001; -.
DR TCDB; 1.A.54.1.1; the presenilin er ca(2+) leak channel (presenilin) family.
DR PhosphoSite; P49768; -.
DR DMDM; 1709856; -.
DR PaxDb; P49768; -.
DR PRIDE; P49768; -.
DR DNASU; 5663; -.
DR Ensembl; ENST00000261970; ENSP00000261970; ENSG00000080815.
DR Ensembl; ENST00000324501; ENSP00000326366; ENSG00000080815.
DR Ensembl; ENST00000344094; ENSP00000339523; ENSG00000080815.
DR Ensembl; ENST00000357710; ENSP00000350342; ENSG00000080815.
DR Ensembl; ENST00000394157; ENSP00000377712; ENSG00000080815.
DR Ensembl; ENST00000394164; ENSP00000377719; ENSG00000080815.
DR Ensembl; ENST00000553855; ENSP00000452242; ENSG00000080815.
DR Ensembl; ENST00000555386; ENSP00000450845; ENSG00000080815.
DR Ensembl; ENST00000557511; ENSP00000451429; ENSG00000080815.
DR GeneID; 5663; -.
DR KEGG; hsa:5663; -.
DR UCSC; uc001xnr.3; human.
DR CTD; 5663; -.
DR GeneCards; GC14P073603; -.
DR HGNC; HGNC:9508; PSEN1.
DR HPA; CAB006844; -.
DR HPA; HPA030760; -.
DR MIM; 104311; gene.
DR MIM; 600274; phenotype.
DR MIM; 607822; phenotype.
DR MIM; 613694; phenotype.
DR MIM; 613737; phenotype.
DR neXtProt; NX_P49768; -.
DR Orphanet; 275864; Behavioral variant of frontotemporal dementia.
DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR Orphanet; 387; Hidradenitis suppurativa.
DR Orphanet; 100070; Progressive non-fluent aphasia.
DR Orphanet; 100069; Semantic dementia.
DR PharmGKB; PA33855; -.
DR eggNOG; NOG237920; -.
DR HOVERGEN; HBG011375; -.
DR InParanoid; P49768; -.
DR KO; K04505; -.
DR OMA; EAQRKVS; -.
DR PhylomeDB; P49768; -.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR SignaLink; P49768; -.
DR ChiTaRS; PSEN1; human.
DR EvolutionaryTrace; P49768; -.
DR GeneWiki; PSEN1; -.
DR GenomeRNAi; 5663; -.
DR NextBio; 22006; -.
DR PMAP-CutDB; P49768; -.
DR PRO; PR:P49768; -.
DR ArrayExpress; P49768; -.
DR Bgee; P49768; -.
DR CleanEx; HS_PSEN1; -.
DR Genevestigator; P49768; -.
DR GO; GO:0016324; C:apical plasma membrane; IBA:RefGenome.
DR GO; GO:0030424; C:axon; IBA:RefGenome.
DR GO; GO:0005938; C:cell cortex; IBA:RefGenome.
DR GO; GO:0009986; C:cell surface; IBA:RefGenome.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0035253; C:ciliary rootlet; IBA:RefGenome.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:Ensembl.
DR GO; GO:0043198; C:dendritic shaft; IBA:RefGenome.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030426; C:growth cone; IBA:RefGenome.
DR GO; GO:0005887; C:integral to plasma membrane; IDA:HGNC.
DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IBA:RefGenome.
DR GO; GO:0045121; C:membrane raft; IBA:RefGenome.
DR GO; GO:0005743; C:mitochondrial inner membrane; IBA:RefGenome.
DR GO; GO:0031594; C:neuromuscular junction; IBA:RefGenome.
DR GO; GO:0043025; C:neuronal cell body; IBA:RefGenome.
DR GO; GO:0005640; C:nuclear outer membrane; IDA:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IBA:RefGenome.
DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005790; C:smooth endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0030018; C:Z disc; IBA:RefGenome.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IEA:InterPro.
DR GO; GO:0045296; F:cadherin binding; IBA:RefGenome.
DR GO; GO:0005262; F:calcium channel activity; IMP:UniProtKB.
DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI.
DR GO; GO:0000186; P:activation of MAPKK activity; IEA:Ensembl.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; TAS:HGNC.
DR GO; GO:0042640; P:anagen; IEA:Ensembl.
DR GO; GO:0000045; P:autophagic vacuole assembly; IEA:Ensembl.
DR GO; GO:0034205; P:beta-amyloid formation; IEA:Ensembl.
DR GO; GO:0050435; P:beta-amyloid metabolic process; IBA:RefGenome.
DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl.
DR GO; GO:0021870; P:Cajal-Retzius cell differentiation; IEA:Ensembl.
DR GO; GO:0001708; P:cell fate specification; IEA:Ensembl.
DR GO; GO:0016337; P:cell-cell adhesion; IMP:MGI.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:Ensembl.
DR GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl.
DR GO; GO:0015871; P:choline transport; IEA:Ensembl.
DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl.
DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl.
DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0001947; P:heart looping; IEA:Ensembl.
DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0015813; P:L-glutamate transport; IEA:Ensembl.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC.
DR GO; GO:0007613; P:memory; IEA:Ensembl.
DR GO; GO:0006839; P:mitochondrial transport; IEA:Ensembl.
DR GO; GO:0002573; P:myeloid leukocyte differentiation; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0050771; P:negative regulation of axonogenesis; IEA:Ensembl.
DR GO; GO:0007175; P:negative regulation of epidermal growth factor-activated receptor activity; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:2000059; P:negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0051444; P:negative regulation of ubiquitin-protein ligase activity; IEA:Ensembl.
DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0048666; P:neuron development; IEA:Ensembl.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:0007220; P:Notch receptor processing; TAS:HGNC.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0043085; P:positive regulation of catalytic activity; IDA:HGNC.
DR GO; GO:0050820; P:positive regulation of coagulation; IEA:Ensembl.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR GO; GO:0001921; P:positive regulation of receptor recycling; IEA:Ensembl.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0006486; P:protein glycosylation; IEA:Ensembl.
DR GO; GO:0016485; P:protein processing; IDA:HGNC.
DR GO; GO:0015031; P:protein transport; IEA:Ensembl.
DR GO; GO:0042325; P:regulation of phosphorylation; IDA:UniProtKB.
DR GO; GO:0043393; P:regulation of protein binding; IEA:Ensembl.
DR GO; GO:0060075; P:regulation of resting membrane potential; IEA:Ensembl.
DR GO; GO:0048167; P:regulation of synaptic plasticity; IEA:Ensembl.
DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl.
DR GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl.
DR GO; GO:0043589; P:skin morphogenesis; IEA:Ensembl.
DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IBA:RefGenome.
DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl.
DR GO; GO:0016080; P:synaptic vesicle targeting; IEA:Ensembl.
DR GO; GO:0002286; P:T cell activation involved in immune response; IEA:Ensembl.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0048538; P:thymus development; IEA:Ensembl.
DR InterPro; IPR002031; Pept_A22A_PS1.
DR InterPro; IPR001108; Peptidase_A22A.
DR InterPro; IPR006639; Preselin/SPP.
DR PANTHER; PTHR10202; PTHR10202; 1.
DR PANTHER; PTHR10202:SF7; PTHR10202:SF7; 1.
DR Pfam; PF01080; Presenilin; 1.
DR PRINTS; PR01072; PRESENILIN.
DR PRINTS; PR01073; PRESENILIN1.
DR SMART; SM00730; PSN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis;
KW Apoptosis; Cardiomyopathy; Cell adhesion; Complete proteome;
KW Direct protein sequencing; Disease mutation; Endoplasmic reticulum;
KW Golgi apparatus; Hydrolase; Membrane; Neurodegeneration;
KW Notch signaling pathway; Phosphoprotein; Polymorphism; Protease;
KW Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1 298 Presenilin-1 NTF subunit.
FT /FTId=PRO_0000025591.
FT CHAIN 299 467 Presenilin-1 CTF subunit.
FT /FTId=PRO_0000025592.
FT CHAIN 346 467 Presenilin-1 CTF12.
FT /FTId=PRO_0000236055.
FT TOPO_DOM 1 82 Cytoplasmic (Potential).
FT TRANSMEM 83 103 Helical; (Potential).
FT TOPO_DOM 104 132 Lumenal (Potential).
FT TRANSMEM 133 153 Helical; (Potential).
FT TOPO_DOM 154 160 Cytoplasmic (Potential).
FT TRANSMEM 161 181 Helical; (Potential).
FT TOPO_DOM 182 190 Lumenal (Potential).
FT TRANSMEM 191 211 Helical; (Potential).
FT TOPO_DOM 212 220 Cytoplasmic (Potential).
FT TRANSMEM 221 241 Helical; (Potential).
FT TOPO_DOM 242 243 Lumenal (Potential).
FT TRANSMEM 244 264 Helical; (Potential).
FT TOPO_DOM 265 380 Cytoplasmic (Potential).
FT TRANSMEM 381 401 Helical; (Potential).
FT TOPO_DOM 402 407 Lumenal (Potential).
FT TRANSMEM 408 428 Helical; (Potential).
FT TOPO_DOM 429 432 Cytoplasmic (Potential).
FT INTRAMEM 433 453 Helical; (Potential).
FT TOPO_DOM 454 467 Cytoplasmic (Potential).
FT REGION 322 450 Required for interaction with CTNNB1.
FT REGION 372 399 Required for interaction with CTNND2.
FT REGION 464 467 Interaction with MTCH1.
FT MOTIF 433 435 PAL.
FT COMPBIAS 94 97 Poly-Val.
FT COMPBIAS 171 174 Poly-Leu.
FT COMPBIAS 418 425 Poly-Leu.
FT ACT_SITE 257 257 Probable.
FT ACT_SITE 385 385 Probable.
FT SITE 291 292 Cleavage; alternate.
FT SITE 292 293 Cleavage; alternate.
FT SITE 298 299 Cleavage.
FT SITE 345 346 Cleavage; by caspase.
FT MOD_RES 43 43 Phosphoserine.
FT MOD_RES 310 310 Phosphoserine; by PKA.
FT MOD_RES 346 346 Phosphoserine; by PKC.
FT MOD_RES 367 367 Phosphoserine.
FT VAR_SEQ 26 29 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_005191.
FT VAR_SEQ 162 184 IHAWLIISSLLLLFFFSFIYLGE -> SMRHRSLLSTLFFL
FT WLGILVTVT (in isoform 4).
FT /FTId=VSP_007986.
FT VAR_SEQ 185 467 Missing (in isoform 4).
FT /FTId=VSP_007987.
FT VAR_SEQ 257 289 Missing (in isoform 7).
FT /FTId=VSP_041440.
FT VAR_SEQ 319 467 STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRA
FT AVQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATA
FT SGDWNTTIACFVAILIGLCLTLLLLAIFKKALPALPISITF
FT GLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINL
FT LSIAPMAPRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRN
FT GKPRGTVI (in isoform 3 and isoform 5).
FT /FTId=VSP_005192.
FT VAR_SEQ 319 376 Missing (in isoform 6).
FT /FTId=VSP_012288.
FT VARIANT 79 79 A -> V (in AD3; no effect on interaction
FT with GFAP).
FT /FTId=VAR_006413.
FT VARIANT 82 82 V -> L (in AD3; no effect on interaction
FT with GFAP).
FT /FTId=VAR_006414.
FT VARIANT 92 92 C -> S (in AD3).
FT /FTId=VAR_016214.
FT VARIANT 96 96 V -> F (in AD3).
FT /FTId=VAR_006415.
FT VARIANT 105 105 F -> L (in AD3).
FT /FTId=VAR_009208.
FT VARIANT 113 113 L -> P (in frontotemporal dementia).
FT /FTId=VAR_016215.
FT VARIANT 115 115 Y -> C (in AD3).
FT /FTId=VAR_006416.
FT VARIANT 115 115 Y -> H (in AD3).
FT /FTId=VAR_006417.
FT VARIANT 116 116 T -> N (in AD3).
FT /FTId=VAR_010120.
FT VARIANT 117 117 P -> L (in AD3).
FT /FTId=VAR_009209.
FT VARIANT 120 120 E -> D (in AD3).
FT /FTId=VAR_006418.
FT VARIANT 120 120 E -> K (in AD3).
FT /FTId=VAR_006419.
FT VARIANT 134 134 L -> R (in AD3; uncertain pathological
FT significance).
FT /FTId=VAR_070023.
FT VARIANT 135 135 N -> D (in AD3).
FT /FTId=VAR_010121.
FT VARIANT 139 139 M -> I (in AD3).
FT /FTId=VAR_006420.
FT VARIANT 139 139 M -> K (in AD3).
FT /FTId=VAR_010122.
FT VARIANT 139 139 M -> T (in AD3).
FT /FTId=VAR_006421.
FT VARIANT 139 139 M -> V (in AD3).
FT /FTId=VAR_006422.
FT VARIANT 143 143 I -> F (in AD3).
FT /FTId=VAR_006423.
FT VARIANT 143 143 I -> T (in AD3).
FT /FTId=VAR_006424.
FT VARIANT 146 146 M -> I (in AD3).
FT /FTId=VAR_006425.
FT VARIANT 146 146 M -> L (in AD3).
FT /FTId=VAR_006426.
FT VARIANT 146 146 M -> V (in AD3).
FT /FTId=VAR_006427.
FT VARIANT 147 147 T -> I (in AD3).
FT /FTId=VAR_010123.
FT VARIANT 163 163 H -> R (in AD3).
FT /FTId=VAR_006428.
FT VARIANT 163 163 H -> Y (in AD3).
FT /FTId=VAR_006429.
FT VARIANT 165 165 W -> C (in AD3).
FT /FTId=VAR_010124.
FT VARIANT 166 166 L -> P (in AD3; onset in adolescence).
FT /FTId=VAR_016216.
FT VARIANT 169 169 S -> L (in AD3).
FT /FTId=VAR_006430.
FT VARIANT 169 169 S -> P (in AD3).
FT /FTId=VAR_006431.
FT VARIANT 171 171 L -> P (in AD3).
FT /FTId=VAR_006432.
FT VARIANT 173 173 L -> W (in AD3).
FT /FTId=VAR_010125.
FT VARIANT 174 174 L -> M (in AD3).
FT /FTId=VAR_016217.
FT VARIANT 205 205 F -> L (in dbSNP:rs1042864).
FT /FTId=VAR_011876.
FT VARIANT 206 206 G -> A (in AD3).
FT /FTId=VAR_016218.
FT VARIANT 209 209 G -> R (in AD3).
FT /FTId=VAR_009210.
FT VARIANT 209 209 G -> V (in AD3).
FT /FTId=VAR_006433.
FT VARIANT 213 213 I -> T (in AD3).
FT /FTId=VAR_006434.
FT VARIANT 214 214 H -> Y (probable disease-associated
FT mutation found in a patient with
FT dementia).
FT /FTId=VAR_070024.
FT VARIANT 219 219 L -> P (in AD3).
FT /FTId=VAR_010126.
FT VARIANT 231 231 A -> T (in AD3).
FT /FTId=VAR_006435.
FT VARIANT 231 231 A -> V (in AD3).
FT /FTId=VAR_006436.
FT VARIANT 233 233 M -> L (in AD3).
FT /FTId=VAR_009211.
FT VARIANT 233 233 M -> T (in AD3).
FT /FTId=VAR_006437.
FT VARIANT 235 235 L -> P (in A3D).
FT /FTId=VAR_006438.
FT VARIANT 246 246 A -> E (in AD3).
FT /FTId=VAR_006439.
FT VARIANT 250 250 L -> S (in AD3).
FT /FTId=VAR_006440.
FT VARIANT 260 260 A -> V (in AD3).
FT /FTId=VAR_006441.
FT VARIANT 262 262 L -> F (in AD3).
FT /FTId=VAR_006442.
FT VARIANT 262 262 L -> V (in AD3).
FT /FTId=VAR_070025.
FT VARIANT 263 263 C -> R (in AD3).
FT /FTId=VAR_006443.
FT VARIANT 264 264 P -> L (in AD3).
FT /FTId=VAR_006444.
FT VARIANT 266 266 G -> S (in AD3).
FT /FTId=VAR_016219.
FT VARIANT 267 267 P -> S (in AD3).
FT /FTId=VAR_006445.
FT VARIANT 267 267 P -> T (in AD3).
FT /FTId=VAR_006446.
FT VARIANT 269 269 R -> G (in AD3).
FT /FTId=VAR_006447.
FT VARIANT 269 269 R -> H (in AD3).
FT /FTId=VAR_006448.
FT VARIANT 271 271 L -> V (in AD3).
FT /FTId=VAR_016220.
FT VARIANT 278 278 R -> T (in AD3).
FT /FTId=VAR_006449.
FT VARIANT 280 280 E -> A (in AD3).
FT /FTId=VAR_006450.
FT VARIANT 280 280 E -> G (in AD3).
FT /FTId=VAR_006451.
FT VARIANT 282 282 L -> R (in AD3).
FT /FTId=VAR_009212.
FT VARIANT 285 285 A -> V (in AD3).
FT /FTId=VAR_006452.
FT VARIANT 286 286 L -> V (in AD3).
FT /FTId=VAR_006453.
FT VARIANT 289 289 S -> C (in AD3).
FT /FTId=VAR_010127.
FT VARIANT 315 315 Y -> C (found in a renal cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_064747.
FT VARIANT 318 318 E -> G (in dbSNP:rs17125721).
FT /FTId=VAR_006454.
FT VARIANT 333 333 D -> G (in CMD1U).
FT /FTId=VAR_064902.
FT VARIANT 378 378 G -> E (in AD3).
FT /FTId=VAR_006455.
FT VARIANT 384 384 G -> A (in AD3).
FT /FTId=VAR_006456.
FT VARIANT 390 390 S -> I (in AD3).
FT /FTId=VAR_010128.
FT VARIANT 392 392 L -> V (in AD3).
FT /FTId=VAR_006457.
FT VARIANT 396 396 A -> T (in AD3; uncertain pathological
FT significance).
FT /FTId=VAR_070026.
FT VARIANT 405 405 N -> S (in AD3).
FT /FTId=VAR_010129.
FT VARIANT 409 409 A -> T (in AD3).
FT /FTId=VAR_009213.
FT VARIANT 410 410 C -> Y (in AD3; dbSNP:rs661).
FT /FTId=VAR_006458.
FT VARIANT 426 426 A -> P (in AD3).
FT /FTId=VAR_006459.
FT VARIANT 431 431 A -> E (in AD3).
FT /FTId=VAR_025605.
FT VARIANT 436 436 P -> Q (in AD3; dbSNP:rs28930977).
FT /FTId=VAR_006460.
FT VARIANT 436 436 P -> S (in AD3).
FT /FTId=VAR_008141.
FT MUTAGEN 66 72 Missing: No effect on interaction with
FT GFAP.
FT MUTAGEN 76 77 KY->AA: No effect on interaction with
FT GFAP.
FT MUTAGEN 82 83 VI->EE: Loss of interaction with GFAP.
FT MUTAGEN 82 82 V->K,E: Loss of interaction with GFAP.
FT MUTAGEN 84 85 ML->EE: Loss of interaction with GFAP.
FT MUTAGEN 256 256 Y->F: Alters gamma-secretase cleavage
FT specificity. Increased production of
FT amyloid beta(42). No effect on enzymatic
FT activity.
FT MUTAGEN 257 257 D->A: Loss of endoproteolytic cleavage;
FT reduces production of amyloid beta in APP
FT processing and of NICD in NOTCH1
FT processing.
FT MUTAGEN 257 257 D->E: Abolishes gamma-secretase activity.
FT Reduces production of amyloid beta in APP
FT processing. Accumulation of full-length
FT PS1. Loss of binding of transition state
FT analog gamma-secretase inhibitor.
FT MUTAGEN 286 286 L->A,E,P,Q,R,W: Increases production of
FT amyloid beta in APP processing.
FT MUTAGEN 286 286 L->E,R: Reduces production of NICD in
FT NOTCH1 processing.
FT MUTAGEN 292 292 M->D: Loss of endoproteolytic cleavage.
FT MUTAGEN 310 310 S->A: Abolishes PKA-mediated
FT phosphorylation; no effect on caspase-
FT mediated cleavage.
FT MUTAGEN 345 345 D->N: Abolishes caspase cleavage.
FT MUTAGEN 346 346 S->A: Abolishes PKC-mediated
FT phosphorylation; no effect on PKA-
FT mediated phosphorylation.
FT MUTAGEN 346 346 S->E: Inhibits caspase-mediated cleavage.
FT Modulates progression of apoptosis.
FT MUTAGEN 373 373 D->N: No effect on caspase cleavage.
FT MUTAGEN 385 385 D->A: Loss of endoproteolytic cleavage.
FT Reduces production of amyloid beta in APP
FT processing. Disassembly of the N-
FT cadherin/PS1 complex at the cell surface.
FT Impairs CDH2 processing.
FT MUTAGEN 385 385 D->E: Abolishes gamma-secretase activity.
FT Reduces production of amyloid beta in APP
FT processing. Accumulation of full-length
FT PS1. Loss of binding of transition state
FT analog gamma-secretase inhibitor.
FT MUTAGEN 385 385 D->N: No effect on caspase cleavage.
FT MUTAGEN 389 389 Y->F: Alters gamma-secretase cleavage
FT specificity. Increased production of
FT amyloid beta(42). No effect on enzymatic
FT activity.
FT MUTAGEN 433 433 P->A: No effect on endoproteolytic
FT cleavage. No effect on APP nor NOTCH1
FT processing. Slightly increased
FT Abeta42/Abeta40 ratio.
FT MUTAGEN 433 433 P->D,F,L,N,V: No endoproteolytic
FT cleavage; no APP nor NOTCH1 processing.
FT No detectable Abetano detectable Abeta.
FT MUTAGEN 433 433 P->G: Very little endoproteolysis. Little
FT APP processing. No NOTCH1 processing.
FT Very low levels Abeta40 and no detectable
FT Abeta42.
FT MUTAGEN 434 434 A->C: Some loss of endoproteolytic
FT cleavage. Some loss of APP and NOTCH1
FT processing. Six-fold increase in
FT Abeta42/Abeta40 ratio.
FT MUTAGEN 434 434 A->D,I,L,V: No endoproteolytic cleavage.
FT No APP nor NOTCH1 processing. No
FT detectable Abeta.
FT MUTAGEN 434 434 A->G: No effect on endoproteolytic
FT cleavage. No effect on APP nor NOTCH1
FT processing. Reduced Abeta42/Abeta40
FT ratio.
FT MUTAGEN 435 435 L->A: No effect on endoproteolytic
FT cleavage. No effect on APP processing.
FT Impaired NOTCH1 processing. Greatly
FT reduced Abeta42/Abeta40 ratio.
FT MUTAGEN 435 435 L->F: No endoproteolytic cleavage. No APP
FT nor NOTCH1 processing. No detectable
FT Abeta.
FT MUTAGEN 435 435 L->G: Greatly reduced endoproteolytic
FT cleavage. Very little APP and NOTCH1
FT processing. Very low levels of Abeta40
FT and no detectable Abeta42.
FT MUTAGEN 435 435 L->I: No effect on endoproteolytic
FT cleavage. No effect on APP nor NOTCH1
FT processing.
FT MUTAGEN 435 435 L->V: No effect on endoproteolytic
FT cleavage. No effect on APP processing.
FT Impaired NOTCH1 processing. Some increase
FT in Abeta42/Abeta40 ratio.
FT CONFLICT 128 128 R -> G (in Ref. 7; AAL16811).
FT HELIX 293 299
FT STRAND 341 345
FT HELIX 356 368
FT TURN 383 385
FT HELIX 386 399
FT TURN 403 406
FT HELIX 407 428
FT STRAND 433 437
FT HELIX 442 449
FT TURN 450 453
FT HELIX 456 458
SQ SEQUENCE 467 AA; 52668 MW; 5E0F451EF82BCF20 CRC64;
MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR
QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE
DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI
YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY
LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE
GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP HRSTPESRAA
VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL
TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI
//

MIM 104311
*RECORD*
*FIELD* NO
104311
*FIELD* TI
*104311 PRESENILIN 1; PSEN1
;;PS1;;
S182
*FIELD* TX

CLONING

By linkage mapping, Sherrington et al. (1995) defined a minimal
read morecosegregating region containing the candidate gene for early-onset
Alzheimer disease type 3 (607822), which had been linked to chromosome
14q24.3. Of 19 different transcripts isolated, 1 transcript, designated
S182 by them, corresponded to a novel gene that encoded a 467-amino acid
protein. Human and murine amino acid sequences shared 92% identity.
Northern blot analysis identified a major 3-kb transcript expressed in
most regions of the human brain and in several peripheral tissues.
Structural analysis predicted an integral membrane protein with at least
7 transmembrane helical domains.

The Alzheimer's Disease Collaborative Group (1995) isolated full-length
cDNA clones for what they referred to as the PS1 gene. Contrary to
previous mapping data, they found that the gene maps just telomeric to
D14S77. The location at the 5-prime end of a specific YAC enabled them
to determine that the gene is oriented 5-prime/3-prime
centromere-telomere. Evidence for alternative splicing of the gene was
found.

Thinakaran et al. (1996) observed a polypeptide of approximately 43 kD
in cells transfected with full-length human PS1 cDNA. Using 2 highly
specific antibodies against nonoverlapping epitopes of presenilin-1,
they demonstrated that the preponderant PS1-related species that
accumulate in cultured mammalian cells and in the brains of rodents,
primates, and humans are approximately 27-kD N-terminal and about 17-kD
C-terminal derivatives. Epitope mapping analysis showed that PS1
cleavage occurred between amino acids 260 and 320. In brains of
transgenic mice expressing human PS1, the 17-kD and the 27-kD PS1
derivatives accumulate to saturable levels, and at about 1:1
stoichiometry, independent of transgene-derived mRNA. The authors
concluded that PS1 is subject to endoproteolytic processing in vivo. In
a British familial Alzheimer disease (FAD) pedigree, a PS1 variant with
a deletion of amino acids 290 to 319 (delE9) (104311.0012) was not
cleaved.

Rogaev et al. (1997) determined that alternative splicing produces
several PSEN1 transcripts which encode distinct protein sequences; exon
9 is specifically removed from PSEN1 transcripts in leukocytes but not
in most other tissues. PSEN1 transcripts are polyadenylated at 2
alternative sites.

Mercken et al. (1996) produced 7 monoclonal antibodies that react with 3
nonoverlapping epitopes on the N-terminal hydrophilic tail of PS1. The
monoclonal antibodies can detect the full-size 47-kD PS1 and the more
abundant 28-kD degradation product in membrane extracts from human brain
and human cell lines. PC12 cells transiently transfected with PS1
constructs containing 2 different Alzheimer mutations, M146V
(104311.0007) and A246E (104311.0003), failed to generate the 28-kD
degradation product in contrast to PC12 cells transfected with wildtype
PS1. Mercken et al. (1996) suggested that type 3 Alzheimer disease may
be the result of impaired proteolytic processing of PS1.

Laudon et al. (2005) determined that 9 of the 10 hydrophobic domains
(HDs) of human PS1 form transmembrane domains. The first hydrophilic
loop is oriented toward the lumen of the endoplasmic reticulum (ER),
whereas the N terminus and large hydrophilic loop, including HD7, are in
the cytosol. The C terminus is localized to the luminal side of the ER.
The catalytic aspartates, asp257 and asp385, are located within HD6 and
HD8, respectively.

GENE STRUCTURE

The Alzheimer's Disease Collaborative Group (1995) determined that the
open reading frame of PS1 is encoded by 10 exons. They concluded that
the PS2 gene (PSEN2; 600759), located on chromosome 1, has a very
similar gene structure.

Rogaev et al. (1997) reported that the PSEN1 gene spans at least 60 kb
and has 13 exons. The first 4 exons contain untranslated sequence, and
exons 1 and 2 represent alternate transcription initiation sites.

GENE FUNCTION

By in situ hybridization to tissues, Kovacs et al. (1996) demonstrated
that the expression patterns of PS1 and PS2 in the brain are similar to
each other and that messages for both are primarily detectable in
neuronal populations. Immunochemical analyses indicated that PS1 and PS2
are similar in size and localize to similar intracellular compartments,
such as the endoplasmic reticulum and Golgi complex. Takashima et al.
(1996) showed that in COS-7 cells overexpressing PS1, the protein is
localized to cellular membranes: plasma, endoplasmic reticulum, and
perinuclear. They observed that PS1 immunoreactivity in the plasma
membrane is concentrated in regions of cell-cell contact, suggesting
that PS1 may be a cell adhesion molecule.

Li et al. (1997) demonstrated that wildtype PS1 and PS2 localize to the
nuclear membrane and associate with interphase kinetochores and
centrosomes, and suggested that the proteins play a role in chromosome
organization and segregation. Li et al. (1997) stated that PS1 and PS2
localization to the membranes of the endoplasmic reticulum and Golgi is
not unexpected for overexpressed membrane proteins because these
locations are the sites of their synthesis and processing. They
developed specific PS1 and PS2 antibodies directed at the N-terminal and
loop domains. They discussed a pathogenic mechanism for FAD in which
mutant presenilins cause chromosome missegregation during mitosis,
resulting in apoptosis and/or trisomy 21 mosaicism. An alternative
hypothesis is that mutant presenilins not appropriately trafficked out
of the endoplasmic reticulum may interfere with normal APP processing.

Page et al. (1996) described the anatomic distribution of PS1 in the
brain and its expression in Alzheimer disease. Using in situ
hybridization in the rat forebrain, they showed that PS1 mRNA expression
is primarily in cortical and hippocampal neurons with less expression in
subcortical structures, in a regional pattern similar to that of amyloid
precursor protein APP695. Excitotoxic lesions led to loss of PS1 signal.
A neuronal pattern of expression of PS1 mRNA was also observed in the
human hippocampal formation. AD and control levels did not differ. PS1
was expressed to a greater extent in brain areas vulnerable to AD than
in areas spared in AD; however, PS1 expression was not sufficient to
mark vulnerable regions. Collectively, the data suggested to Page et al.
(1996) that the neuropathogenic process consequent to PS1 mutations
begins in neuronal cell populations.

- Gamma-secretase Activity

PS1 and PS2 are important determinants of gamma-secretase activity
responsible for proteolytic cleavage of amyloid precursor protein (APP;
104760) and NOTCH receptor proteins (see 190198). Gamma-secretase is a
multiprotein complex consisting of PS1 or PS2, nicastrin (605254), APH1
(see APH1A; 607629), and PEN2 (PSENEN; 607632). See review by De
Strooper (2003).

To clarify whether PS1, which has little or no homology to any known
aspartyl protease, is itself a transmembrane aspartyl protease, a
gamma-secretase cofactor, or helps to colocalize gamma-secretase and
APP, Li et al. (2000) reported photoaffinity labeling of PS1 (and PS2)
by potent gamma-secretase inhibitors that were designed to function as
transition-state analog inhibitors directed to the active site of an
aspartyl protease. Li et al. (2000) suggested that their observation
indicates that PS1 (and PS2) may contain the active site of
gamma-secretase. Interestingly, the intact, single-chain form of
wildtype PS1 was not labeled by an active site-directed photoaffinity
probe, suggesting that intact wildtype PS1 may be an aspartyl protease
zymogen. Upon gel exclusion chromatography, solubilized gamma-secretase
activity coeluted with PS1. Anti-PS1 antibody immunoprecipitated
gamma-secretase activity from the solubilized gamma-secretase
preparation. The authors interpreted the data as indicating that
gamma-secretase activity is catalyzed by a PS1-containing macromolecular
complex.

Kopan and Goate (2000) reviewed the evidence that presenilins are
founding members of a novel class of aspartyl proteases that hydrolyze
peptide bonds embedded within a membrane. The authors stated that
although PS1 and PS2 both appear to be gamma secretases, it is not clear
if the 2 enzymes normally have similar or different substrates, since
they reside in different complexes. They proposed that the key to the
regulation of cleavage may depend on the characterization of other
proteins that are present in the high molecular weight complex that
contains gamma-secretase activity.

Using coimmunoprecipitation and nickel affinity pull-down approaches,
Lee et al. (2002) showed that nicastrin and presenilin heterodimers
physically associated with APH1A and APH1B (607630) in vivo to form the
gamma-secretase complex that is required for the intramembrane
proteolysis of many membrane proteins, including APP and NOTCH. Francis
et al. (2002) observed a reduction in the levels of processed presenilin
and a reduction in gamma-secretase cleavage of beta-APP and Notch
substrates after RNA-mediated interference assays that inactivated Aph1,
Pen2, or nicastrin in cultured Drosophila cells. They concluded that
APH1, PEN2, and nicastrin are required for the activity and accumulation
of gamma-secretase. Using coimmunoprecipitation experiments, Steiner et
al. (2002) also showed that PEN2 is a critical component of
PSEN1/gamma-secretase and PSEN2/gamma-secretase complexes. They observed
that the absence of Psen1 or both Psen1 and Psen2 in mice resulted in
reduced PEN2 levels. Additionally, Steiner et al. (2002) reported that
downregulation of PEN2 by RNA interference was associated with reduced
presenilin levels, impaired nicastrin maturation, and deficient
gamma-secretase complex formation.

Gamma-secretase activity requires the formation of a stable, high
molecular mass protein complex that, in addition to the endoproteolyzed
fragmented form of presenilin, contains essential cofactors including
nicastrin, APH1, and PEN2. Takasugi et al. (2003) showed that Drosophila
APH1 increases the stability of Drosophila presenilin holoprotein in the
complex. Depletion of PEN2 by RNA interference prevented endoproteolysis
of presenilin and promoted stabilization of the holoprotein in both
Drosophila and mammalian cells, including primary neurons. Coexpression
of Drosophila Pen2 with Aph1 and nicastrin increased the formation of
presenilin fragments as well as gamma-secretase activity. Thus, Takasugi
et al. (2003) concluded that APH1 stabilizes the presenilin holoprotein
in the complex, whereas PEN2 is required for endoproteolytic processing
of presenilin and conferring gamma-secretase activity to the complex.

Using Western blot analysis and immunogold electron microscopy,
Pasternak et al. (2003) demonstrated that significant amounts of
nicastrin, Psen1, and App colocalized with Lamp1 (153330) in the outer
membranes of rat lysosomes. Furthermore, rat lysosomal membranes were
enriched in acidic gamma-secretase activity that was precipitable with
anti-nicastrin antibody.

Kaether et al. (2004) determined that the very C terminus of PS1
interacts with the transmembrane domain of nicastrin and may penetrate
into the membrane. Deletion of the last amino acid of PS1 completely
blocked gamma-secretase assembly and release of PS1 from the ER,
suggesting that unincorporated PS1 is actively retained within the ER.
Kaether et al. (2004) identified a hydrophobic stretch of amino acids
within the PS1 C terminus, distinct from the nicastrin-binding site,
that was required to retain unincorporated PS1 within the ER. Deletion
of the retention signal resulted in release of PS1 from the ER and
assembly of a nonfunctional gamma-secretase complex, suggesting that at
least part of the retention motif is required for PS1 function.

Cai et al. (2006) showed that PSEN1, via its loop region, binds
phospholipase D1 (PLD1; 602382) and recruits it to the Golgi/trans-Golgi
network (TGN). Overexpression of PLD1 in mouse neuroblastoma (N2a) cells
decreased gamma-secretase-mediated beta-amyloid generation, whereas
downregulation of PLD1 increased beta-amyloid production. Further
studies showed that PLD1 disrupted association of gamma-secretase
protein components, independent of PLD1 catalytic activity. In a
companion paper, Cai et al. (2006) found that overexpression of
catalytically active PLD1 promoted generation of beta-amyloid-containing
vesicles from the TGN. Although PLD1 enzymatic activity was decreased in
N2a cells with FAD PSEN1 mutations, overexpression of wildtype PLD1, but
not catalytically inactive PLD1, in these cells increased cell surface
delivery of beta-amyloid at axonal terminals and rescued impaired axonal
growth and neurite branching. The findings showed that PLD1 regulates
intracellular trafficking of beta-amyloid, distinct from its effect on
gamma-secretase activity.

- Role in Beta-amyloid Production

Duff et al. (1996) demonstrated that transgenic mice overexpressing
mutant, but not wildtype, presenilin-1 show a selective increase in
brain A-beta-42(43). These results indicated that the presenilin
mutations probably cause Alzheimer disease through a gain of deleterious
function that increases the amount of the deposited A-beta-42(43) in the
brain. While Davis et al. (1998) showed that there was no difference in
amyloid deposition between wildtype mice and those with loss of 1
functional PS1 allele, Qian et al. (1998) showed that mice carrying the
A246E mutation showed increased levels of A-beta-42(43), further
supporting the gain-of-function hypothesis.

Citron et al. (1997) noted that several lines of evidence strongly
supported the conclusion that progressive cerebral deposition of amyloid
beta protein is a seminal event in familial Alzheimer disease
pathogenesis. They carried out experiments to test the hypothesis that
FAD mutations act by fostering deposition of amyloid beta protein
particularly in the highly amyloidogenic 42-residue form described by
Jarrett et al. (1993). In transfected cell lines, mutant PS1 and PS2
resulted in a highly significant increase in beta-amyloid 42. The PS2
Volga mutation (N141I; 600759.0001) led to a 6- to 8-fold increase in
the production of total amyloid beta-42; none of the PS1 mutations had
such a dramatic effect, suggesting an intrinsic difference in the
effects of PS1 and PS2 mutations. Transgenic mice carrying mutant PS1
genes overproduced amyloid beta-42 in the brain, which was detectable at
2 to 4 months of age. Citron et al. (1997) stated that their combined in
vitro and in vivo data clearly demonstrated that the FAD-linked
presenilin mutations directly or indirectly altered the level of
gamma-secretase, but not of alpha- or beta-secretase, resulting in
increased amyloid beta-42 production which may lead to cerebral
beta-amyloidosis and AD.

Scheuner et al. (1996) showed that conditioned media from fibroblasts or
plasma of affected members of pedigrees with PS1/PS2-linked mutations
show a significant increase in the ratio of A-beta-1-42(43)/A-beta-1-40
relative to unaffected family members. Borchelt et al. (1996) found that
this ratio was uniformly elevated in the conditioned media of
independent N2a (a stable mouse neuroblastoma) cell lines transfected
with and expressing 3 FAD-linked PS1 variants relative to cells
expressing similar levels of wildtype PS1. Similarly, they found that
this ratio was elevated in brains of young transgenic mice coexpressing
a chimeric APP- and FAD-linked PS1 variant compared with brains of
transgenic mice expressing APP alone or coexpressing wildtype PS1 and
APP. The authors concluded that these results support the view that
mutations in PS1 cause AD by increasing the extracellular concentration
of amyloid-beta peptides 1-42(43), which foster amyloid-beta deposition.

Point mutations in the PS1 gene result in a selective increase in the
production of the amyloidogenic peptide amyloid-beta(1-42) by
proteolytic processing of APP. The possible role of PS1 in normal APP
processing was studied by De Strooper et al. (1998) in neuronal cultures
derived from PS1-deficient mouse embryos. They found that cleavage by
alpha- and beta-secretase of the extracellular domain of APP was not
affected by the absence of PS1, whereas cleavage by gamma-secretase of
the transmembrane domain of APP was prevented, causing C-terminal
fragments of APP to accumulate and a 5-fold drop in the production of
amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency
specifically decreased the turnover of the membrane-associated fragments
of APP. Thus, PS1 appears to facilitate a proteolytic activity that
cleaves the integral membrane domain of APP. The results indicated to
the authors that mutations in PS1 that manifest clinically cause a gain
of function, and that inhibition of PS1 activity is a potential target
for anti-amyloidogenic therapy in Alzheimer disease.

As outlined earlier, accumulation of amyloid-beta protein in the
cerebral cortex is an early and invariant event in the pathogenesis of
Alzheimer disease. The final step in the generation of A-beta from APP
is an apparently intramembranous proteolysis by gamma-secretase(s). The
most common cause of familial Alzheimer disease is mutation of the genes
encoding presenilins 1 and 2, which alters gamma-secretase activity to
increase the production of the highly amyloidogenic A-beta-42 isoform.
Moreover, deletion of presenilin-1 in mice greatly reduces
gamma-secretase activity, indicating that presenilin-1 mediates most of
the proteolytic event. Wolfe et al. (1999) reported that mutation of
either of 2 conserved transmembrane (TM) aspartate residues in
presenilin-1, asp257 (in TM6) and asp385 (in TM7), substantially reduced
A-beta production and increased the amounts of the carboxy-terminal
fragments of APP that are the substrates of gamma-secretase. They
observed these effects in 3 different cell lines as well as in cell-free
microsomes. Either of the asp-to-ala mutations also prevented the normal
endoproteolysis of presenilin-1 in the TM6-TM7 cytoplasmic loop. In a
functional presenilin-1 variant (carrying a deletion in exon 9;
104311.0012) that is associated with familial Alzheimer disease and
which does not require this cleavage, the asp385-to-ala mutation still
inhibited gamma-secretase activity. These results were taken to indicate
that the 2 transmembrane aspartate residues are critical for both
presenilin-1 endoproteolysis and gamma-secretase activity, and suggested
that presenilin-1 either is a unique diaspartyl cofactor for
gamma-secretase or is itself gamma-secretase, an autoactivated
intramembranous aspartyl protease.

Russo et al. (2000) demonstrated that a peculiar form of beta-amyloid
that is devoid of the first 10 amino acids accumulates in the brains of
patients carrying PS1 mutations and is more abundant than in subjects
affected by other types of Alzheimer disease. Russo et al. (2000) used
immunoblotting to detect various A-beta species present in brain tissue
from 17 subjects with sporadic AD, 11 with familial AD linked to
mutation in the PS1 gene, 2 with familial AD linked to the V717I
mutation in the APP gene, and 3 healthy controls. In the soluble
fraction prepared from all the diseased brains, A-beta
electrophoretically resolved into 3 bands of relative molecular mass of
4.5 kD, 4.2 kD, and 3.5 kD, which were not detectable in controls. The
4.5-kD species contains A-beta(1-40/42), the 4.2 kD species is
A-beta(py3-42), and the 3.5 kD species is A-beta(4-42) and
A-beta(py11-42). The smallest band is significantly more prominent in
subjects carrying PS1 mutations than in those with sporadic AD or in
those with a defective APP gene, indicating that amino-terminally
truncated forms are increased in PS1 mutants. Russo et al. (2000)
suggested that the overexpression of amino-terminally truncated amyloid
beta species indicates that not only is cleavage by gamma-secretase
affected by PS1 mutation, but that cleavage by beta-secretase is as
well.

Wilson et al. (2002) analyzed the production of several forms of
secreted and intracellular beta-amyloid forms in mouse cells lacking
PS1, PS2, or both proteins. Although most amyloid beta species were
abolished in PS1/PS2 -/- cells, the production of intracellular
A-beta-42 generated in the endoplasmic reticulum/intermediate
compartment was unaffected by the absence of these proteins, either
singly or in combination. Wilson et al. (2002) concluded that production
of this pool of amyloid beta occurs independently of PS1/PS2, and
therefore, another gamma-secretase activity must be responsible for
cleavage of APP within the early secretory compartments.

Phiel et al. (2003) showed that glycogen synthase kinase-3-alpha (GSK3A;
606784) is required for maximal production of the beta-amyloid-40 and
-42 peptides generated from the amyloid precursor protein by
presenilin-dependent gamma-secretase cleavage. In vitro, lithium, a
GSK3A inhibitor, blocked the production of the beta-amyloid peptides by
interfering with the gamma-secretase step. In mice expressing familial
AD-associated mutations in APP and PSEN1, lithium reduced the levels of
beta-amyloid peptides. Phiel et al. (2003) noted that GSK3A also
phosphorylates the tau protein (MAPT; 157140), the principal component
of neurofibrillary tangles in AD, and suggested that inhibition of GSK3A
may offer a new therapeutic approach to AD.

Pitsi and Octave (2004) found that expression of PS1 in insect cells
expressing the C-terminal fragment of human APP (C99) increased
production of beta-amyloid and proportionally increased intracellular
levels of C99. Using pulse-chase experiments, they showed that C99
accumulation resulted from increased C99 half-life. Inhibition of
gamma-secretase activity did not alter the ability of PS1 to increase
intracellular levels of C99, suggesting that binding of PS1 to C99 does
not necessarily lead to its immediate processing. Pitsi and Octave
(2004) concluded that PS1 contains a substrate docking site and that
processing of C99 is spatiotemporally regulated.

Lleo et al. (2004) used a fluorescence resonance energy transfer-based
assay (fluorescence lifetime imaging; FLIM) to analyze how NSAIDs
influence APP-PSEN1 interactions. In vitro and in vivo, ibuprofen,
indomethacin, or flurbiprofen, but not aspirin or naproxen, had an
allosteric effect on the conformation of PSEN1, which changed the
gamma-secretase activity on APP to increase production of the shorter
beta-38 cleavage product.

Kumar-Singh et al. (2006) studied amyloid A-beta and APP processing for
a set of 9 clinical PSEN mutations using an ELISA-based in vitro method.
All mutations significantly increased the ratio of A-beta-42 to
A-beta-40 in vitro by significantly decreasing A-beta-40 with
accumulation of APP C-terminal fragments, a sign of decreased PSEN
activity. A significant increase in absolute levels of A-beta-42 was
observed for only half of the mutations tested. They also showed that
age of onset of PSEN1-linked familial Alzheimer disease correlated
inversely with the ratio of A-beta-42/A-beta-40 and absolute levels of
A-beta-42, but directly with A-beta-40 levels. Together, the data of
Kumar-Singh et al. (2006) suggested that A-beta-40 may be protective by
perhaps sequestering the more toxic A-beta-42 and facilitating its
clearance.

- Role in Notch Signaling Pathway

Signaling through the Notch receptor proteins (see 190198), which is
involved in crucial cell fate decisions during development, requires
ligand-induced cleavage of Notch. This cleavage occurs within the
predicted transmembrane domain, releasing the Notch intracellular domain
(NICD), and is reminiscent of gamma-secretase-mediated cleavage of APP.
Deficiency of presenilin-1 inhibits processing of APP by gamma-secretase
in mammalian cells, and genetic interactions between Notch and PS1
homologs in C. elegans indicate that the presenilins may modulate the
Notch signaling pathway. De Strooper et al. (1999) reported that in
mammalian cells PS1 deficiency also reduces the proteolytic release of
NICD from a truncated Notch construct, thus identifying the specific
biochemical step of the Notch signaling pathway that is affected by PS1.
Moreover, several gamma-secretase inhibitors blocked this same step in
Notch processing, indicating that related protease activities are
responsible for cleavage within the predicted transmembrane domains of
Notch and APP. Thus, the targeting of gamma-secretase for the treatment
of Alzheimer disease may risk toxicity caused by reduced Notch
signaling.

Struhl and Greenwald (1999) showed that null mutations in the Drosophila
presenilin gene abolish Notch signal transduction and prevent its
intracellular domain from entering the nucleus. Furthermore, they
provided evidence that presenilin is required for the proteolytic
release of the intracellular domain from the membrane following
activation of Notch by ligand. In Drosophila, Struhl and Adachi (2000)
assayed the substrate requirements for presenilin-dependent processing
of Notch and other type I transmembrane proteins in vivo. They found
that presenilin-dependent cleavage does not depend critically on the
recognition of particular sequences in these proteins, but rather on the
size of the extracellular domain: the smaller the size, the greater the
efficiency of cleavage. Hence, Notch, beta-APP, and perhaps other
proteins may be targeted for presenilin-mediated transmembrane cleavage
by upstream processing events that sever the extracellular domain from
the rest of the protein.

Ye et al. (1999) described loss-of-function mutations in the Drosophila
presenilin gene that caused lethal Notch-like phenotypes such as
maternal neurogenic effects during embryogenesis, loss of lateral
inhibition within proneural cell clusters, and absence of wing margin
formation. They showed that presenilin is required for the normal
proteolytic production of carboxy-terminal Notch fragments that are
needed for receptor maturation and signaling, and that genetically it
acts upstream of both the membrane-bound form and the activated nuclear
form of Notch. The findings linked the role of presenilin in Notch
signaling to its effect on amyloid production in Alzheimer disease.

Takahashi et al. (2000) found that Mesp2 (605195) initiates the
establishment of rostrocaudal polarity by controlling 2 Notch signaling
pathways. Initially, Mesp2 activates a Ps1-independent Notch signaling
cascade to suppress Dll1 (see 602768) expression and specify the rostral
half of the somite. Ps1-mediated Notch signaling is required to induce
Dll1 expression in the caudal half of the somite. Therefore, Mesp2- and
Ps1-dependent activation of Notch signaling pathways might
differentially regulate Dll1 expression, resulting in the establishment
of the rostro-caudal polarity of somites.

Ikeuchi and Sisodia (2003) showed that the Notch ligands Delta-1
(606582) and Jagged-2 (602570) are subject to presenilin-dependent,
intramembranous gamma-secretase processing, resulting in the production
of soluble intracellular derivatives. The authors also showed that the
Delta-1 intracellular domain (DICD) that is generated by the
gamma-cleavage is transported into the nucleus and likely plays a role
in transcriptional events. The authors proposed that the Jagged-2
intracellular domain (JICD) would play a similar role.

- Interactions with Cadherin Proteins

Zhang et al. (1998) showed that presenilin-1 forms a complex with
beta-catenin (CTNNB1; 116806) in vivo that increases beta-catenin
stability. Pathogenic mutations in the PS1 gene reduce the ability of
presenilin-1 to stabilize beta-catenin and lead to increased degradation
of beta-catenin in the brains of transgenic mice. Moreover, beta-catenin
levels are markedly reduced in the brains of Alzheimer disease patients
with PS1 mutations. Loss of beta-catenin signaling increases neuronal
vulnerability to apoptosis induced by amyloid-beta precursor protein.
Thus, mutations in the PS1 gene may increase neuronal apoptosis by
altering the stability of beta-catenin, predisposing individuals to
early-onset Alzheimer disease.

Kang et al. (2002) showed that PS1 functions as a scaffold that rapidly
couples beta-catenin phosphorylation through 2 sequential kinase
activities independent of the Wnt (see 164820)-regulated axin
(603816)/CK1-alpha (600505) complex. Presenilin deficiency resulted in
increased beta-catenin stability in vitro and in vivo by disconnecting
the stepwise phosphorylation of beta-catenin, both in the presence and
absence of Wnt stimulation. These findings highlighted an aspect of
beta-catenin regulation outside of the canonical Wnt-regulated pathway
and a function of presenilin separate from intramembrane proteolysis.

In MDCK cells, Georgakopoulos et al. (1999) found that PS1 accumulated
at intercellular contacts where it colocalized with components of the
cadherin-based adherens junctions. PS1 fragments formed complexes with
E-cadherin (CDH1; 192090), beta-catenin, and alpha-catenin (CTNNA1;
116805), all components of adherens junctions. In confluent MDCK cells,
PS1 formed complexes with cell surface E-cadherin; disruption of
Ca(2+)-dependent cell-cell contacts reduced surface PS1 and the levels
of PS1-E-cadherin complexes. PS1 overexpression in human kidney cells
enhanced cell-cell adhesion. These data showed that PS1 incorporates
into the cadherin/catenin adhesion system and regulates cell-cell
adhesion. PS1 concentrates at intercellular contacts in epithelial
tissue; in brain, it forms complexes with both E- and N-cadherin
(114020) and concentrates at synaptic adhesions. That PS1 is a
constituent of the cadherin/catenin complex makes that complex a
potential target for PS1 mutations associated with familial Alzheimer
disease.

PS1 interacts with beta-catenin and promotes its turnover through
independent mechanisms. Consistent with this activity, Xia et al. (2001)
reported that PS1 is important in controlling epidermal cell
proliferation in vivo. PS1 knockout mice that were rescued through
neuronal expression of a human PS1 transgene developed spontaneous skin
cancers. PS1-null keratinocytes exhibited higher cytosolic beta-catenin
and beta-catenin/lymphoid enhancer factor (LEF1; 153245)-mediated
signaling. This effect could be reversed by reintroducing wildtype PS1,
but not a PS1 mutant active in Notch processing but defective in
beta-catenin binding. Nuclear beta-catenin protein can be detected in
tumors. Elevated beta-catenin/LEF signaling is correlated with
activation of its downstream target cyclin D1 (168461) and accelerated
entry from G1 into S phase of the cell cycle. The findings demonstrated
a function of PS1 in adult tissues, and suggested that deregulation of
the beta-catenin pathway contributes to the skin tumor phenotype.
Hartmann (2001) commented that PS1 has evolved 'from a mere
AD-associated protein into a multifunctional maverick sitting at the
heart of an expanding number of cellular signaling mechanisms.'

In rodent neuronal cell cultures, Marambaud et al. (2003) found that
Psen1 promoted an epsilon-cleavage of N-cadherin, resulting in the
production of a soluble cytosolic fragment termed N-Cad/CTF2. The
activity was stimulated by NMDA receptor agonists. Further studies
showed that N-Cad/CTF2 bound the transcription factor CREB-binding
protein (CBP; 600140) in the cytosol and promoted its degradation
through the ubiquitin-proteasome system, thus decreasing CREB-mediated
transcription. In human cell culture, FAD-associated mutant PSEN1
inhibited this activity, and the mutant proteins were unable to suppress
CREB-mediated transcription. Marambaud et al. (2003) suggested that
FAD-associated PSEN1 mutations may lead to a gain of transcriptional
function or at least transcriptional 'dysregulation.'

Teo et al. (2005) demonstrated that introduction of the PSEN1 mutant
L286V (104311.0004) protein into rat neural precursor cells inhibited
neurite outgrowth and neuronal differentiation by causing an increase in
beta-catenin-mediated signaling and transcription. Molecular inhibition
of beta-catenin/CBP-mediated transcription corrected these defects. Teo
et al. (2005) also found that L286V mutant cells contained high levels
of full-length N-cadherin and essentially no processed N-cadherin,
reflecting a decrease in PSEN1-mediated epsilon-cleavage, as reported by
Marambaud et al. (2003). Decreased processed N-cadherin was associated
with increased levels of CBP, but not increased levels of p300 (602700),
a similar protein that is part of the transcriptional complex. The
findings suggested that CBP and p300 play unique and distinct roles in
gene regulation. Teo et al. (2005) concluded that defective N-cadherin
processing in the PSEN1 mutant cells led to increased
beta-catenin/CBP-dependent transcription at the expense of
beta-catenin/p300-mediated transcription, with a resultant block in
neuronal differentiation. Within a broader context, Teo et al. (2005)
suggested that this increased transcription may decrease the rate at
which neuronal precursor cells differentiate into neurons in AD brains,
which may exacerbate the decline in neural plasticity in the disease.

- Other Functions

Kamal et al. (2000) demonstrated that the axonal transport of APP in
neurons is mediated by the direct binding of APP to the kinesin light
chain (600025) subunit of kinesin-I. Kamal et al. (2001) identified an
axonal membrane compartment that contains APP, beta-secretase (604252),
and presenilin-1. The fast anterograde axonal transport of this
compartment is mediated by APP and kinesin-I. Proteolytic processing of
APP can occur in the compartment in vitro and in vivo in axons. This
proteolysis generates amyloid-beta and a carboxy-terminal fragment of
APP, and liberates kinesin-I from the membrane. Kamal et al. (2001)
concluded that APP functions as a kinesin-I membrane receptor, mediating
the axonal transport of beta-secretase and presenilin-1, and that
processing of APP to amyloid-beta by secretases can occur in an axonal
membrane compartment transported by kinesin-I.

ERBB4 (600543) is a transmembrane receptor tyrosine that regulates cell
proliferation and differentiation. After binding its ligand heregulin
(142445) or activation of protein kinase C (see 176960) by TPA, the
ERBB4-ectodomain is cleaved by a metalloprotease. Ni et al. (2001)
reported a subsequent cleavage by gamma-secretase that releases the
ERBB4 intracellular domain from the membrane and facilitates its
translocation to the nucleus. Gamma-secretase cleavage was prevented by
chemical inhibitors or a dominant-negative presenilin. Inhibition of
gamma-secretase also prevented growth inhibition by heregulin. Ni et al.
(2001) concluded that gamma-secretase cleavage of ERBB4 may represent
another mechanism for receptor tyrosine kinase-mediated signaling.

Using binding assays with recombinant proteins, Nielsen et al. (2002)
determined that PS1 interacts with a splice variant of glial fibrillary
acidic protein (GFAP; 137780), which they called GFAP-epsilon. This
variant contains a unique C terminus which is required for interaction
with PS1. The originally identified GFAP protein, which they called
GFAP-alpha, did not interact with PS1. By introducing point mutations in
PS1 followed by yeast 2-hybrid analysis, they found that 2
nonconservative amino acid substitutions abolished interaction with
GFAP-epsilon, but 2 conservative substitutions, both associated with
Alzheimer disease, did not effect GFAP-epsilon binding. By transfection
in human embryonic kidney cells and in mouse neuroblastoma cells,
Nielsen et al. (2002) found that, while most GFAP-epsilon localized to
filamentous structures, a subpopulation colocalized with PS1 in the
perinuclear region and in cytoplasmic granules.

Katayama et al. (2001) and Yasuda et al. (2002) determined that
FAD-linked mutations in PSEN1 disturb the unfolded protein response
(UPR) which is activated in response to endoplasmic reticulum (ER)
stress caused by the accumulation of misfolded proteins in the lumen of
the ER. Cell culture studies showed that PSEN1 mutants inhibited
activation of ER stress transducers Ire1-alpha (604033), ATF6 (605537),
and PERK (604032). This leads to attenuation of the induction of the ER
chaperone GRP78/BiP (138120) and inhibition of the
translation-suppressing molecules eIF2-alpha (603907) and PERK. The
authors concluded that this complex perturbation of the UPR leads to
further accumulation of proteins in the ER, subsequently increasing
vulnerability to ER stress. The FAD-linked PSEN1 mutations thus appear
to result in a gain of function.

Tu et al. (2006) showed that recombinant presenilins, but not PSEN1 with
the M146V mutation or PSEN2 with the N141I mutation, formed
low-conductance cation-permeable channels in planar lipid bilayers
following expression in insect cells. Embryonic fibroblasts from mice
lacking both Psen1 and Psen2 had Ca(2+) signaling defects due to leakage
from the ER, and the deficient calcium signaling in these cells could be
rescued by expression of wildtype PSEN1 or PSEN2, but not by expression
of PSEN1 with the M146V mutation or PSEN2 with the N141I mutation. The
ER Ca(2+) leak function of presenilins was independent of their
gamma-secretase activities. Tu et al. (2006) proposed that presenilins
have a Ca(2+) signaling function, supporting the connection between
deranged neuronal Ca(2+) signaling and Alzheimer disease.

Landman et al. (2006) demonstrated that dysregulation of the TRPM7
(605692)-associated Mg(2+)-inhibited cation channel underlies ion
channel dysfunction in PSEN1 FAD-mutant cells. The channel deficits were
restored by the addition of phosphatidylinositol 4,5-bisphosphate
(PIP2), suggesting that an imbalance in PIP2 metabolism may be a factor
in disease pathogenesis.

Zhang et al. (2009) used a genetic approach to inactivate presenilins
conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons
of the hippocampal Schaeffer-collateral pathway. They showed that
long-term potentiation induced by theta-burst stimulation is decreased
after presynaptic but not postsynaptic deletion of presenilins.
Moreover, they found that presynaptic but not postsynaptic inactivation
of presenilins alters short-term plasticity and synaptic facilitation.
The probability of evoked glutamate release, measured with the
open-channel NMDA (N-methyl-D-aspartate) receptor antagonist MK-801, is
reduced by presynaptic inactivation of presenilins. Notably, depletion
of endoplasmic reticulum Ca(2+) stores by thapsigargin, or blockade of
Ca(2+) release from these stores by ryanodine receptor (see RYR3,
180903) inhibitors, mimics and occludes the effects of presynaptic
presenilin inactivation. Zhang et al. (2009) concluded that,
collectively, their results indicated a selective role for presenilins
in the activity-dependent regulation of neurotransmitter release and
long-term potentiation induction by modulation of intracellular Ca(2+)
release in presynaptic terminals, and further suggested that presynaptic
dysfunction might be an early pathogenic event leading to dementia and
neurodegeneration in Alzheimer disease.

MOLECULAR GENETICS

- Alzheimer Disease

Sherrington et al. (1995) identified 5 different missense mutations in
the PSEN1 gene that cosegregated with early-onset familial Alzheimer
disease type 3 (104311.0001-104311.0005). Because these changes occurred
in conserved domains of this gene and were not present in normal
controls, they were considered to be causative of disease.

Analyzing 40 families multiply affected by early-onset AD (under 60
years of age), in none of which any of the published mutations had been
found, the Alzheimer's Disease Collaborative Group (1995) found 6 novel
missense mutations in 13 families. None of these mutations occurred in
either elderly unaffected individuals from the families concerned,
control samples, or individuals with late-onset disease. The fact that
no nonsense mutations were identified suggested that PS1 mutations cause
alteration rather than loss of function of this protein. There was
evidence that some of the mutations caused earlier onset ages than
others. For example, 3 families with the M146V mutation had onset ages
between 36 and 40 years, whereas families with the C410Y (104311.0005)
and E280A (104311.0008) mutations had mean onset ages between 45 and 50
years. All 11 of the mutations described to that time altered residues
that are conserved in the mouse homologs of PS1 and PS2. Of these
mutations, 2 occurred at each of the codons 146, 163, and 280.
Furthermore, the M146V mutation (104311.0007) had occurred, apparently
independently, in 3 pedigrees with different ethnic backgrounds. There
also appeared to be a clustering of mutations in transmembrane domain 2.
Predictions of protein secondary structure for the presenilins indicated
to the authors that the proteins may have between 6 and 9 transmembrane
domains; for this reason, the proposed gene name 'seven transmembrane
protein' (STM) seemed unwise. Wasco et al. (1995) added 2 more novel PS1
mutations, bringing the total to 13.

Sherrington et al. (1995) pointed out that the AD3 locus is associated
with the most aggressive form of Alzheimer disease, suggesting that
mutations at the locus affect a biologically fundamental process. Clark
et al. (1996) and St. George-Hyslop et al. (1996) reviewed the role of
PS1 and PS2 in familial early-onset Alzheimer disease. Clark et al.
(1996) tabulated mutations in the 2 genes, most of them in the PS1 gene.

In a systematic mutation analysis of all coding and 5-prime-noncoding
exons of PS1 and PS2 in a population-based epidemiologic series of 101
unrelated familial and sporadic presenile AD cases, Cruts et al. (1998)
identified 4 different PS1 missense mutations in 6 familial cases, 2 of
which were autosomal dominant. Three new mutations resulted in onset
ages above 55 years, with 1 segregating in an autosomal dominant family
with mean onset age of 64 years. One PS2 mutation was identified in a
sporadic case with onset age of 62 years. The data provided estimates
for PS1 and PS2 mutation frequencies in presenile AD of 6% and 1%,
respectively. In all 101 patients in this study, mutations in the
amyloid precursor protein gene had previously been excluded. When family
history was accounted for, mutation frequencies for PS1 were 9% in
familial cases and 18% in autosomal dominant cases. Further,
polymorphisms were detected in the promoter and the 5-prime noncoding
region of PS1 and in intronic and exonic sequences of PS2 that will be
useful in genetic association studies.

Gustafson et al. (1998) presented a 50-year history of a family with
Alzheimer disease linked to chromosome 14. The authors found 6 cases of
Alzheimer disease in 4 consecutive generations. All 6 affected cases
demonstrated the typical neurologic signs and symptoms of Alzheimer
disease. Cognitive decline began between 35 and 49 years of age.
Mutation analysis of the PSEN1 gene on chromosome 14 demonstrated a
met146-to-ile substitution (104311.0001).

Cruts and Van Broeckhoven (1998) counted 43 mutations that had been
identified in the PS1 gene that led to familial presenile AD (onset
before age 65 years). By contrast, only 3 mutations had been identified
in PS2. Poorkaj et al. (1998) identified 3 novel PS1 mutations in
early-onset AD. One of these mutations, ala426 to pro (104311.0014), was
the most C-terminal PS1 mutation identified to that time.

Dermaut et al. (1999) stated that 49 different mutations in the coding
region of the PSEN1 gene had been identified, making it the most
frequently mutated gene in early-onset (onset age less than 65 years)
Alzheimer disease. A glu318-to-gly (E318G) substitution was identified
in the PSEN1 gene by several workers in familial AD cases with onset
ages of 35 to 64 years. In an extensive study, Dermaut et al. (1999)
came to the conclusion, however, that the E318G change was not causally
related to either AD or other types of dementia. They found the mutation
in heterozygous state in 4.1% of controls. They granted that it could
not be excluded that the mutation was associated with dementia in
homozygous state; however, there was no evidence supporting autosomal
recessive inheritance in familial AD. Goldman et al. (2005) reported 2
unrelated patients with presenile dementia who carried the E318G change.
However, genetic analysis of family members of the first patient showed
that an unaffected family member carried the change and 1 affected
member did not. Goldman et al. (2005) concluded that the E318G change is
a polymorphism with uncertain clinical significance.

Among 414 patients, 372 with AD and 42 asymptomatic persons with a
strong family history of AD, Rogaeva et al. (2001) identified 36 unique
mutations, including 21 novel mutations, in the PSEN1 gene in 48
patients (11%). As 90% of those with PSEN1 mutations were affected by
age 60 years, Rogaeva et al. (2001) concluded that PSEN1 screening in
early-onset AD would likely be successful.

Theuns et al. (2000) systematically screened 3.5 kb of the PSEN1
upstream region and found 4 novel polymorphisms. Genetic analysis
confirmed association of 2 of these polymorphisms with increased risk
for early-onset AD. In addition, they detected 2 different mutations in
early-onset AD cases, a -280C-G transversion and a -2818A-G transition,
the positions of which were numbered relative to the transcription
initiation site in exon 1A of PSEN1. Analysis of the mutant and wildtype
-280 variants using luciferase reporter gene expression in transiently
transfected neuroblastoma cells showed a 30% decrease in transcriptional
activity for the mutant -280G PSEN1 promoter variant compared with the
wildtype -280C variant. The data suggested that the increased risk for
early-onset AD associated with PSEN1 may result from genetic variations
in the regulatory region leading to altered expression levels of the
PSEN1 protein.

Lambert et al. (2001) studied 287 individuals with Alzheimer disease. In
addition, brain samples from a further 99 cases were studied. They
carried out genotype analysis at the polymorphic site at position -48 in
the PS1 gene promoter. Lambert et al. (2001) found an increased risk of
developing Alzheimer disease associated with the -48CC genotype (odds
ratio = 1.55; 95% CI 1.03 to 2.35). This appeared to be present in both
familial and sporadic cases and independent of the APOE4 (see 107741)
allele genotype. They also found that the A-beta load in the brains of
individuals with the -48CC genotype was significantly increased (p less
than 0.003).

Theuns et al. (2003) characterized the PSEN1 promoter by deletion
mapping, and analyzed the effect of the -22C and -22T (also known as
-48C/T based on a different numbering system) alleles on the
transcriptional activity of PSEN1 in a transient transfection system. A
neuron-specific 2-fold decrease in promoter activity for the -22C risk
allele was observed, which in homozygous individuals may lead to a
critical decrease in PSEN1 expression. The deletion mapping suggested
that the 13-bp region (-33/-20) spanning the -22C-T polymorphism may
harbor a binding site for a negative regulatory factor. Theuns et al.
(2003) suggested that this factor may have a higher affinity for the
-22C risk allele and may be strongly dependent on downstream sequences
for cell type-specific expression differences.

In affected members of 24 of 31 families with early-onset AD, Raux et
al. (2005) identified mutations in the PSEN1 gene. The mean age of
disease onset was 41.7 years. Combined with earlier studies, the authors
estimated that 66% of families with early-onset AD are attributable to
mutations in the PSEN1 gene.

- Dilated Cardiomyopathy

Li et al. (2006) hypothesized that, since presenilins are expressed in
the heart and are critical to cardiac development, mutations in
presenilin may also be associated with dilated cardiomyopathy (CMD1U;
613694). They evaluated a total of 315 index patients with dilated
cardiomyopathy for sequence variation in PSEN1 and PSEN2 (600759). A
novel heterozygous PSEN1 missense mutation (104311.0034) was identified
in 1 family, and a single heterozygous PSEN2 missense mutation
(600759.0008) was found in 2 other families. The PSEN1 mutation was
associated with complete penetrance and progressive disease that
resulted in the necessity of cardiac transplantation or in death.
Calcium signaling was altered in cultured skin fibroblasts from PSEN1
and PSEN2 mutation carriers.

- Familial Acne Inversa

Wang et al. (2010) identified a family segregating autosomal dominant
acne inversa-3 (ACNINV3; 613737) that was caused by a single-basepair
frameshift mutation in PSEN1 (104311.0038). Wang et al. (2010) showed
that heterozygous loss-of-function mutations in gamma-secretase
components PSEN1, PSENEN (607632), and NCSTN (605254) can cause familial
acne inversa. All Alzheimer disease/dementia-causing PSEN mutations
reported to that time had been missense mutations or in-frame deletions
or insertions. No affected individual studied by Wang et al. (2010) 50
years old or older had symptoms of Alzheimer disease or dementias.

GENOTYPE/PHENOTYPE CORRELATIONS

To investigate the influence of the glu280-to-ala presenilin-1 gene
mutation (E280A; 104311.0009) on regional cerebral perfusion, Johnson et
al. (2001) used SPECT scanning in 57 individuals from 1 large pedigree
with early-onset Alzheimer disease. The sample included 23 individuals
who were not PS1 mutation carriers and were cognitively normal, 18 who
were asymptomatic carriers, and 16 who were mutation carriers with a
clinical diagnosis of AD. Asymptomatic subjects with PS1 mutations
demonstrated reduced perfusion in comparison with the normal control
subjects in the hippocampal complex, anterior and posterior cingulate,
posterior parietal lobe, and anterior frontal lobe. The AD patients
demonstrated decreased perfusion in the posterior parietal and superior
frontal cortex in comparison with the normal control subjects. This
method discriminated 86% of the subjects in the 3 groups (p less than
0.0005). Johnson et al. (2001) concluded that regional cerebral
perfusion abnormalities based on SPECT are detectable before development
of the clinical symptoms of Alzheimer disease in carriers of the
glu280-to-ala PS1 mutation.

By genotype analysis of a large Colombian kindred with 109 carriers of
the E280A PS1 mutation, including 52 members with AD, Pastor et al.
(2003) found that those with at least 1 APOE4 allele were more likely to
develop AD at an earlier age than those without an APOE4 allele,
indicating an epistatic effect. Promoter APOE variants did not influence
either the onset or the duration of the disease.

Ringman et al. (2005) reported that 51 nondemented carriers of
FAD-linked PSEN1 mutations, ranging in age from 18 to 47 years,
performed worse on neuropsychologic tests compared to noncarriers. The
findings were consistent with early problems with memory, visuospatial
function, and executive function in patients who eventually develop AD.

Moonis et al. (2005) found that 6 presymptomatic carriers of FAD-linked
PSEN1 mutations, ranging in age from 34 to 55 years, had significantly
lower CSF beta-amyloid-42 levels compared to 6 noncarriers. Although the
authors stated that the mechanism for decline in CSF beta-amyloid is
uncertain, it has been suggested that aggregation of beta-amyloid in the
brain may leave less to circulate in the CSF; thus, decreased CSF levels
may reflect a high concentration of brain amyloid plaque accumulation.

EVOLUTION

Highly sequence-similar presenilin homologs are known in plants,
invertebrates and vertebrates. Ponting et al. (2002) searched various
databases to identify a family of proteins homologous to presenilins.
Members of this family, which they termed presenilin homologs, have
significant sequence similarities to presenilins and also possess 2
conserved aspartic acid residues within adjacent predicted transmembrane
segments. The presenilin homolog family was found throughout the
eukaryotes, in fungi as well as plants and animals, and in archaea. Five
presenilin homologs were detected in the human genome, of which 3
possess 'protease-associated' domains that are consistent with the
proposed protease function of presenilins. Based on these findings, the
authors proposed that presenilins and presenilin homologs represent
different sub-branches of a larger family of polytopic
membrane-associated aspartyl proteases.

ANIMAL MODEL

Trower et al. (1996) used knowledge of the pufferfish (Fugu rubripes)
genome to characterize the 14q24.3 region associated with autosomal
dominant early-onset Alzheimer disease. Identification of genes in
genomic regions associated with human diseases has been greatly
facilitated by the development of techniques such as exon trapping
(Buckler et al., 1991) and cDNA selection (Parimoo et al., 1991). Direct
sequencing of disease loci has also been shown to be one of the most
effective methods of gene detection, but it requires substantial
sequencing capacity. The pufferfish (Fugu rubripes) genome is 7- to
8-fold smaller than that of the human (approximately 400 Mb compared to
approximately 3,000 Mb), but it appears to contain a similar complement
of genes. Thus, a typical cosmid clone of genomic DNA might be expected
to contain 7 to 8 Fugu genes compared to only 1 human gene. Therefore,
sequencing regions of the Fugu genome syntenic with a particular human
disease region should accelerate the identification of candidate genes.
Trower et al. (1996) demonstrated that 3 genes that are linked to FOS
(164810) on 14q in the AD3 region have homologs in the Fugu genome
adjacent to the Fugu FOS gene: dihydrolipoamide succinyltransferase
(126063), S31iii125, and S20i15. In Fugu these 3 genes lie within a
12.4-kb region, compared to more than 600 kb in the human AD3 locus. The
results demonstrated the conservation of synteny between the genomes of
Fugu in man and highlighted the utility of this approach for
sequence-based identification of genes in human disease genomic regions.

To understand the normal function of PS1, Shen et al. (1997) generated a
targeted null mutation in the murine homolog of the gene. They found
that homozygous PS1-deficient mice died shortly after natural birth or
cesarean section. The skeleton of homozygous mutants was grossly
deformed. Hemorrhages occurred in the CNS of PS1-null mutants with
varying location, severity, and time of onset. The ventricular zone of
homozygous deficient brains was strikingly thinner by embryonic day
14.5, indicating an impairment in neurogenesis. Bilateral cerebral
cavitation caused by massive neuronal loss in specific subregions of the
mutant brain was prominent after embryonic day 16.5. These results
showed that PS1 is required for proper formation of the axial skeleton,
normal neurogenesis, and neuronal survival. Davis et al. (1998) and Qian
et al. (1998) generated mice deficient in PS1 and showed that the
defects caused by the deficiency, described in detail by Shen et al.
(1997), could be rescued by either wildtype human PS1 or by a human
FAD-linked PS1 variant (A246E; 104311.0003), suggesting that even the
mutant protein retains sufficient normal function in murine
embryogenesis.

Donoviel et al. (1999) generated PS2-null mice by gene targeting, and
subsequently, PS1/PS2 double-null mice. Mice homozygous for a targeted
null mutation in PS2 exhibited no obvious defects; however, loss of PS2
on a PS1-null background led to embryonic lethality at embryonic day
9.5. Embryos lacking both presenilins, and surprisingly, those carrying
only a single copy of PS2 on a PS1-null background, exhibited multiple
early patterning defects, including lack of somite segmentation,
disorganization of the trunk ventral neural tube, midbrain mesenchyme
cell loss, anterior neuropore closure delays, and abnormal heart and
second branchial arch development. In addition, Delta like-1 (176290)
and Hes5, 2 genes that lie downstream in the Notch pathway, were
misexpressed in presenilin double-null embryos. Hes5 expression was
undetectable in these mice, whereas Delta like-1 was expressed
ectopically in the neural tube and brain of double-null embryos.
Donoviel et al. (1999) concluded that the presenilins play a widespread
role in embryogenesis, that there is functional redundancy between PS1
and PS2, and that both vertebrate presenilins, like their invertebrate
homologs, are essential for Notch signaling.

Wittenburg et al. (2000) demonstrated that in addition to its role in
cell fate decisions in nonneuronal tissues, presenilin activity is
required in terminally differentiated neurons in vivo. Mutations in the
C. elegans presenilin genes sel-12 and hop-1 result in a defect in the
temperature memory of the animals. This defect is caused by the loss of
presenilin function in 2 cholinergic interneurons that display neurite
morphology defects in presenilin mutants. The morphology and function of
the affected neurons in sel-12 mutant animals can be restored by
expressing sel-12 only in these cells. The wildtype human PS1, but not
the familial Alzheimer disease (FAD) mutant PS1 A246E (104311.0003), can
also rescue these morphologic defects. As lin-12 mutant animals display
similar morphologic and functional defects to presenilin mutants,
Wittenburg et al. (2000) suggested that presenilins mediate their
activity in postmitotic neurons by facilitating Notch signaling.
Wittenburg et al. (2000) concluded that their data indicates
cell-autonomous and evolutionarily conserved control of neural
morphology and function by presenilins.

Leissring et al. (2000) generated mutant PS1 knockin (KI) mice by
replacing the endogenous mouse PS1 gene with human PS1 carrying the
M146V mutation (104311.0007). In the KI mice, PS1 protein was expressed
at physiologic levels and the endogenous tissue and cellular expression
pattern was maintained. They found that agonist-evoked calcium signals
were markedly potentiated in fibroblasts obtained from the KI mice. The
KI cells also showed deficits in capacitative calcium entry, i.e., the
influx of extracellular calcium triggered by depletion of intracellular
calcium store. Both of these alterations were caused by an abnormal
elevation of endoplasmic reticulum calcium stores.

Grilli et al. (2000) evaluated the relationship between PS1 and
excitotoxicity in 4 different experimental models of neurotoxicity by
using primary neurons from transgenic mice overexpressing a human
FAD-linked PS1 variant, L286V (104311.0004); transgenic mice
overexpressing human wildtype PS1; PS1 knockout mice; and wildtype mice
in which PS1 expression was knocked down by antisense treatment. The
results suggested that expression of FAD-linked PS1 variants increases
the vulnerability of neurons to a specific type of damage in which
excitotoxicity plays a relevant role. The data also supported the view
that reduction of endogenous PS1 expression results in neuroprotection.

To determine if amyloid beta peptide vaccinations had deleterious or
beneficial functional consequences, Morgan et al. (2000) tested 8 months
of amyloid beta vaccination in transgenic models of Alzheimer disease in
which mice develop learning deficits as amyloid accumulates. These
models included the PS1 mutant, generated by Duff et al. (1996), and the
APP mutant, generated by Hsiao et al. (1996), and a double transgenic
that contained both mutations. Morgan et al. (2000) showed that
vaccination with amyloid beta protected transgenic mice from the
learning and age-related memory deficits that normally occur in this
mouse model for Alzheimer disease. During testing for potential
deleterious effects of the vaccine, all mice performed superbly on the
radial-arm water-maze test of working memory. Later, at an age when
untreated transgenic mice showed memory deficits, the
amyloid-beta-vaccinated transgenic mice showed cognitive performance
superior to that of the control transgenic mice and, ultimately,
performed as well as nontransgenic mice. The amyloid beta-vaccinated
mice also had a partial reduction in amyloid burden at the end of the
study. Morgan et al. (2000) concluded that this therapeutic approach may
thus prevent and possibly treat Alzheimer dementia.

Handler et al. (2000) analyzed Psen1-deficient mouse embryos and
observed that lack of Psen1 leads to premature differentiation of neural
progenitor cells. They concluded that Psen1 has a role in a cell fate
decision between postmitotic neurons and neural progenitor cells.
Handler et al. (2000) also detected changes in expression of genes
involved in Notch signaling. They concluded that Psen1 controls neuronal
differentiation in association with the downregulation of Notch
signaling during neurogenesis.

Due to the perinatal lethality of Psen1 knockout mice, Yu et al. (2001)
developed a conditional knockout mouse (cKO), in which Psen1
inactivation was restricted to the postnatal forebrain. The cKO mice
were viable with no gross abnormalities, allowing Yu et al. (2001) to
investigate the effects of Psen1 inactivation on amyloid precursor
protein processing the Notch signaling pathway, and synaptic and
cognitive function in the adult brain. They concluded from their studies
that inactivation of Psen1 function in the adult cerebral cortex leads
to reduced beta-amyloid generation and subtle cognitive deficits without
affecting expression of Notch downstream target genes.

Feng et al. (2001) found that mice with selective deletion of the Psen1
gene in excitatory neurons of the forebrain showed deficient
enrichment-induced neurogenesis in the hippocampal dentate gyrus.
However, the mutant mice showed normal synaptic properties and learning
comparable to wildtype. Feng et al. (2001) postulated that adult
neurogenesis in the hippocampus may play a role in the periodic
clearance of outdated hippocampal memory traces after cortical
consolidation, thus allowing for new memory processing.

Using 3 groups of transgenic mice carrying the presenilin A246E mutation
(104311.0003), the amyloid precursor protein K670N/M671L mutation (APP;
104760.0008), or both mutations, Dineley et al. (2002) showed that
coexpression of both mutant transgenes resulted in accelerated
beta-amyloid accumulation, first detected at 7 months in the cortex and
hippocampus, compared to the APP or PS1 transgene alone. Contextual fear
learning, a hippocampus-dependent associative learning task, but not
cued fear learning, was impaired in mice carrying both mutations or the
APP mutation, but not the PS1 mutation alone. The impairment manifested
at 5 months of age, preceding detectable plaque deposition, and worsened
with age. Dineley et al. (2002) also found increased levels of alpha-7
nicotinic acetylcholine receptor protein in the hippocampus, which they
hypothesized contributes to disease progression via chronic activation
of the ERK MAPK cascade.

Jankowsky et al. (2004) studied beta-amyloid-40 and -42 levels in a
series of transgenic mice that coexpressed the APP 'Swedish' mutation
(K670N/M671L) with 2 FAD-PS1 variants, A246E and the exon 9 deletion
(104311.0012), that differentially accelerate amyloid pathology in the
brain. There was a direct correlation between the concentration of
beta-amyloid-42 and the rate of amyloid deposition. The shift in
beta-amyloid-42:beta-amyloid-40 ratios associated with the expression of
FAD-PS1 variants was due to a specific elevation in the steady-state
levels of beta-amyloid-42, while maintaining a constant level of
beta-amyloid-40. Jankowsky et al. (2004) suggested that PS1 variants may
not simply alter the preferred cleavage site for gamma-secretase, but
rather that they may have more complex effects on the regulation of
gamma-secretase and its access to substrates.

Saura et al. (2004) generated a transgenic conditional double knockout
mouse lacking both Psen1 and Psen2 in the postnatal forebrain. The mice
showed impairments in hippocampal memory and synaptic plasticity at the
age of 2 months, and later developed neurodegeneration of the cerebral
cortex accompanied by increased levels of the Cdk5 activator p25
(603460) and hyperphosphorylated tau. The authors concluded that PSEN1
and PSEN2 have essential roles in synaptic plasticity, learning, and
memory. Beglopoulos et al. (2004) found that double knockout mice
lacking Psen1 and Psen2 in the postnatal forebrain had reduced levels of
the toxic beta-amyloid peptides beta-40 and beta-42 and strong
microglial activation in the cerebral cortex. Gene expression profiling
showed an upregulation of genes associated with inflammatory responses.
The results suggested that the memory deficits and neurodegeneration
observed in the double knockout mice were not caused by beta-amyloid
accumulation and implicated an inflammatory component to the
neurodegenerative process.

Tournoy et al. (2004) reported that in PS1 +/- PS2 -/- mice, PS1 protein
concentration was considerably lowered, functionally reflected by
reduced gamma-secretase activity and impaired beta-catenin (CTNNB1;
116806) downregulation. Their phenotype was normal up to 6 months, when
the majority of the mice developed an autoimmune disease characterized
by dermatitis, glomerulonephritis, keratitis, and vasculitis, as seen in
human systemic lupus erythematosus (152700). Besides B cell-dominated
infiltrates, the authors observed a hypergammaglobulinemia with immune
complex deposits in several tissues, high-titer nuclear autoantibodies,
and an increased CD4+/CD8+ ratio. The mice further developed a benign
skin hyperplasia similar to human seborrheic keratosis (182000) as
opposed to malignant keratocarcinomata observed in skin-specific PS1
'full' knockouts.

Lazarov et al. (2005) found that exposure of transgenic mice
coexpressing FAD-linked APP and PS1 variants to an enriched environment
composed of large cages, running wheels, colored tunnels, toys, and
chewable material resulted in pronounced reductions in cerebral
beta-amyloid levels and amyloid deposits compared with animals raised
under standard housing conditions. The enzymatic activity of a
beta-amyloid-degrading endopeptidase, neprilysin (MME; 120520), was
elevated in the brains of enriched mice and inversely correlated with
amyloid burden. Moreover, DNA microarray analysis revealed selective
upregulation in levels of transcripts encoded by genes associated with
learning and memory, vasculogenesis, neurogenesis, cell survival
pathways, beta-amyloid sequestration, and prostaglandin synthesis. These
studies provided evidence that environmental enrichment leads to
reductions in steady-state levels of cerebral beta-amyloid peptides and
amyloid deposition and selective upregulation in levels of specific
transcripts in brains of transgenic mice.

Guo et al. (2003) generated transgenic Drosophila in which the size of
the eye was correlated with the level of endogenous gamma-secretase
activity. The system was very sensitive to the levels of 3 genes
required for APP gamma-secretase activity: presenilin, nicastrin
(605254), and aph1 (see 607629). Using this system, the authors
identified a region on the second chromosome that contains a gene or
genes whose product(s) may promote gamma-secretase activity.

Esselens et al. (2004) found that cultured Ps1 -/- mouse hippocampal
neurons showed increased amounts of Tln (ICAM5; 601852) protein and
accumulation of Tln in phagocytic vacuoles distinct from classic
autophagic vacuoles. Both the increased amount of Tln and Tln
accumulation were independent of Ps1 gamma-secretase activity, since
expression of dominant-negative human PS1 mutants in Ps1 -/- cells
reversed both defects. Esselens et al. (2004) suggested that PS1 may
have a role in targeting phagocytic vacuoles for lysosomal degradation.

Ganguly et al. (2008) showed that in Drosophila Ubqn (UBQLN1; 605046)
binds to Psen1 and antagonizes Psen1 function in vivo. Loss of Ubqn
suppressed phenotypes that resulted from loss of Psen1 function in vivo.
Overexpression of Ubqn in the eye resulted in adult-onset, age-dependent
retinal degeneration, which could be suppressed by Psen1 overexpression
and enhanced by expression of a dominant-negative version of Psen1.
Expression of a human AD-associated UBQLN1 variant led to more severe
degeneration than expression of wildtype UBQLN1. The findings identified
Ubqn as a regulator of Psen1, supported a role for UBQLN1 in AD
pathogenesis, and suggested that expression of a human AD-associated
variant can cause neurodegeneration independent of amyloid production.

Using morpholinos directed against splice acceptor sites in the
zebrafish Psen1 transcript, Nornes et al. (2008) developed mutant
zebrafish with aberrant splicing in the region between Psen1 exons 6 and
8. This mutation produced a truncated peptide with potent
dominant-negative effect on Psen1 protein activity, including Notch
signaling, and caused hydrocephaly. The effects of the mutation was
independent of gamma-secretase, and did not disturb the formation or
behavior of ventricular cilia.

Using an N-ethyl-N-nitrosurea mutagenesis screen, Bai et al. (2011)
identified Columbus mutant mice, which exhibited motor axon midline
crossing and a severe defect in ventral root formation. Bai et al.
(2011) found that the Columbus mutation was a T-to-A transversion in
intron 11 of the Psen1 gene that resulted in loss of Psen1 protein
expression. Mouse embryos with targeted disruption of the Psen1 gene
displayed a similar combination of pathfinding errors to those observed
in Columbus mutants, including failure to form discrete ventral roots
and midline crossing of motor axons. Motor neurons and commissural
interneurons in Columbus mutants acquired an inappropriate attraction to
floor plate netrin (see 601614) due to lack of gamma-secretase
processing of the netrin signaling component Dcc (120470). Incomplete
Dcc processing resulted in defective Slit (see 603742)/Robo (see 602430)
silencing of netrin attractive signals and failure of commissural axons
to exit the floor plate. Bai et al. (2011) concluded that PSEN1-mediated
gamma-secretase activity is crucial to coordinate the attractive and
repulsive signals that direct neural projections across the midline.

By screening a library of about 80,000 chemical compounds, Kounnas et
al. (2010) identified a class of gamma-secretase modulators (GSMs),
diarylaminothiazoles, or series A GSMs, that could target production of
A-beta-42 and A-beta-40 in cell lines and in Tg 2576 transgenic AD mice.
Immobilized series A GSMs bound to Pen2 and, to a lesser degree, Ps1.
Series A GSMs reduced gamma-secretase activity without interfering with
related off-target reactions, lowered A-beta-42 levels in both plasma
and brain of Tg 2576 mice, and reduced plaque density and amyloid in Tg
2576 hippocampus and cortex. Daily dosing was well tolerated over the
7-month study.

Heneka et al. (2013) found that Nlrp3-null (606416) or Casp1-null
(147678) mice carrying mutations associated with familial Alzheimer
disease were largely protected from loss of spatial memory and other
sequelae associated with Alzheimer disease, and demonstrated reduced
brain caspase-1 and interleukin-1-beta (147720) activation as well as
enhanced amyloid-beta clearance. Furthermore, NLRP3 inflammasome
deficiency skewed microglial cells to an M2 phenotype and resulted in
the decreased deposition of amyloid-beta in the APP (104760)/PS1 model
of Alzheimer disease. Heneka et al. (2013) concluded that their results
showed an important role for the NLRP3/caspase-1 axis in the
pathogenesis of Alzheimer disease.

*FIELD* AV
.0001
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, MET146LEU

In 2 unrelated families with chromosome 14-linked early-onset Alzheimer
disease (607822), Sherrington et al. (1995) identified a mutation in the
PSEN1 gene, resulting in a met146-to-leu (M146L) substitution. The
authors detected the mutation in affected family members but not in
asymptomatic family members aged more than 2 standard deviations beyond
the mean age of onset and not on 284 chromosomes from unrelated,
neurologically normal subjects drawn from comparable ethnic origins. The
2 families reported by Sherrington et al. (1995) were from southern
Italy. Sorbi et al. (1995) studied 15 unrelated Italian families with
necropsy-proven early-onset familial AD and found the met146-to-leu
substitution in 3.

Morelli et al. (1998) described this mutation, due to an A-to-T
transversion at the first position of codon 146, in an Argentinian
family with early-onset FAD.

Halliday et al. (2005) identified the M146L substitution in 2 sibs with
early-onset FAD. Family history suggested that their father was also
affected. Neuropathologic examination of both patients showed numerous
cortical plaques and neurofibrillary tangles, consistent with AD. In
addition, both cases showed ballooned neurons and numerous tau (MAPT;
157140)-immunoreactive Pick bodies in upper frontotemporal cortical
layers and in the hippocampal dentate gyrus. Halliday et al. (2005)
suggested that the M146L mutation may specifically predispose to both AD
and Pick pathology by affecting multiple intracellular pathways
involving tau phosphorylation.

For 2 other mutations in the same codon, see met146-to-val (104311.0007)
and met146-to-ile (104311.0015).

.0002
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, HIS163ARG

In an American pedigree with chromosome 14-linked Alzheimer disease
(607822), Sherrington et al. (1995) found a mutation in the PSEN1 gene,
resulting in a his163-to-arg (H163R) substitution. The same mutation was
found in a small French-Canadian pedigree with early-onset Alzheimer
disease.

.0003
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ALA246GLU

In a pedigree with chromosome 14-linked early-onset Alzheimer disease
(607822), Sherrington et al. (1995) identified a mutation in the PSEN1
gene, resulting in an ala246-to-glu substitution (A246E).

.0004
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, LEU286VAL

In a pedigree with chromosome 14-linked early-onset Alzheimer disease
(607822), Sherrington et al. (1995) identified a mutation in the PSEN1
gene, resulting in a leu286-to-val (L286V) substitution.

.0005
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, CYS410TYR

In 2 pedigrees with early-onset Alzheimer disease, Sherrington et al.
(1995) identified a mutation in the PSEN1 gene, resulting in a
cys410-to-tyr (C410Y) substitution.

.0006
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, MET139VAL

In 2 families with early-onset Alzheimer disease (607822), the
Alzheimer's Disease Collaborative Group (1995) detected a mutation in
the PSEN1 gene, resulting in a met139-to-val (M139V) substitution. In
both families, the mean age of onset was 39 to 41 years.

Hull et al. (1998) described a German family with early-onset Alzheimer
disease caused by the M139V mutation. From the age of 43 years, the
proband had complained of deficits in short-term memory. Relatives had
noticed his symptoms even earlier and dated the onset of deficits to age
38 years when he showed increasing interruptions during speech followed
by social withdrawal. There was a strong family history of dementia.
Through 3 generations the onset of dementia in this family was between
42 and 45 years. Fox et al. (1997) reported on this mutation in a
British family.

Rippon et al. (2003) reported an African American family with atypical
early-onset AD caused by the M139V mutation.

.0007
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, MET146VAL

In 3 unrelated early-onset AD families (607822), the Alzheimer's Disease
Collaborative Group (1995) found a met146-to-val (M146V) mutation in the
PSEN1 gene. See also the M146L mutation (104311.0001). The age of onset
was unusually early in these 3 families, between 36 and 40 years.

.0008
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, HIS163TYR

In a Swedish family in which 8 members had early-onset Alzheimer disease
(607822), the Alzheimer's Disease Collaborative Group (1995) identified
an his163-to-tyr (H163Y) mutation. The average age of onset was 47
years. See also the H163R mutation (104311.0002).

.0009
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, GLU280ALA

In 4 families with onset of AD in their late forties (607822), the
Alzheimer's Disease Collaborative Group (1995) found a glu280-to-ala
(E280A) mutation in the AD3 gene.

With this and other missense mutations in the PS1 gene, increased levels
of amyloid beta-peptides ending at residue 42 are found in plasma and
skin fibroblast media of gene carriers. A-beta-42 aggregates readily and
appears to provide a nidus for the subsequent aggregations of A-beta-40,
resulting in the formation of innumerable neuritic plaques. To obtain in
vivo information about how PS1 mutations cause AD pathology at such
early ages, Lemere et al. (1996) characterized the neuropathologic
phenotype of 4 patients from a large Colombian kindred bearing the
glu280-to-ala substitution in PS1. Using antibodies specific to the
alternative C-termini of A-beta, they detected massive deposition of
A-beta-42 (the earliest and predominant form of plaque A-beta to occur
in AD) in many brain regions. Quantification revealed a significant
increase in the A-beta-42 form, but not the A-beta-40 form, in the
brains from 4 patients with the PS1 mutation compared with those from 12
sporadic AD patients. Thus, Lemere et al. (1996) concluded that the
mutant PS1 protein appears to alter the proteolytic processing of the
beta-amyloid precursor protein at the C-terminus of A-beta to favor
deposition of A-beta-42.

Lopera et al. (1997) screened all members of 5 extended families (nearly
3,000 individuals) in a community based in Antioquia, Colombia, where
early-onset Alzheimer disease due to the glu280-to-ala mutation had been
shown to be unusually frequent. Using standard diagnostic criteria, a
case series of 128 individuals was identified, of which 6 had definitive
(autopsy-proven) early-onset AD, 93 had probable early-onset AD, and 29
had possible early-onset AD. The patients had a mean age at onset of
46.8 years (range, 34 to 62 years). The average interval until death was
8 years. Headache was noted in affected individuals significantly more
frequently than in those not affected. The most frequent presentations
were memory loss followed by behavioral and personality changes and
progressive loss of language ability. In the final stages, gait
disturbances, seizures, and myoclonus were frequent.

Johnson et al. (2001) demonstrated that regional cerebral perfusion
abnormalities based on SPECT are detectable before development of the
clinical symptoms of Alzheimer disease in carriers of the glu280-to-ala
PS1 mutation.

By genotype analysis of a large Colombian kindred with 109 carriers of
the E280A PS1 mutation, including 52 members with AD, Pastor et al.
(2003) found that those with at least 1 APOE4 allele (see 107741) were
more likely to develop AD at an earlier age than those without an APOE4
allele, indicating an epistatic effect. Promoter APOE variants did not
influence either the onset or the duration of the disease.

.0010
ALZHEIMER DISEASE, FAMILIAL, 3
ALZHEIMER DISEASE, FAMILIAL, WITH SPASTIC PARAPARESIS AND UNUSUAL
PLAQUES, INCLUDED
PSEN1, GLU280GLY

In 2 families with multiple cases of Alzheimer disease with onset in the
early forties (607822), the Alzheimer's Disease Collaborative Group
(1995) found a glu280-to-gly (E280G) mutation in the AD3 gene. See also
the E280A mutation (104311.0009).

In 1 of the families with the E280G mutation reported by the Alzheimer's
Disease Collaborative Group (1995), O'Riordan et al. (2002) described an
atypical disease pattern in 3 additional members from the third
generation who developed symptoms in their forties (see 607822). One had
cognitive impairment, spastic paraparesis, and white matter
abnormalities on MRI. One of his sibs developed dementia and myoclonus
and had white matter abnormalities on MRI. Another sib had
ophthalmoplegia, spastic-ataxic quadriparesis, and cotton-wool plaques
with amyloid angiopathy on brain biopsy (MRI was not performed). The
authors suggested that the MRI findings may reflect an ischemic
leukoencephalopathy due to amyloid angiopathy affecting meningocortical
vessels.

In a patient with Alzheimer disease with spastic paraparesis and
cotton-wool plaques with onset at age 52 years, Rogaeva et al. (2003)
identified the E280G mutation, which they incorrectly reported as E280Q.
Rogaeva (2004) reported the correct mutation as E280G. There were 4
other affected members in the patient's family.

.0011
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, PRO267SER

In one family with early-onset AD (607822) with a mean onset of 35
years, the Alzheimer's Disease Collaborative Group (1995) detected a
pro267-to-ser (P267S) mutation in the AD3 gene.

.0012
ALZHEIMER DISEASE, FAMILIAL, 3
ALZHEIMER DISEASE, FAMILIAL, WITH SPASTIC PARAPARESIS AND UNUSUAL
PLAQUES, INCLUDED
PSEN1, IVS8AS, G-T, -1, EX9DEL

Perez-Tur et al. (1995) found a heterozygous mutation changing G to T in
the splice acceptor site for exon 9 in a family segregating Alzheimer
disease with linkage to chromosome 14 (607822). RT-PCR of cDNA isolated
from lymphoblasts of affected members demonstrated an aberrant band in
the sequence of which exon 9 was deleted in-frame, removing amino acids
290 to 319. The authors suggested that since the predicted protein
structure would retain the same overall topology as the wildtype
protein, exon 9 was of particular relevance to the abnormal physiology
of presenilin 1 in Alzheimer disease.

Thinakaran et al. (1996) demonstrated that PS1 undergoes endoproteolytic
processing in vivo to yield 27-kD N-terminal and 17-kD C-terminal
derivatives, cleaved between amino acids 260 and 320. In a British FAD
pedigree with the PS1 exon 9 deletion, there was no cleavage of PS1.

Crook et al. (1998) described the same deletion of exon 9 in a Finnish
pedigree with 17 affected individuals of both sexes in 3 generations
suffering from a novel variant of Alzheimer disease. The mechanism of
the deletion of exon 9 in this family was not a mutation in the acceptor
splice site, however, and remained to be determined. The disorder in the
Finnish pedigree was characterized by progressive dementia that was in
most cases preceded by spastic paraparesis (see 607822). Neuropathologic
investigations showed numerous distinct, large, round, and eosinophilic
plaques, as well as neurofibrillary tangles and amyloid angiopathy
throughout the cerebral cortex. The predominant plaques resembled
cotton-wool balls and were immunoreactive for A-beta, but lacked a
congophilic dense core or marked plaque-related neuritic pathology.

Crook et al. (1998) referred to this mutation as the delta-9 mutation.
They stated that it was the only known structural mutation in the PSEN1
gene; previously identified mutations had been missense mutations. The
delta-9 mutant protein is not metabolized to the stable 18-kD N-terminal
and the 28-kD C-terminal fragments, and thus the mutant holoprotein
accumulates. Unlike the missense mutations, the delta-9 mutation rescues
the egl phenotype caused by mutations in sel-12, the C. elegans homolog
of the presenilins. Of the mutations described in the PSEN1 gene, the
delta-9 mutation has the greatest effect on A-beta-42(43) production.

The missense mutations in the PSEN1 gene give rise to phenotypic
manifestations that differ very little from classic AD, apart from an
unusually early onset. Kwok et al. (1997) reported another family with
an association between a splice acceptor site mutation of PSEN1
(resulting in the delta-9 deletion) and presenile AD with spastic
paraparesis. Kwok et al. (1997) reported a second family in which an
arg278-to-thr missense mutation (104311.0017) was associated with
presenile AD and spastic paraparesis. In a fourth case, reported by Kwok
et al. (1997), the mutation was not identified. As summarized by Crook
et al. (1998), spastic paraparesis had been reported in 2 of 4 families
with the delta-9 mutation and in 2 other families. Thus, the association
of this syndrome with the delta-9 mutation is not a simple one.

In this variant form of Alzheimer disease, spastic paraparesis precedes
dementia and large A-beta-amyloid plaques resembling cotton-wool balls
are a leading neuropathologic feature. The disorder has been described
in a Finnish pedigree (Verkkoniemi et al., 2000; Crook et al., 1998) and
in an Australian pedigree (Smith et al., 2001). In the family of Smith
et al. (2001), the onset of dementia was delayed and modified in
subjects with spastic paraparesis. This phenotypic variation suggested
that modifying factors are associated with exon 9 deletions.

.0013
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, GLU120ASP

Reznik-Wolf et al. (1996) used denaturing gradient gel electrophoresis
to examine the PS1 gene in several Israeli families with early-onset AD
(607822). They found that 2 siblings with early-onset AD carried a
missense mutation changing codon 120 from glutamic acid to aspartic
acid. This allele was not found in 118 control individuals.

.0014
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ALA426PRO

In a Scottish-Irish family with early-onset AD (607822), Poorkaj et al.
(1998) identified an A-to-C change at nucleotide 1278 in the PSEN1 gene
that resulted in an ala426-to-pro (A426P) substitution.

.0015
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, MET146ILE

In a Danish family with autosomal dominant early-onset AD (607822)
spanning 3 generations, Jorgensen et al. (1996) identified a G-A
transition in the PSEN1 gene, resulting in a met146-to-ile (M146I)
substitution. The average age of disease onset was 44 years.

In a Swedish family with Alzheimer disease in 4 consecutive generations,
Gustafson et al. (1998) identified a single base substitution (ATG to
ATC) in codon 146 of the PSEN1 gene, resulting in an M146I substitution.

.0016
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, LEU250SER

Harvey et al. (1998) described a family in which 7 members had
early-onset Alzheimer disease (607822) due to a leu250-to-ser (L250S)
missense mutation in the PSEN1 gene. Detailed clinical information was
available on 5 members. All had an early age at onset, with a median age
of 52 years. Age at onset varied between 49 and 56 years, with duration
of illness varying between 6 years and 15 years. Myoclonus, depression,
and psychosis were features in this family; seizures were not reported.

.0017
ALZHEIMER DISEASE, FAMILIAL, WITH SPASTIC PARAPARESIS AND UNUSUAL
PLAQUES
PSEN1, ARG278THR

Kwok et al. (1997) described an arg278-to-thr mutation of the PSEN1 gene
associated with Alzheimer disease with spastic paraparesis and
distinctive large eosinophilic plaques (see 607822), as well as
neurofibrillary tangles and amyloid angiopathy throughout the cerebral
cortex. The predominant plaques resembled cotton-wool balls and were
immunoreactive for A-beta, but lacked a congophilic dense core or marked
plaque-related neuritic pathology. This pathologic change was seen in 2
families with deletion of exon 9 of the PSEN1 gene (104311.0012).

.0018
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, IVS4DS, 1-BP DEL, G

In 2 autopsy-confirmed cases with early-onset Alzheimer disease
(607822), Tysoe et al. (1998) identified a single-base deletion of a G
at the splice donor site of intron 4 of the PSEN1 gene. De Jonghe et al.
(1999) identified the same mutation in 4 additional, unrelated
early-onset AD cases and demonstrated that the mutation segregates in an
autosomal dominant manner and that all cases have 1 common ancestor. De
Jonghe et al. (1999) showed that the intron 4 mutation produces 3
different transcripts, 2 deletion transcripts (1 involving a deletion of
all of exon 4 and the other involving a deletion of part of exon 4), and
a transcript that results in insertion of a threonine between codons 113
and 114. The truncated proteins were not detectable in vivo in brain
homogenates or in lymphoblast lysates of mutation carriers. In vitro,
HEK293 cells overexpressing the insertion cDNA construct or either of
the deletion constructs showed amyloid beta-42 secretion approximately 3
to 4 times greater than normal only for the insertion cDNA construct.
Increased amyloid beta-42 production was also observed in brain
homogenates. De Jonghe et al. (1999) concluded that in the case of the
intron 4 mutation, the Alzheimer disease pathophysiology results from
increased amyloid beta-42 secretion by the insertion transcript,
comparable with cases carrying a dominant PSEN1 missense mutation.

.0019
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, 1548GC-TG

Devi et al. (2000) studied 2 children who developed dementia in their
late twenties (607822). Their father had early-onset, autopsy-confirmed
Alzheimer disease. The younger of the 2 children had AD confirmed at
autopsy. Sequencing of the coding region of the PSEN1 gene revealed a
GC-to-TG substitution at nucleotides 1548-1549, affecting codon 434.
There was no DNA source available on their father for mutation analysis.
The disease course in these 3 individuals was characterized by cognitive
and behavioral problems accompanied by myoclonus, seizures, and aphasia
within 5 years after onset.

.0020
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, CYS92SER

Lewis et al. (2000) showed that cys92-to-ser (C92S), the PS1 homolog of
the C. elegans sel-12 loss of function mutation cys60 to ser, increased
amyloid beta-42 production when expressed in a neuroglioma cell line,
similar to other pathogenic PS1 mutations. They noted, but did not cite,
a report identifying C92S as the pathogenic mutation in an Italian
family with familial Alzheimer disease (607822). The results suggested
that all FAD-linked PS1 mutations result in increased amyloid beta-42
production through a partial loss of function mechanism.

.0021
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, GLY206ALA

Athan et al. (2001) found that among 206 Caribbean Hispanic families
with 2 or more living members with AD, 19 (9.2%) had at least 1
individual with onset of AD before the age of 55 years (607822). In 8 of
these 19 families, a gly206-to-ala mutation in the PSEN1 gene was
identified. Although not known to be related, all carriers of the G206A
mutation tested shared a variant allele at 2 nearby microsatellite
polymorphisms, indicating a common ancestor.

.0022
ALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND APRAXIA
PSEN1, GLY266SER

In a Japanese family with 6 individuals of both genders in 2 generations
affected by a variant form of Alzheimer disease characterized by senile
dementia preceded by spastic paraparesis and apraxia (see 607822),
Matsubara-Tsutsui et al. (2002) identified a G-to-A transition in codon
266 of exon 8 of the PSEN1 gene, resulting in a gly-to-ser (G266S)
substitution. The deceased patients were between 48 and 51 years of age.

.0023
DEMENTIA, FRONTOTEMPORAL
PSEN1, LEU113PRO

Raux et al. (2000) reported 6 members of a family with early-onset
frontotemporal dementia (600274), confirmed by imaging studies, in an
autosomal dominant inheritance pattern. In 2 patients available for
testing, the authors found a novel heterozygous T-to-A mutation in the
PSEN1 gene, resulting in a leu113-to-pro substitution. The mutation was
absent in a healthy sister and in 50 unrelated patients. Raux et al.
(2000) noted that this phenotype is usually associated with mutation in
the MAPT gene (157140).

.0024
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, LEU166PRO

Moehlmann et al. (2002) identified a leu166-to-pro (L166P) mutation in
the PSEN1 gene in a female proband in whom the onset of familial
Alzheimer disease was in adolescence (607822). Generalized seizures
began at age 15, major depression occurred at age 19, memory was clearly
impaired by 24, ataxia and spastic paraplegia were recorded by 27, and
moderate stage dementia by 28. Dementia, ataxia, and spasticity
progressed until death at age 35. Numerous A-beta-immunopositive
neuritic and cotton-wool plaques were seen throughout the cerebral
cortex and A-beta-immunopositive amyloid cores were abundant in the
cerebellar cortex. This was stated to be 1 of 11 mutations associated
with FAD and located in the third transmembrane domain (TM3) of PSEN1.
An analysis of other FAD-associated and artificial L166 mutants showed
increased A-beta(42) levels in all, suggesting that leucine-166 is
critically required for the specificity of gamma-secretase cleavage.
However, none of the L166 mutations inhibited gamma-secretase activity.

.0025
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, LEU174MET

Bertoli Avella et al. (2002) studied a Cuban family with autosomal
dominant presenile AD (607822) through 6 generations that descended from
a Spanish founder who migrated from the Canary Islands in the early 19th
century. Mean age at onset was 59 years. Memory impairment was the main
symptom in all patients; ischemic episodes were described in 4.
Neuropathologic examination of brain material in 1 patient revealed
neuronal loss, amyloid plaques, and neurofibrillary tangles. A maximum
lod score of 3.79 at theta = 0.0 was obtained for marker D14S43, located
in a 9-cM interval of the PSEN1 gene in which all patients shared the
same haplotype. Sequencing of the PSEN1 gene revealed a heterozygous
520C-A substitution in exon 6, which was predicted to cause a
leu174-to-met (L174M) substitution in the third transmembrane domain of
the protein. Leu174 is highly conserved among species and is identical
in presenilin-1 and presenilin-2 proteins.

.0026
ALZHEIMER DISEASE, FAMILIAL, 3, WITH UNUSUAL PLAQUES
PSEN1, LEU271VAL

In a family with autosomal dominant early-onset Alzheimer disease (see
607822), Kwok et al. (2003) identified a C-T mutation in the PSEN1 gene,
resulting in a leu271-to-val (L271V) substitution and deletion of exon
8. Mean age of disease onset was 49 years, and although no affected
family members had spastic paraparesis, all developed myoclonus late in
the illness. Neuropathologic examination of 2 patients revealed a large
number of neocortical large spherical plaques without defined cores or
neuritic dystrophy, reminiscent of cotton wool plaques. Biochemical
analysis of the mutated protein showed that it resulted in increased
secretion of the amyloid-beta-42 peptide.

.0027
PICK DISEASE OF BRAIN
PSEN1, GLY183VAL

In a patient with Pick disease (172700), Dermaut et al. (2004)
identified a G-to-T transversion in exon 6 of the PSEN1 gene, resulting
in a gly183-to-val (G183V) substitution. The mutation occurs at a
conserved residue within a splice signal. The mutation was not detected
in more than 1,000 patients with dementia and normal controls. Four sibs
of the proband had the mutation; 1 was clearly affected and 3 other
showed evidence compatible with cognitive deterioration or early-stage
cognitive decline. Neuropathologic examination of the proband showed tau
(MAPT; 157140)-immunoreactive Pick bodies without beta-amyloid plaques.
Dermaut et al. (2004) suggested that the G183V mutation results in a
partial loss of function of the PSEN1 protein.

.0028
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, PRO436GLN

Beck et al. (2004) reported a patient with sporadic early-onset AD
(607822) who was a somatic mosaic for a 71111C-A transversion in exon 12
of the PSEN1 gene. The mutation, which had been described by Taddei et
al. (1998), was predicted to result in substitution of glutamine at
proline-436 (P436Q). The index patient presented at age 52 years with a
10-year history of progressive parkinsonian syndrome, spastic
paraparesis, and dementia; she died 6 years later. The degree of
mosaicism was 8% in peripheral lymphocytes and 14% in the cerebral
cortex of the index patient. Her daughter, who presented at age 27 years
with progressive cerebellar syndrome, spastic paraparesis, and dementia,
was heterozygous for the mutation; she died 12 years after diagnosis.
The authors hypothesized that mosaicism may be an important mechanism in
the etiology of sporadic AD and other apparently sporadic
neurodegenerative diseases such as Parkinson disease (see 168601), motor
neuron disease, and Creutzfeldt-Jakob disease (123400).

.0029
ALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND UNUSUAL
PLAQUES
PSEN1, 6-BP INS, NT715

In 2 sibs with early-onset Alzheimer disease with spastic paraparesis
and unusual plaques (see 607822), Moretti et al. (2004) identified a
heterozygous 6-bp insertion (715insTTATAT) in exon 3 of the PSEN1 gene,
resulting in the addition of phenylalanine and isoleucine between codons
156 and 157. The affected region encodes the intracellular loop between
transmembrane domains 2 and 3 of PSEN1 and is highly conserved. The
patients showed an unusually aggressive form of disease, with early
onset and rapid progression.

.0030
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ARG278ILE

In 2 sibs with early-onset Alzheimer disease (607822) presenting as
language impairment, Godbolt et al. (2004) identified a heterozygous
mutation in the PSEN1 gene, resulting in an arg278-to-ile (R278I)
substitution. Both patients presented at around age 50 with difficulty
in word finding and impaired frontal executive function, but with
relative preservation of memory. Although neither patient fulfilled
clinical consensus criteria for AD, the authors noted that a different
mutation at the same codon, R278T (104311.0017), had been associated
with an atypical AD phenotype characterized by spastic paraparesis.
Codon 278 lies in the cytoplasmic region between transmembrane regions 6
and 7 which is active in the formation of the gamma-secretase complex
that mediates beta-amyloid generation (Takasugi et al., 2003).

.0031
ALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND APRAXIA
PSEN1, LEU85PRO

In a patient with very-early-onset Alzheimer disease with spastic
paraparesis and apraxia (607822), Ataka et al. (2004) identified a
heterozygous 254T-C transition in exon 4 of the PSEN1 gene, resulting in
a leu85-to-pro (L85P) substitution. Functional expression studies showed
that the L85P mutation resulted in a 2-fold increase in amyloid-beta-42
production. The patient had onset at age 26 years, and symptoms and
neuroimaging were consistent with the 'visual variant' of AD in which
there is a visuospatial cognitive deficit.

.0032
ALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND UNUSUAL
PLAQUES
PSEN1, 3-BP DEL

In a Japanese patient with a phenotype with overlapping features of
early-onset Alzheimer disease with spastic paraparesis and unusual
plaques (see 607822) and Lewy body dementia (DLB; 127750), Ishikawa et
al. (2005) identified a 3-bp deletion (ACC) in exon 12 of the PSEN1
gene, resulting in the absence of residue thr440 at the cytoplasmic
C-terminus of the protein. The patient's father had early-onset dementia
with the onset of parkinsonism 9 years later, consistent with Lewy body
dementia. However, the patient had early-onset parkinsonism with the
onset of dementia 7 years later, and developed seizures and features of
spasticity late in the illness. Neuropathologic examination of the
patient showed severe neuronal loss with gliosis in various brain
regions, as well as alpha-synuclein (SNCA; 163890)-immunopositive Lewy
bodies, amyloid (APP; 104760)-immunopositive cotton-wool plaques,
cerebral amyloid angiopathy, and corticospinal degeneration. The
patient's clinical diagnosis was Parkinson disease with dementia, and
the pathologic diagnosis was AD with spastic paraparesis. No mutations
were identified in the SNCA or APP genes. Ishikawa et al. (2005)
emphasized the unusual phenotypic features in this patient. The thr440
deletion induced both alpha-synuclein and beta-amyloid pathology to
equal extents, suggesting that normal PSEN1 protein may play a role in
interactions between the 2 molecules.

.0033
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ALA431GLU

In affected members of 9 Mexican families with early-onset Alzheimer
disease-3 (607822), Yescas et al. (2006) identified a heterozygous
mutation in exon 12 of the PSEN1 gene, resulting in an ala431-to-glu
(A431E) substitution. The A431E mutation was found in 19 (32%) of 60
apparently unaffected family members, suggesting either a presymptomatic
state or reduced penetrance. All families were from the state of Jalisco
in western Mexico, and haplotype analysis indicated a founder effect.
The A431E mutation was not identified in 100 control individuals.

Murrell et al. (2006) found the A431E mutation in 20 individuals with
AD3 from 15 families identified in Guadalajara, southern California, and
Chicago. Age at disease onset ranged from 33 to 44 years, and spasticity
was a common clinical feature. Fourteen families were of Mexican mestizo
descent, and of these families, 9 could trace the illness to ancestors
from the state of Jalisco in Mexico. The remaining proband had a more
remote Mexican ancestry. The findings further supported a founder effect
for the A431E mutation.

.0034
CARDIOMYOPATHY, DILATED, 1U
PSEN1, ASP333GLY

Li et al. (2006) described heterozygosity for a novel PSEN1 missense
mutation, asp333 to gly (D333G), associated with dilated cardiomyopathy
(CMD1U; 613694) in 1 African American family. The amino acid
substitution arose from a 1539A-G transition in exon 10. Affected
members were identified in 3 generations. The PSEN1 mutation was
associated with complete penetrance and progressive disease that
resulted in the necessity of cardiac transplantation or in death.

.0035
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ALA79VAL

In 3 affected members of a family with AD3 (607822), Kauwe et al. (2007)
identified a heterozygous C-to-T transition in exon 4 of the PSEN1 gene,
resulting in an ala79-to-val (A79V) substitution. The patients had
late-onset AD (greater than 75 years) that was confirmed at autopsy. An
unaffected mutation carrier in the family was found to have increased
CSF beta-amyloid-42, suggesting that this may be used as an
endophenotype or marker for the disease. In vitro functional expression
studies in mouse embryonic fibroblasts transfected with the A79V
mutation showed increased beta-amyloid-42 compared to controls.

.0036
ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, SER170PHE

In 3 affected members of a family with early-onset AD3 (607822), Snider
et al. (2005) identified a heterozygous C-to-T transition in exon 6 of
the PSEN1 gene, resulting in a ser170-to-phe (S170F) substitution. All 3
patients developed gradual onset of memory loss beginning at 26 to 27
years of age, with an average duration of disease of 11 years before
death. The clinical courses were complicated by myoclonus, seizures, and
extrapyramidal signs. Postmortem examination confirmed AD in all 3
patients. The proband also had widespread Lewy body pathology in the
brainstem, limbic system, and neocortex; specific staining for Lewy
bodies was not performed in the other 2 family members.

In a man with early-onset AD associated with cerebellar ataxia, Piccini
et al. (2007) identified a heterozygous S170F mutation in the PSEN1
gene, which was not identified in 94 control individuals. The patient
presented at age 28 years with delusions and lower limb jerks
accompanied by intentional myoclonus and cerebellar ataxia. He had rapid
progression with global impairment of all cognitive functions and became
bedridden, anarthric, and incontinent by age 33. He died of
bronchopneumonia at age 35. Postmortem examination showed severe
beta-amyloid deposition in the cerebral and cerebellar cortices, amyloid
angiopathy, and severe loss of Purkinje cells and fibers in the
cerebellum. Neurofibrillary tangles were also present in the cerebral
cortex. In vitro cellular studies indicated that the S170F mutation
resulted in a 2.8-fold increase of both beta-amyloid-42 and -40 as well
as a 60% increase of secreted APP compared to wildtype PSEN1. Soluble
and insoluble fractions of the patient's brain tissue showed a
prevalence of N-terminally truncated beta-amyloid species at residues 40
and 42. Piccini et al. (2007) suggested that the unique processing
pattern of APP and high levels of N-terminally truncated species was
correlated with the severity of the phenotype in this patient, but also
noted the different phenotype from that described by Snider et al.
(2005).

.0037
ALZHEIMER DISEASE, FAMILIAL, 3, WITH UNUSUAL PLAQUES
PSEN1, GLY217ARG

In 2 affected members of a family of Irish/English descent with
Alzheimer disease with unusual cotton wool plaques (see 607822), Norton
et al. (2009) identified a heterozygous G-to-C transversion in the PSEN1
gene, resulting in a gly217-to-arg (G217R) substitution. There were 8
affected family members. The mean age at onset was 45.5 years, and the
mean age at death was 55.5 years. Postmortem examination of 1 affected
family member showed classic Alzheimer disease changes and large cotton
wool plaques. Spastic paraparesis was not a clinical feature. In vitro
functional expression assays showed that the G217R mutation increased
the ratio of beta-amyloid 42/40, confirming its pathogenicity.

.0038
ACNE INVERSA, FAMILIAL, 3
PSEN1, 1-BP DEL, 725C

In a Han Chinese family segregating autosomal dominant familial acne
inversa (613737), Wang et al. (2010) identified heterozygosity for a
single-basepair deletion at nucleotide 725 of the PSEN1 gene (725delC).
The mutation resulted in frameshift and a premature termination codon
(P242LfsX11). No affected individual 50 years old or older had symptoms
of Alzheimer disease or dementia. This mutation was not identified in
chromosomes from 200 ethnically matched control individuals.

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*FIELD* CN
Ada Hamosh - updated: 3/21/2013
Patricia A. Hartz - updated: 3/20/2012
Patricia A. Hartz - updated: 5/10/2011
Patricia A. Hartz - updated: 1/14/2010
Cassandra L. Kniffin - updated: 12/17/2009
Ada Hamosh - updated: 8/27/2009
Cassandra L. Kniffin - updated: 4/30/2009
Cassandra L. Kniffin - updated: 4/15/2008
Cassandra L. Kniffin - updated: 1/29/2008
Cassandra L. Kniffin - updated: 3/29/2007
Paul J. Converse - updated: 3/2/2007
Cassandra L. Kniffin - updated: 12/6/2006
Victor A. McKusick - updated: 11/27/2006
Victor A. McKusick - updated: 9/29/2006
George E. Tiller - updated: 9/11/2006
Cassandra L. Kniffin - updated: 8/29/2006
Cassandra L. Kniffin - updated: 7/14/2006
Patricia A. Hartz - updated: 3/31/2006
Cassandra L. Kniffin - updated: 3/13/2006
George E. Tiller - updated: 2/17/2006
Cassandra L. Kniffin - updated: 12/8/2005
Cassandra L. Kniffin - updated: 11/16/2005
Cassandra L. Kniffin - updated: 11/3/2005
George E. Tiller - updated: 10/21/2005
Cassandra L. Kniffin - updated: 9/22/2005
Cassandra L. Kniffin - updated: 7/25/2005
Cassandra L. Kniffin - updated: 6/17/2005
Cassandra L. Kniffin - updated: 5/13/2005
Stylianos E. Antonarakis - updated: 3/29/2005
George E. Tiller - updated: 3/2/2005
Cassandra L. Kniffin - updated: 2/18/2005
Cassandra L. Kniffin - updated: 1/20/2005
Cassandra L. Kniffin - updated: 9/27/2004
George E. Tiller - updated: 8/19/2004
Cassandra L. Kniffin - updated: 8/9/2004
Cassandra L. Kniffin - updated: 2/6/2004
Cassandra L. Kniffin - updated: 1/7/2004
Cassandra L. Kniffin - updated: 8/8/2003
Cassandra L. Kniffin - reorganized: 5/28/2003
Ada Hamosh - updated: 4/3/2003
Victor A. McKusick - updated: 3/26/2003
Dawn Watkins-Chow - updated: 3/17/2003
Cassandra L. Kniffin - updated: 1/16/2003
Victor A. McKusick - updated: 1/8/2003
Cassandra L. Kniffin - updated: 12/19/2002
George E. Tiller - updated: 12/13/2002
Patricia A. Hartz - updated: 11/8/2002
Stylianos E. Antonarakis - updated: 10/3/2002
Ada Hamosh - updated: 9/30/2002
Michael J. Wright - updated: 7/26/2002
Victor A. McKusick - updated: 7/3/2002
Cassandra L. Kniffin - updated: 6/21/2002
Cassandra L. Kniffin - updated: 6/4/2002
Victor A. McKusick - updated: 6/3/2002
Victor A. McKusick - updated: 2/22/2002
Dawn Watkins-Chow - updated: 2/14/2002
Victor A. McKusick - updated: 1/8/2002
Ada Hamosh - updated: 1/2/2002
Ada Hamosh - updated: 12/17/2001
Victor A. McKusick - updated: 10/2/2001
Ada Hamosh - updated: 8/29/2001
Paul J. Converse - updated: 4/9/2001
Paul J. Converse - updated: 2/16/2001
Majed J. Dasouki - updated: 1/30/2001
Ada Hamosh - updated: 12/21/2000
Victor A. McKusick - updated: 11/30/2000
Stylianos E. Antonarakis - updated: 10/11/2000
Victor A. McKusick - updated: 8/14/2000
Paul J. Converse - updated: 8/14/2000
Ada Hamosh - updated: 8/2/2000
Ada Hamosh - updated: 8/1/2000
Ada Hamosh - updated: 6/5/2000
Ada Hamosh - updated: 5/31/2000
Wilson H. Y. Lo - updated: 4/6/2000
Ada Hamosh - updated: 2/3/2000
Stylianos E. Antonarakis - updated: 1/7/2000
Ada Hamosh - updated: 8/18/1999
Victor A. McKusick - updated: 4/6/1999
Victor A. McKusick - updated: 2/24/1999
Victor A. McKusick - updated: 1/26/1999
Victor A. McKusick - updated: 10/14/1998
Victor A. McKusick - updated: 9/9/1998
Victor A. McKusick - updated: 7/7/1998
Rebekah S. Rasooly - updated: 5/7/1998
Clair A. Francomano - updated: 5/7/1998
Victor A. McKusick - updated: 4/6/1998
Victor A. McKusick - updated: 3/26/1998
Victor A. McKusick - updated: 2/20/1998
Ada Hamosh - updated: 1/20/1998
Victor A. McKusick - updated: 11/5/1997
Victor A. McKusick - updated: 9/3/1997
Jennifer P. Macke - updated: 6/9/1997
Jennifer P. Macke - updated: 5/22/1997
Victor A. McKusick - updated: 6/4/1997
Victor A. McKusick - updated: 2/3/1997
Orest Hurko - updated: 5/14/1996
Orest Hurko - updated: 1/25/1996

*FIELD* CD
Victor A. McKusick: 11/4/1992

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alopez: 2/16/2011
alopez: 2/8/2011
terry: 2/2/2011
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terry: 6/25/2004
tkritzer: 2/18/2004
ckniffin: 2/6/2004
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carol: 6/4/2002
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mgross: 6/3/2002
terry: 6/3/2002
terry: 3/11/2002
carol: 3/11/2002
terry: 2/22/2002
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alopez: 1/8/2002
terry: 1/8/2002
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alopez: 12/18/2001
terry: 12/17/2001
carol: 10/10/2001
mcapotos: 10/9/2001
terry: 10/2/2001
cwells: 9/14/2001
cwells: 8/31/2001
terry: 8/29/2001
terry: 8/15/2001
mgross: 4/9/2001
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mgross: 2/26/2001
mgross: 2/23/2001
terry: 2/16/2001
carol: 1/30/2001
carol: 12/23/2000
terry: 12/21/2000
mcapotos: 12/12/2000
mcapotos: 12/7/2000
terry: 11/30/2000
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carol: 11/6/2000
mgross: 10/11/2000
carol: 8/14/2000
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alopez: 8/2/2000
alopez: 8/1/2000
alopez: 6/7/2000
terry: 6/5/2000
alopez: 6/1/2000
carol: 6/1/2000
carol: 5/31/2000
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alopez: 2/3/2000
mgross: 1/7/2000
alopez: 8/19/1999
terry: 8/18/1999
terry: 7/7/1999
terry: 5/20/1999
carol: 5/13/1999
alopez: 4/7/1999
carol: 4/6/1999
carol: 3/10/1999
carol: 3/7/1999
terry: 2/24/1999
carol: 1/29/1999
terry: 1/26/1999
alopez: 10/14/1998
terry: 10/14/1998
alopez: 9/10/1998
terry: 9/9/1998
terry: 7/24/1998
carol: 7/9/1998
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terry: 5/29/1998
joanna: 5/13/1998
psherman: 5/7/1998
dholmes: 5/7/1998
carol: 4/20/1998
terry: 4/20/1998
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alopez: 3/26/1998
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terry: 2/20/1998
alopez: 1/20/1998
terry: 11/11/1997
terry: 11/5/1997
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jenny: 8/27/1997
alopez: 7/30/1997
alopez: 7/25/1997
mark: 7/16/1997
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carol: 11/4/1996
mark: 10/25/1996
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terry: 10/22/1996
mark: 10/22/1996
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terry: 4/15/1996
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terry: 3/18/1996
mark: 2/19/1996
mark: 2/10/1996
terry: 2/5/1996
mark: 1/25/1996
terry: 1/19/1996
mark: 12/11/1995
terry: 11/17/1995
mark: 11/2/1995
carol: 9/29/1994
mimadm: 4/12/1994
pfoster: 3/24/1994
warfield: 3/23/1994

MIM 600274
*RECORD*
*FIELD* NO
600274
*FIELD* TI
#600274 FRONTOTEMPORAL DEMENTIA; FTD
;;FRONTOTEMPORAL LOBAR DEGENERATION WITH TAU INCLUSIONS;;
read moreFTLD WITH TAU INCLUSIONS;;
DEMENTIA, FRONTOTEMPORAL, WITH PARKINSONISM;;
FRONTOTEMPORAL DEMENTIA WITH PARKINSONISM;;
FRONTOTEMPORAL LOBE DEMENTIA; FLDEM;;
FTDP17;;
MULTIPLE SYSTEM TAUOPATHY WITH PRESENILE DEMENTIA; MSTD;;
DISINHIBITION-DEMENTIA-PARKINSONISM-AMYOTROPHY COMPLEX; DDPAC;;
WILHELMSEN-LYNCH DISEASE; WLD;;
FRONTOTEMPORAL DEMENTIA-AMYOTROPHIC LATERAL SCLEROSIS; FTD-ALS;;
PALLIDOPONTONIGRAL DEGENERATION; PPND
PICK COMPLEX, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because this form of
frontotemporal dementia (FTD) is caused by mutation in the gene encoding
microtubule-associated protein tau (MAPT; 157140) on chromosome 17q21.
Most cases are caused by heterozygous mutation, although rare homozygous
mutations have been reported.

DESCRIPTION

Frontotemporal dementia (FTD) refers to a clinical manifestation of the
pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the
most common subtype of FTLD, is a behavioral variant characterized by
changes in social and personal conduct with loss of volition, executive
dysfunction, loss of abstract thought, and decreased speech output. A
second clinical subtype of FTLD is 'semantic dementia,' characterized by
specific loss of comprehension of language and impaired facial and
object recognition. A third clinical subtype of FTLD is 'primary
progressive aphasia' (PPA), characterized by a reduction in speech
production, speech errors, and word retrieval difficulties resulting in
mutism and an inability to communicate. All subtypes have relative
preservation of memory, at least in the early stages. FTLD is often
associated with parkinsonism or motor neuron disease (MND) resembling
amyotrophic lateral sclerosis (ALS; 105400) (reviews by Tolnay and
Probst, 2002 and Mackenzie and Rademakers, 2007). Mackenzie et al.
(2009, 2010) provided a classification of FTLD subtypes according to the
neuropathologic findings (see PATHOGENESIS below).

- Clinical Variability of Tauopathies

Tauopathies comprise a clinically variable group of neurodegenerative
diseases characterized neuropathologically by accumulation of abnormal
MAPT-positive inclusions in nerve and/or glial cells. In addition to
frontotemporal dementia, semantic dementia, and PPA, different clinical
syndromes with overlapping features have been described, leading to
confusion in the terminology (Tolnay and Probst, 2002). Other terms used
historically include parkinsonism and dementia with pallidopontonigral
degeneration (PPND) (Wszolek et al., 1992);
disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et
al., 1994); frontotemporal dementia with parkinsonism (FLDEM) (Yamaoka
et al., 1996); and multiple system tauopathy with presenile dementia
(MSTD) (Spillantini et al., 1997). These disorders are characterized by
variable degrees of frontal lobe dementia, parkinsonism, motor neuron
disease, and amyotrophy.

Other neurodegenerative associated with mutations in the MAPT gene
include Pick disease (172700) and progressive supranuclear palsy (PSP;
601104),

Inherited neurodegenerative tauopathies linked to chromosome 17 and
caused by mutation in the MAPT gene have also been collectively termed
'FTDP17' (Lee et al., 2001).

Kertesz (2003) suggested the term 'Pick complex' to represent the
overlapping syndromes of FTD, primary progressive aphasia (PPA),
corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease.
He noted that frontotemporal dementia may also be referred to as
'clinical Pick disease' and that the term 'Pick disease' should be
restricted to the pathologic finding of Pick bodies.

- Genetic Heterogeneity of Frontotemporal Lobar Degeneration

Mutations in several different genes can cause frontotemporal dementia
and frontotemporal lobar degeneration, with or without motor neuron
disease. See FTLD with TDP43 inclusions (607485), caused by mutation in
the GRN gene (138945) on chromosome 17q21; FTLD mapping to chromosome 3
(600795), caused by mutation in the CHMP2B gene (609512); inclusion body
myopathy with Paget disease and FTD (IBMPFD; 167320), caused by mutation
in the VCP gene (601023) on chromosome 9p13; ALS6 (608030), caused by
mutation in the FUS gene (137070) on 16p11; ALS10 (612069), caused by
mutation in the TARDBP gene (605078) on 1p36; and FTDALS (105550),
caused by mutation in the C9ORF72 gene (614260) on 9p.

In 1 family with FTD, a mutation was identified in the presenilin-1 gene
(PSEN1; 104311) on chromosome 14, which is usually associated with a
familial form of early-onset Alzheimer disease (AD3; 607822).

CLINICAL FEATURES

Schmitt et al. (1984) reported a family in which 10 individuals had
amyotrophic lateral sclerosis, parkinsonism-dementia or both. The
proband was a 59-year-old man who died after a 14-year course of an
illness characterized by progressive dementia, parkinsonism, and ALS.
The affected persons were rather widely separated in the family,
suggesting to the authors recessive inheritance 'with genetic
epistasis.' The pathologic features consisted particularly of Alzheimer
neurofibrillary tangles in many areas.

Wszolek et al. (1992) reported a large kindred in which 32 members in 8
generations had a neurodegenerative disorder characterized by
progressive parkinsonism with dystonia, dementia, ocular motility
abnormalities, pyramidal tract dysfunction, frontal lobe release signs,
perseverative vocalizations, and urinary incontinence. The course was
exceptionally 'aggressive'; onset of symptoms and death consistently
occurred in the fifth decade. In the 4 patients so studied, positron
emission tomographic (PET) studies with labeled 6-fluoro-L-dopa (6FD)
demonstrated markedly reduced striatal uptake of the 6FD. Autopsy
findings included severe neuronal loss with gliosis in substantia nigra,
pontine tegmentum, and globus pallidus, with less involvement of the
caudate and the putamen. There were no plaques, tangles, Lewy bodies, or
amyloid bodies. The pedigree was entirely consistent with autosomal
dominant inheritance. Wszolek et al. (1992) proposed the designation
autosomal dominant parkinsonism and dementia with pallidopontonigral
degeneration (PPND). Wijker et al. (1996) stated that the kindred
described by Wszolek et al. (1992) contained 34 affected individuals
over 9 generations. The onset of the disease varied from 32 to 58 years.
Wijker et al. (1996) estimated that the disease penetrance was 15% by
age 40, 80% by age 45, and more than 90% after 50.

Delisle et al. (1999) reported 2 brothers from a French family who
presented early in the fourth decade with a neurodegenerative disorder
characterized by an akinetic rigid syndrome and dementia. There was
widespread neuronal and glial tau accumulation in the cortex, basal
ganglia, brainstem nuclei, and white matter.

Yamaoka et al. (1996) described FLDEM as characterized by behavioral and
neuropsychologic features reflecting frontal lobe dysfunction. The
changes in behavior and personality that are observed within this
clinical category may not present as a distinct phenotype and may even
suggest other diagnoses such as schizophrenia, amyotrophy, depression,
or dysphasia among various affected members of a family (Lynch et al.,
1994).

Lynch et al. (1994) described 13 affected individuals, 6 of whom were
living, in family Mo. The mean age of onset was 45 years. Personality
and behavioral changes, including the Kluever-Bucy syndrome, were the
first symptoms in 12 individuals. All affected individuals demonstrated
rigidity, bradykinesia, and postural instability. Mean duration of the
disease was 13 years. Genetic etiology was suspected because of the
familial clustering in family Mo, despite their wide geographic
distribution. Clinical features of individual family members suggested a
variety of unrelated clinical diagnoses. Two members who had died before
the study was initiated had been institutionalized and carried the
diagnosis of schizophrenia. Five family members had depression or
alcoholism as young adults. A clinical diagnosis of amyotrophy was made
in another. In retrospect, when all the cases were viewed as a group,
there was a common theme. Disinhibition occurred early in the disease
course. This was manifested by alcoholism, hyperreligiosity,
inappropriate sexual behavior, excessive eating, and shoplifting.
Curiously, many exhibited a pattern of hoarding and craving of sweets.
Eventually, all affected family members developed frontal lobe dementia,
affecting behavior and judgment more than language and praxis, and
parkinsonism.

Yamaoka et al. (1996) studied a family in which members of 3 generations
(and by implication a fourth earlier generation) suffered from FLDEM.
Clinical features were summarized for 13 patients; autopsy information
was available for 3. The proband had onset of symptoms at age 52 years.
Early difficulties included 'depression,' personality changes, and
multiple physical complaints, including difficulty with walking. Family
members described the patient as severely amotivational, apathetic, and
sometimes explosively irritable. He showed impairments in naming,
visuoperception, and executive functions, but the rapid forgetting and
apraxia typical of AD were not observed. Brain magnetic resonance
imaging was normal. Resting-state fluorodeoxyglucose positron-emission
tomography showed reduced uptake in the anterior portion of the frontal
and temporal lobes but no diffuse hypometabolism and no reduction of the
parietotemporal cortices as is typical in AD. The average age of onset
of the disorder in this family was 54.9 years, with a range of 45 to 63
years. The average duration of disease in 5 individuals on whom data
were available was 9.2 years. Although impaired memory abilities were
reported, problems with judgment and problem solving, perseveration,
lack of insight, and poor social awareness were more prominent.

Murrell et al. (1997) described an autosomal dominant presenile dementia
affecting 39 individuals in 7 generations. In the affected members of
the family, clinical symptoms began at an average age of approximately
48 years. The presenting clinical features included disequilibrium, neck
stiffness, dysphagia, and memory loss. As the disease progressed,
further cognitive decline, superior gaze palsy, and dystaxia were also
observed. The average duration from onset of symptoms to death was
approximately 10 years.

Iijima et al. (1999) described a family with presenile dementia in a
mother and her 2 sons. Mean age of onset was 35 years. All 3 patients
presented with personality changes progressing to impaired cognition and
memory, as well as disorientation. Later, they became mute and
apathetic. Iijima et al. (1999) suggested that the clinicopathologic
findings were different from those usually described with FTDP17, even
though they found a ser305-to-asn amino acid substitution in the tau
gene (157140.0010; see MOLECULAR GENETICS). They thought that the
features in their family resembled those found in sporadic corticobasal
degeneration. They pointed to the report by Brown et al. (1996) of a
case of familial corticobasal degeneration with similarities to their
family.

Wilhelmsen et al. (2004) reported a family in which at least 6 members
spanning 2 generations had a neurodegenerative illness comprising
frontotemporal dementia and features of amyotrophic lateral sclerosis
(FTD-ALS). Four other members were reportedly affected. Frank disease
onset was in the sixth decade, with a rapid progression to death within
a few years; however, some patients showed frontal and anterior temporal
lobe dysfunction from earlier in life. Variable clinical features
included personality changes, cognitive decline, and variable motor
dysfunction characterized by weakness, dysarthria, hyperreflexia, and/or
parkinsonism. Wilhelmsen et al. (2004) emphasized the motor
abnormalities in this family and noted that the predilection for ALS,
not dementia, first brought the family to neurologic attention.

Doran et al. (2007) reported a large family from Liverpool, England, in
which 8 individuals had frontotemporal dementia associated with the MAPT
intron 10 +16 mutation (157140.0006). All patients were initially
diagnosed with Alzheimer disease because of presentation of memory
deficits and word-finding difficulties. Prototypic features of
frontotemporal dementia, such as disinhibition and personality changes,
were not noted initially. Doran et al. (2007) noted the phenotypic
variability of this mutation.

Josephs et al. (2009) suggested that there are 2 distinct subtypes of
right temporal variant frontotemporal dementia, in which the right
temporal lobe is the most atrophic region on brain imaging. Among 20
individuals with these imaging findings, 12 had the behavioral variant
of FTD, and 8 had semantic dementia. In the behavioral variant group,
the most common features were personality change and inappropriate
behavior, whereas in the semantic dementia group, the most common
features were prosopagnosia, word-finding difficulties, comprehension
problems, and topographagnosia. Brain imaging also showed that the
behavioral variant group had greater volume loss in the frontal lobes
compared to the semantic group, whereas the semantic group showed
greater fusiform loss. All 8 behavioral variant patients with
pathologic/genetic studies showed abnormalities in the tau protein,
including 7 with MAPT mutations, whereas all 3 with semantic dementia
studied showed abnormalities in TDP43. These findings suggested that
there may be 2 subtypes of right temporal variant frontotemporal
dementia.

- Neuropathologic Findings

Neuropathologic examination of 6 affected family members by Lynch et al.
(1994) demonstrated frontotemporal atrophy and neuronal loss superficial
(layer 2) spongiform change, and neuronal loss with gliosis in the
substantia nigra and amygdala. Anterior horn cell loss was found in each
of the 2 spinal cords examined. One of these was from a person with
signs and symptoms of amyotrophy.

Yamaoka et al. (1996) performed full neuropathologic study of 1 member
of a family with FLDEM (subject 37), with onset at age 45. Gross
examination of the brain showed mild atrophy of the frontal, parietal,
and occipital lobes, with moderate atrophy of the temporal lobe. There
was severe ventricular dilatation. On microscopic examination, the
distribution of cell loss was moderate to severe in the midbrain,
amygdala, and entorhinal cortex, with variable involvement in the
neocortex. The substantia nigra showed severe neuronal loss and moderate
pigment incontinence. Lewy bodies and other inclusions were absent.
Limited pathology reports available on 2 other subjects showed neuronal
loss and gliosis most prominent in the temporal lobe, the third nerve
nucleus, and the substantia nigra. Senile plaques, tangles, and Pick
bodies were not seen.

In 9 affected individuals reported by Murrell et al. (1997),
neuropathologic studies showed neuronal loss in several areas of the
central nervous system, as well as argentophilic tau-immunopositive
inclusions in neurons and in oligodendroglia.

Reed et al. (1998) presented the neuropathologic findings in affected
members of the PPND kindred reported by Wszolek et al. (1992). Features
included abundant ballooned neurons in neocortical and subcortical
regions as well as tau-positive inclusions. Electron microscopy showed
that the abnormal tau proteins formed flat twisted ribbons similar to
those observed in corticobasal degeneration. Reed et al. (1998)
concluded that PPND could be subcategorized into the tauopathy group of
chromosome 17-linked neurodegenerative disorders.

Hutton et al. (1998) pointed out that most cases of frontotemporal
dementia show neuronal and/or glial inclusions that stain positively
with antibodies raised against the microtubule-associated protein tau,
although the tau pathology varies considerably in both its quantity (or
severity) and characteristics. The pathologic heterogeneity among
families with FTD was emphasized by McKhann et al. (2001) and by Morris
et al. (2001).

Neuropathologic examination of 1 affected family member with FTD-ALS by
Wilhelmsen et al. (2004) showed cortical atrophy, atrophy of the
hippocampus and amygdala, depigmentation of the substantia nigra and
locus ceruleus, and both alpha-synuclein (SNCA; 163890) and tau
inclusions. No mutations were identified in the MAPT gene. Protein
analysis showed that the insoluble tau consisted predominantly of the
4R/0N isoform. Linkage analysis suggested a disease locus on chromosome
17q between markers D17S1862 and D17S928 (lod score of 2.05), distal to
the MAPT gene.

Forman et al. (2006) performed a clinicopathologic assessment of 124
patients with either a clinical or pathologic diagnosis of
frontotemporal dementia. Neuropathologic examination showed that 46% had
a tauopathy, 29% had FTLD with ubiquitin inclusions, and 17% had
findings consistent with Alzheimer disease. Patients with FTLD with
ubiquitin inclusions were more likely to present with social and
language dysfunction; tauopathies were more commonly associated with an
extrapyramidal disorder; and AD was associated with greater deficits in
memory and executive function.

OTHER FEATURES

Boeve et al. (2006) performed polysomnography on 6 affected and 5
at-risk members of the PPND family originally reported by Wszolek et al.
(1992). None of the 11 individuals had a history of dream enactment
behavior suggesting rapid eye movement (REM) sleep behavior disorder or
electrophysiologic features of REM sleep without atonia. Neuropathologic
examination of several family members showed severe neuronal loss in the
substantia nigra and locus ceruleus, suggesting that these regions are
not involved in REM sleep behavior disorder. REM sleep behavior disorder
has been described in some patients with parkinsonism and
synucleinopathies. By contrast, Boeve et al. (2006) concluded that REM
sleep behavior disorder is rare in tauopathies, suggesting differences
in the selective vulnerability of brainstem circuits between the
synucleinopathies and tauopathies.

Using fluid attenuation inversion recovery (FLAIR) MRI, Frank et al.
(2007) detected increased T2 signal and atrophy of the mesial temporal
lobes bilaterally in 3 of 4 unrelated patients with the N279K MAPT
mutation (157140.0009) and a family history of PPND. One of 3 patients
with MRI changes was asymptomatic, as was the patient without detectable
MRI changes.

DIAGNOSIS

McKhann et al. (2001) reported on the deliberations of an international
work group on the clinical and pathologic diagnosis of FTD and Pick
disease. It was emphasized that the clinical course and treatment of
patients with FTD are different from those of patients with AD.

Lantos et al. (2002) characterized the neuropathologic findings of 12
brains with the intronic tau 10 +16 mutation (157140.0006). They found
that the lesions varied considerably in type, distribution, and
severity, both between and within families, but that the hallmark
lesions are tau-positive inclusions in neuronal and glial cells. Due to
the variable nature of the pathologic findings, the authors suggested
that definitive diagnosis requires clinical symptomatology, family
history, and molecular genetics.

Mendez et al. (2007) evaluated the diagnosis and 2-year follow-up of 134
patients with suspected FTD. At 2 years, 63 patients were diagnosed with
FTD, and 71 had other conditions. On initial assessment, 17.2% of
patients met all 5 core criteria for the diagnosis: insidious onset and
gradual progression, decline in social interpersonal conduct, impaired
regulation of personal conduct, emotional blunting, and loss of insight.
The positive predictive value for these criteria was 100%, but the
negative predictive value was only 64% owing to many false-positives.
Evidence of frontotemporal changes on neuroimaging, including MRI,
SPECT, and PET scans were more sensitive (63.5 to 90.5%), but less
specific (70.4 to 74.6%). Significant worsening in naming and executive
function on serial neuropsychologic tests supported the diagnosis.
Mendez et al. (2007) emphasized the difficulty in early diagnosis of FTD
due to the variable presentation, and suggested that neuroimaging
studies in addition to consensus criteria be used for more accurate
diagnosis.

Cairns et al. (2007) provided a report of the consensus statement for
neuropathologic diagnostic and nosologic criteria from the Consortium
for Frontotemporal Lobar Degeneration.

- Differential Diagnosis

Lynch et al. (1994) commented on personality changes similar to those
seen in Pick disease as well as in other types of frontal lobe dementia.
However, nigral and anterior horn degeneration distinguished the
disorder in the Mo family from classic Pick disease. The pathologic
features distinguished disinhibition-dementia-parkinsonism-amyotrophy
complex from the ALS-parkinsonism-dementia complex of Guam (105500). The
late amyotrophy seen in 2 of the affected individuals and the early
personality changes seen in 12 of the 13 affected individuals were
thought to distinguish the disorder from parkinsonism-dementia with
pallidopontonigral degeneration.

INHERITANCE

In the pedigree described by Lynch et al. (1994), transmission was from
females to either females or males; there was no opportunity for
male-to-male transmission. In cases where there is familial aggregation,
FLDEM appears to be inherited as an autosomal dominant disorder with
age-dependent penetrance (Yamaoka et al., 1996).

Goldman et al. (2005) analyzed the family histories of 269 probands with
various forms of frontotemporal dementia. The cohort included 99
patients diagnosed with FTD, 27 with FTD-ALS, 53 with semantic dementia,
29 with progressive nonfluent aphasia, 18 with progressive supranuclear
palsy, and 43 with corticobasal degeneration. Those with FTD-ALS showed
the highest overall positive family history (59.2%), whereas those with
semantic dementia showed the lowest positive family history (17%). The
pattern of inheritance in all cases was consistent with autosomal
dominant.

PATHOGENESIS

Several neurodegenerative diseases are characterized by the presence of
abundant neurofibrillary lesions within certain regions of the brain.
These lesions consist of abnormal filaments that are made of
microtubular-associated protein tau (MAPT) in the hyperphosphorylated
state. The most common of these disorders is Alzheimer disease, in which
tau-positive deposits are found in neurofibrillary tangles, neuropil
threads, and neurites of plaques. Lesions made of hyperphosphorylated
tau similar to those found in AD are present in Down syndrome (190685),
Niemann-Pick disease type C (257220), Gerstmann-Straussler-Scheinker
disease (137440), prion protein amyloid angiopathy (see 176640), etc.

Spillantini et al. (1997) described an apparently 'new' familial disease
with autosomal dominant inheritance that is characterized by an abundant
and widespread tau pathology in both nerve cells and glial cells in the
absence of beta-amyloid deposits. They named the condition 'familial
multiple system tauopathy with presenile dementia' (MSTD). The tau
deposits were in the form of twisted filaments that differed in diameter
and periodicity from the paired helical filaments of Alzheimer disease.
They stained by both phosphorylation-independent and -dependent anti-tau
antibodies. Moreover, tau immunoreactivity coexisted with heparan
sulfate in affected neurons and glial cells. Tau protein extracted from
filaments of familial MSTD showed a minor 72-kD band and 2 major bands
of 64 and 68 kD that contained mainly hyperphosphorylated 4-repeat tau
isoforms of 383 and 412 amino acids. Some clinical overlap was noted
with progressive supranuclear palsy (601104) and corticobasal
degeneration, both conditions in which tau-positive neurofibrillary
lesions are found. However, they considered MSTD to be distinct from
either of these disorders.

Van Leeuwen et al. (2006) detected aberrant frameshifted proteins, APP+1
(APP; 104760) and UBB+1 (UBB; 191339), within the neuropathologic
hallmarks of Alzheimer disease and other MAPT-related dementias,
including Pick disease, progressive supranuclear palsy, and less
commonly frontotemporal dementia. Van Leeuwen et al. (2006) postulated
that accumulation of APP+1 and UBB+1, which represents defective
proteasome function, contributes to various forms of dementia.

Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin
(RELN; 600514) fragment in CSF from 19 patients with AD compared to 11
nondemented controls. Western blot and PCR analysis confirmed increased
levels of reelin protein and mRNA in tissue samples from the frontal
cortex of AD patients. Reelin was not increased in plasma samples,
suggesting distinct cellular origins. The reelin 180-kD fragment was
also increased in CSF samples of other neurodegenerative disorders,
including frontotemporal dementia, PSP, and PD.

Neumann et al. (2006) identified TDP43 as the major disease protein in
both ubiquitin-positive, tau-, and alpha-synuclein-negative FTLD and
amyotrophic lateral sclerosis (see 105400). Pathologic TDP43 is
hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal
fragments and was recovered only from affected central nervous system
regions, including hippocampus, neocortex, and spinal cord. Neumann et
al. (2006) concluded that TDP43 represents the common pathologic
substrate linking these neurodegenerative disorders.

Mackenzie et al. (2009, 2010) provided recommendations for a
classification of FTLD subtypes according to the neuropathologic
findings. The 2 main neuropathologic subtypes of FTLD are those with
tau-positive inclusions (FTLD-tau), caused by MAPT mutations, and those
with ubiquitinated inclusions, formerly known as FTLDU. FTLDU has been
found to be heterogeneous, with most cases specifically due to TDP43
(TARDBP; 605078)-positive inclusions. Mutations in the TARDBP, GRN, VCP,
and TARDBP genes can all result in FTLD with TDP43-positive inclusions.
Two further subtypes include FTLD-FUS (608030), characterized by
FUS-positive inclusions and FTLD-UPS (600795), characterized by
inclusions with immunoreactivity to the ubiquitinated proteasome system.
Mackenzie et al. (2010) emphasized that this classification is based on
neuropathology and does not necessarily presuppose a primary role of the
signature protein in pathogenesis.

MAPPING

Lynch et al. (1994) performed linkage analysis in the Mo family with
microsatellite polymorphisms associated with HOX2B, giving a maximum lod
score of 3.03 at theta = 0.0, and with GP3A, giving a maximum lod score
of 3.28 at theta = 0.0. This localized the disorder to chromosome
17q21-q23. By linkage studies, Wilhelmsen et al. (1994) mapped the
disinhibition-dementia-parkinsonism-amyotrophy complex locus in this
family to a 12-cM (sex averaged) region between D17S800 and D17S787 on
17q21-q22.

In the large kindred with PPND described by Wszolek et al. (1992),
Wijker et al. (1996) found linkage to chromosome 17q21 (maximum lod
score of 9.08 at marker D17S958). Multilocus analysis positioned the
disease gene in a region of approximately 10 cM between D17S250 and
D17S943. Wijker et al. (1996) suggested that PPND and DDPAC may
originate from mutations in the same gene.

In a family with FLDEM studied at Duke University and referred to as
DUK1684, Yamaoka et al. (1996) demonstrated linkage to 17q21 with a
multipoint location score of 5.52. Yamaoka et al. (1996) suggested that
FLDEM, DDPAC, and PPND are allelic disorders.

In 3 unrelated families with autosomal dominant frontotemporal dementia,
Heutink et al. (1997) reported linkage to markers in 17q21-q22, with a
maximum lod score of 4.70 at theta = 0.05 with marker D17S932. The
disorder in 1 of these families had previously been reported as
hereditary Pick disease, inappropriately in the view of the authors,
because there was no histologic evidence of Pick bodies. They
recommended that the term Pick disease be reserved for those cases of
frontotemporal dementia with histologic Pick bodies.

Spillantini et al. (1997) stated that preliminary results of a genomic
screen suggested that MSTD is linked to 17q21, the same region where the
tau gene localizes. They noted that frontotemporal dementia with
parkinsonism had been linked to chromosome 17 in unpublished studies.

In the 7-generation family studied by Murrell et al. (1997), a limited
genomic screen by use of DNA samples from 28 family members localized
the gene for this disorder to a 3-cM region on chromosome 17, between
markers THRA1 (190120) (which maps to 17q11.2) and D17S791. Other
disorders that map to the same region include DDPAC/FLDEM,
pallidopontonigral degeneration, and familial progressive subcortical
gliosis (221820). All of these disorders may be allelic, though they do
show some differences in clinical and pathologic features.

According to Hutton et al. (1998), 13 families had been described with
autosomal dominant frontotemporal dementia with parkinsonism linked to
chromosome 17; they symbolized the disorder FTDP17 and stated that the
same disorder has historically been termed Pick disease. In addition to
those already mentioned, families were reported by Wilhelmsen et al.
(1994), Wijker et al. (1996), Foster et al. (1997), Baker et al. (1997),
and Dark (1997).

In a genomewide association study in 1,713 individuals of European
ancestry with Parkinson disease and 3,978 controls, followed by
replication in 3,361 cases and 4,573 controls, Simon-Sanchez et al.
(2009) identified association with the MAPT gene (157140) on 17q21
(dbSNP rs393152, OR = 0.77, p = 1.95 x 10(-16)).

MOLECULAR GENETICS

- Mutations in the MAPT Gene

Hutton et al. (1998) sequenced the MAPT gene in 13 families with FTDP17
and identified 3 missense mutations (gly272 to val, 157140.0002; pro301
to leu, 157140.0001; and arg406 to trp, 157140.0003) and 3 mutations in
the 5-prime splice site of exon 10. The splice site mutations all
destabilized a potential stem-loop structure that is probably involved
in regulating the alternative splicing of exon 10. This causes more
frequent use of the 5-prime splice site and an increased proportion of
tau transcripts that include exon 10. The increase of exon 10+ mRNA was
expected to increase the proportion of tau transcripts containing 4
microtubule-binding repeats, which is consistent with the neuropathology
described in families with FTDP17. In the kindred studied by Wilhelmsen
et al. (1994) and Lynch et al. (1994), Hutton et al. (1998) demonstrated
a splice donor site mutation in the MAPT gene (157140.0004).

In affected members of the PPND kindred reported by Wszolek et al.
(1992), Clark et al. (1998) identified a heterozygous mutation in the
MAPT gene (N279K; 157140.0009). Delisle et al. (1999) identified the
N279K mutation in 2 French brothers with parkinsonism and dementia.
Tsuboi et al. (2002) compared the clinical phenotypes of the original
American family reported by Wszolek et al. (1992) and the French family
reported by Delisle et al. (1999). The families shared many features,
including autosomal dominant inheritance, age of onset and disease
duration, parkinsonism, personality changes, dementia, pyramidal signs,
and eye movement abnormalities.

In 1 of the families initially reported by Lanska et al. (1994) as
having early-onset progressive frontal lobe dementia associated with
prominent subcortical gliosis (221820), Petersen et al. (1995) found
linkage to chromosome 17q21-q22. Although Petersen et al. (1995)
originally described diffuse prion plaques and protease-resistant prion
fragments in members of 1 of the families reported by Lanska et al.
(1994), no mutations were identified in the PRNP gene. Gambetti (1997)
later excluded prion pathology upon revisiting this family. Goedert et
al. (1999) identified a heterozygous mutation in the MAPT gene
(157140.0006) in affected members of this family, indicating a diagnosis
of tau-related frontotemporal dementia. Neuropathologic examination
showed hyperphosphorylated tau in both neurons and glial cells.
Ultrastructurally, the tau filaments were characterized by wide twisted
ribbons made of 4-repeat tau isoforms. Goedert et al. (1999) noted that
phenotypic heterogeneity associated with MAPT mutations has led to
classification of related diseases into distinct entities.

Seelaar et al. (2008) found a family history consistent with autosomal
dominant inheritance in 98 (27%) of 364 probands with frontotemporal
dementia. Among the familial cases, mutations in the GRN and MAPT gene
were identified in 6% and 11%, respectively. Those with GRN mutations
had a higher mean age at onset (61.8 years) compared to those with MAPT
mutations (52.4). Neuropathologic findings, when available, were
consistent with genetic analysis.

Among 225 patients with a diagnosis of FTLD, Rohrer et al. (2009) found
that 41.8% had some family history of the disorder, although only 10.2%
had a clear autosomal dominant history. Those with the behavioral
variant of the disorder were more likely to have a positive family
history than those with the language syndromes. Mutations in the MAPT
and GRN genes were found in 8.9% and 8.4% of the cohort, respectively.

- Mutation in the PSEN1 Gene

Raux et al. (2000) reported 6 members of a family with early-onset
frontotemporal dementia, confirmed by imaging studies, with autosomal
dominant inheritance. In 2 patients available for testing, the authors
found a novel heterozygous mutation in the presenilin-1 gene (L113P;
104311.0023).

- Genetic Modifiers and Susceptibility Alleles

Short et al. (2002) determined the tau haplotype frequencies and APOE
(107741) allele frequencies in 63 patients with sporadic disease
categorized by clinical subtype of frontotemporal lobar degeneration
(FTLD). The clinical subtypes are determined by the distribution of
pathologic findings: in the frontal lobe, frontotemporal dementia (FD)
and progressive nonfluent aphasia (PA), and in the temporal lobes,
anomic aphasia (AA) in the left, and visual aphasia in the right. No tau
mutations were found. Short et al. (2002) found that the APOE4 allele
and the tau H2 haplotype were more common in patients with AA than FD.
The tau H2 haplotype was more common in APOE4-positive patients with AA
and less common in APOE4-negative patients with FD. Thus, there are
genetic differences between the clinical subtypes of FTLD. In addition,
the increase of tau H2 frequency in patients with an APOE4 allele and AA
suggested that there may be an interaction between these 2 genes,
resulting in a specific clinical phenotype.

Verpillat et al. (2002) found that the H1/H1 tau genotype was
significantly overrepresented in 100 patients with frontotemporal
dementia compared to controls (odds ratio for H1/H1 = 1.95). In
addition, there was a significant negative effect in carriers of both
the H1/H1 genotype and the APOE2 allele.

Verpillat et al. (2002) determined the APOE genotype frequencies in 94
unrelated patients with frontotemporal dementia and 392 age- and
sex-matched controls without cognitive deficits or behavioral
disturbances (after excluding 6 patients with autosomal dominant
inheritance and mutation in the MAPT gene). Homozygosity for the E2E2
genotype was significantly associated with frontotemporal dementia (odds
ratio = 11.3, P = 0.033, exact test) but based on very few subjects (3
patients and 1 control). The result was even more significant in the
group with a positive familial history (odds ratio = 23.8, P = 0.019,
exact test). For the metaanalysis of the APOE polymorphism in
frontotemporal dementia, Verpillat et al. (2002) pooled 10 case-control
studies with available genotype or allele information (total of 364
patients and 2,671 controls), but the E2E2 genotype did not reach
statistical significance. Because of heterogeneity, Verpillat et al.
(2002) analyzed on one hand the neuropathologically-confirmed studies
and on the other hand the clinical-based studies. A significant increase
in the E2 allele frequency was found in the
neuropathologically-confirmed patients, and heterogeneity disappeared
(Mantel-Haenszel statistics). The authors concluded that the APOE E2
allele may be a risk factor for frontotemporal dementia, but that the
data should be interpreted with caution due to the rarity of the E2E2
genotype.

Borroni et al. (2005) found no association between FTD and the H1 or H2
MAPT haplotypes among 86 patients with FTD and 50 control individuals.
However, the findings suggested an earlier age at onset in patients
carrying an H2 allele.

Among 32 patients with a clinical diagnosis of frontotemporal dementia,
including 15 patient with primary progressive aphasia, Acciarri et al.
(2006) found increased frequency of the APOE E2 and E4 alleles and
significantly decreased frequency of the E3 allele compared to 87
control individuals. The E2E4 genotype in particular was significantly
associated with primary progressive aphasia.

GENOTYPE/PHENOTYPE CORRELATIONS

Among 22 patients with FTLD due to a MAPT mutation, Whitwell et al.
(2009) found different patterns of gray matter atrophy using MRI
voxel-based morphometry. All patients showed gray matter loss in the
anterior temporal lobes, with varying degrees of involvement of the
frontal and parietal lobes. Within the temporal lobe, individuals with
the IVS10+16 IVS10+16 (157140.0006), IVS10+3, N279K (157140.0009), or
S305N (157140.0010) mutations showed gray matter loss particularly
affecting the medial temporal lobes, including the hippocampus and
amygdala. These mutations are all predicted to influence the alternative
splicing of MAPT pre-mRNA, resulting in increased 4R tau isoforms. In
contrast, patients with the P301L (157140.0001) or V337M (157140.0008)
mutations showed gray matter loss particularly affecting the inferior
and lateral temporal lobes, with a relative sparing of the medial
temporal lobe. P301L and V337M mutation carriers also showed gray matter
loss in the basal ganglia. These mutations are predicted to affect the
structure and functional properties of the tau protein, which are more
prone to aggregation. The different patterns suggested a potential
difference in mutant protein function resulting from different
pathogenic mutations.

ANIMAL MODEL

To model tauopathies, Ishihara et al. (1999) overexpressed the smallest
human tau isoform in the central nervous system of transgenic mice.
These mice acquired age-dependent central nervous system pathology,
including insoluble, hyperphosphorylated tau and argyrophilic
intraneuronal inclusions formed by tau-immunoreactive filaments.
Inclusions were present in cortical and brainstem neurons but were most
abundant in spinal cord neurons, where they were associated with axon
degeneration, diminished microtubules, and reduced axonal transport in
ventral roots, as well as spinal cord gliosis and motor weakness. These
transgenic mice recapitulated key features of tauopathies and provided
models for elucidating mechanisms underlying diverse tauopathies.

Noting that earlier mouse models had focused on neuronal tau pathology,
Higuchi et al. (2002) generated transgenic mice overexpressing human tau
in glia as well as in neurons. The animals showed accumulation of
abnormal tau aggregates in glial cells with progressing age, loss of
neurons and glial cells, disruption of myelin sheaths, and progressive
motor disturbances such as weakness and dystonia.

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49. van Leeuwen, F. W.; van Tijn, P.; Sonnemans, M. A. F.; Hobo, B.;
Mann, D. M. A.; Van Broeckhoven, C.; Kumar-Singh, S.; Cras, P.; Leuba,
G.; Savioz, A.; Maat-Schieman, M. L. C.; Yamaguchi, H.; Kros, J. M.;
Kamphorst, W.; Hol, E. M.; de Vos, R. A. I.; Fischer, D. F.: Frameshift
proteins in autosomal dominant forms of Alzheimer disease and other
tauopathies. Neurology 66 (suppl. 1): S86-S92, 2006.

50. Verpillat, P.; Camuzat, A.; Hannequin, D.; Thomas-Anterion, C.;
Puel, M.; Belliard, S.; Dubois, B.; Didic, M.; Lacomblez, L.; Moreaud,
O.; Golfier, V.; Campion, D.; Brice, A.; Clerget-Darpoux, F.: Apolipoprotein
E gene in frontotemporal dementia: an association study and meta-analysis. Europ.
J. Hum. Genet. 10: 399-405, 2002.

51. Verpillat, P.; Camuzat, A.; Hannequin, D.; Thomas-Anterion, C.;
Puel, M.; Belliard, S.; Dubois, B.; Didic, M.; Michel, B.-F.; Lacomblez,
L.; Moreaud, O.; Sellal, F.; Golfier, V.; Campion, D.; Clerget-Darpoux,
F.; Brice, A.: Association between the extended tau haplotype and
frontotemporal dementia. Arch. Neurol. 59: 935-939, 2002.

52. Whitwell, J. L.; Jack, C. R., Jr.; Boeve, B. F.; Senjem, M. L.;
Baker, M.; Ivnik, R. J.; Knopman, D. S.; Wszolek, Z. K.; Petersen,
R. C.; Rademakers, R.; Josephs, K. A.: Atrophy patterns in IVS10+16,
IVS10+3, N279K, S305N, P301L, and V337M MAPT mutations. Neurology 73:
1058-1065, 2009.

53. Wijker, M.; Wszolek, Z. K.; Wolters, E. C. H.; Rooimans, M. A.;
Pals, G.; Pfeiffer, R. F.; Lynch, T.; Rodnitzky, R. L.; Wilhelmsen,
K. C.; Arwert, F.: Localization of the gene for rapidly progressive
autosomal dominant parkinsonism and dementia with pallido-ponto-nigral
degeneration to chromosome 17q21. Hum. Molec. Genet. 5: 151-154,
1996.

54. Wijker, M.; Wszolek, Z. K.; Wolters, E. C. H.; Rooimans, M. A.;
Pals, G.; Pfeiffer, R. F.; Lynch, T.; Rodnitzky, R. L.; Wilhelmsen,
K. C.; Arwert, F.: Localization of the gene for rapidly progressive
autosomal dominant parkinsonism and dementia with pallido-ponto-nigral
degeneration to chromosome 17q21. Hum. Molec. Genet. 5: 151-154,
1996.

55. Wilhelmsen, K. C.; Forman, M. S.; Rosen, H. J.; Alving, L. I.;
Goldman, J.; Feiger, J.; Lee, J. V.; Segall, S. K.; Kramer, J. H.;
Lomen-Hoerth, C.; Rankin, K. P.; Johnson, J.; Feiler, H. S.; Weiner,
M. W.; Lee, V. M.-Y.; Trojanowski, J. Q.; Miller, B. L.: 17q-linked
frontotemporal dementia-amyotrophic lateral sclerosis without tau
mutations with tau and alpha-synuclein inclusions. Arch. Neurol. 61:
398-406, 2004.

56. Wilhelmsen, K. C.; Lynch, T.; Pavlou, E.; Higgins, M.; Hygaard,
T. G.: Localization of disinhibition-dementia-parkinsonism-amyotrophy
complex to 17q21-22. Am. J. Hum. Genet. 55: 1159-1165, 1994.

57. Wszolek, Z. K.; Pfeiffer, R. F.; Bhatt, M. H.; Schelper, R. L.;
Cordes, M.; Snow, B. J.; Rodnitzky, R. L.; Wolters, E. C.; Arwert,
F.; Calne, D. B.: Rapidly progressive autosomal dominant parkinsonism
and dementia with pallido-ponto-nigral degeneration. Ann. Neurol. 32:
312-320, 1992.

58. Yamaoka, L. H.; Welsh-Bohmer, K. A.; Hulette, C. M.; Gaskell,
P. C., Jr.; Murray, M.; Rimmler, J. L.; Helms, B. R.; Guerra, M.;
Roses, A. D.; Schmechel, D. E.; Pericak-Vance, M. A.: Linkage of
frontotemporal dementia to chromosome 17: clinical and neuropathological
characterization of phenotype. Am. J. Hum. Genet. 59: 1306-1312,
1996.

*FIELD* CS
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Central nervous system];
Frontal lobe dementia;
Language impairment;
Word-finding difficulties;
Decrease in abstract thinking;
Motor symptoms may be present;
Parkinsonism;
Amyotrophic lateral sclerosis;
Cortical and subcortical neuronal loss in the frontal and temporal
regions;
Tau-positive inclusions may be found;
Ubiquitin-positive inclusions;
Primitive reflexes (palmomental, snout, glabellar);
[Behavioral/psychiatric manifestations];
Personality changes;
Lack of motivation;
Inappropriate laughter;
Apathy;
Irritability;
Disinhibition;
Kluver-Bucy syndrome;
Inappropriate sexual behavior;
Hyperphagia;
Hyperoralia

MISCELLANEOUS:
Mean age at onset 45 years;
Highly variable phenotype that includes several subtypes (see, e.g.,
607485, 601104);
Genetic heterogeneity (see, e.g., 600795, 105550);
Most cases do not have mutations in the MAPT gene, but map to chromosome
17q

MOLECULAR BASIS:
Caused by mutation in the microtubule-associated tau protein gene
(MAPT, 157140.0001);
Caused by mutation in the presenilin-1 gene (PSEN1, 104311.0023)

*FIELD* CN
Cassandra L. Kniffin - revised: 6/9/2004

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

*FIELD* ED
joanna: 07/26/2010
ckniffin: 8/9/2004
ckniffin: 6/9/2004
alopez: 10/27/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 3/23/2011
Cassandra L. Kniffin - updated: 3/8/2011
Cassandra L. Kniffin - updated: 1/4/2010
Cassandra L. Kniffin - updated: 3/27/2009
Cassandra L. Kniffin - updated: 3/16/2009
Cassandra L. Kniffin - updated: 12/5/2008
Cassandra L. Kniffin - updated: 4/18/2008
Cassandra L. Kniffin - updated: 4/4/2008
Cassandra L. Kniffin - updated: 12/5/2007
Cassandra L. Kniffin - updated: 9/20/2007
Ada Hamosh - updated: 10/25/2006
Ada Hamosh - updated: 9/8/2006
Cassandra L. Kniffin - updated: 6/12/2006
Cassandra L. Kniffin - updated: 5/24/2006
Cassandra L. Kniffin - updated: 4/20/2006
Cassandra L. Kniffin - updated: 4/10/2006
Cassandra L. Kniffin - updated: 11/3/2005
Cassandra L. Kniffin - updated: 6/9/2004
Michael B. Petersen - updated: 7/2/2003
Victor A. McKusick - updated: 1/8/2003
Cassandra L. Kniffin - updated: 10/1/2002
Cassandra L. Kniffin - reorganized: 6/5/2002
Cassandra L. Kniffin - updated: 6/4/2002
Victor A. McKusick - updated: 12/21/2001
Ada Hamosh - updated: 2/22/2000
Victor A. McKusick - updated: 6/29/1998

*FIELD* CD
Victor A. McKusick: 1/4/1995

*FIELD* ED
terry: 04/04/2013
carol: 10/4/2011
wwang: 5/18/2011
carol: 5/2/2011
carol: 4/26/2011
terry: 4/20/2011
carol: 4/14/2011
wwang: 4/12/2011
terry: 3/30/2011
ckniffin: 3/23/2011
wwang: 3/11/2011
terry: 3/10/2011
ckniffin: 3/8/2011
ckniffin: 3/7/2011
ckniffin: 1/14/2011
alopez: 1/4/2010
terry: 5/14/2009
alopez: 4/15/2009
wwang: 4/10/2009
ckniffin: 3/27/2009
wwang: 3/26/2009
ckniffin: 3/16/2009
wwang: 12/15/2008
ckniffin: 12/5/2008
carol: 9/19/2008
wwang: 4/23/2008
ckniffin: 4/18/2008
wwang: 4/17/2008
ckniffin: 4/4/2008
wwang: 12/11/2007
ckniffin: 12/5/2007
wwang: 10/2/2007
ckniffin: 9/20/2007
terry: 9/14/2007
ckniffin: 2/19/2007
alopez: 11/2/2006
terry: 10/25/2006
alopez: 9/20/2006
terry: 9/8/2006
ckniffin: 7/17/2006
carol: 6/21/2006
ckniffin: 6/12/2006
wwang: 5/25/2006
ckniffin: 5/24/2006
wwang: 4/24/2006
ckniffin: 4/20/2006
wwang: 4/19/2006
ckniffin: 4/10/2006
wwang: 11/11/2005
ckniffin: 11/3/2005
ckniffin: 6/11/2004
carol: 6/11/2004
ckniffin: 6/9/2004
ckniffin: 6/8/2004
cwells: 7/2/2003
ckniffin: 6/20/2003
carol: 1/14/2003
tkritzer: 1/10/2003
terry: 1/8/2003
carol: 10/21/2002
ckniffin: 10/4/2002
ckniffin: 10/1/2002
carol: 6/5/2002
ckniffin: 6/5/2002
ckniffin: 6/4/2002
cwells: 1/10/2002
cwells: 12/28/2001
terry: 12/21/2001
alopez: 10/27/2000
alopez: 2/22/2000
carol: 6/29/1998
terry: 6/29/1998
terry: 1/7/1997
jamie: 12/18/1996
mark: 11/15/1996
terry: 11/15/1996
mimadm: 9/23/1995
carol: 1/4/1995

MIM 607822
*RECORD*
*FIELD* NO
607822
*FIELD* TI
#607822 ALZHEIMER DISEASE 3
;;AD3;;
ALZHEIMER DISEASE 3, EARLY-ONSET;;
ALZHEIMER DISEASE, FAMILIAL, 3
read moreALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND UNUSUAL
PLAQUES, INCLUDED;;
ALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND APRAXIA,
INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because early-onset familial
Alzheimer disease-3 (AD3) is caused by mutation in the presenilin-1 gene
(PSEN1; 104311).

For a phenotypic description and a discussion of genetic heterogeneity
of Alzheimer disease, see 104300.

CLINICAL FEATURES

Campion et al. (1995) studied a large pedigree that included 34 subjects
with early-onset progressive dementia with mean age at onset at 46 plus
or minus 3.5 years and mean age at death at 52.6. Myoclonus and
extrapyramidal signs were common; seizures were present in all affected
subjects. There were neuropathologic changes typical of Alzheimer
disease in the 2 brains examined.

Lopera et al. (1997) described a large pedigree with early-onset
Alzheimer disease from a community based in Antioquia, Colombia.
Affected patients had a mean age at onset of 46.8 years (range, 34 to 62
years) with an average interval of 8 years until death. Headache was
noted in affected individuals significantly more frequently than in
those not affected. The most frequent presentations were memory loss
followed by behavioral and personality changes and progressive loss of
language ability. In the final stages, gait disturbances, seizures, and
myoclonus were frequent.

Hull et al. (1998) described a German family with early-onset Alzheimer
disease with a mutation in the PSEN1 gene. From the age of 43 years, the
proband had complained of deficits in short-term memory. Relatives had
noticed his symptoms even earlier and dated the onset of deficits to age
38 years when he showed increasing interruptions during speech followed
by social withdrawal. There was a strong family history of dementia.
Through 3 generations the onset of dementia in this family was between
42 and 45 years.

Rippon et al. (2003) reported an African American family with autosomal
dominant rapidly progressive dementia and psychosis occurring early in
the fifth decade. Two brothers presented with personality changes,
labile mood, language difficulties, psychosis, primitive reflexes
consistent with frontotemporal dementia (600274), but also were found to
have memory impairment and neuropathologic findings diagnostic of AD.
Both brothers had a mutation in the PSEN1 gene (104311.0006). Their
father reportedly had died in his sixth decade with a similar illness.
The authors commented on the atypical clinical presentation.

Godbolt et al. (2004) reported 2 sibs with early-onset Alzheimer disease
confirmed by genetic analysis (104311.0030). Both patients presented at
around age 50 with difficulty in word finding and impaired frontal
executive function, but with relative preservation of memory. The sister
exhibited dysfluent speech with phonemic paraphasias, dysgraphia, and
dyspraxia. She later developed mutism, generalized rigidity, myoclonus
of the upper limbs, dystonic posturing of the right hand, and shuffling
gait. The brother exhibited impaired repetition of sentences and
polysyllabic words, nominal dysphasia, dysgraphia, and dyscalculia. MRI
of both patients showed multiple foci of white matter signal changes.

Ataka et al. (2004) reported a Japanese patient with onset of memory
impairment and difficulty driving a car at age 26. Neuropsychologic
testing showed that he had visual constructional apraxia, visuospatial
agnosia, and optic ataxia, consistent with the 'visual variant' of AD in
which there is a visuospatial cognitive deficit. The patient was
heterozygous for a PSEN1 mutation (104311.0031).

Halliday et al. (2005) reported 2 sibs with early-onset FAD and mutation
(M146L; 104311.0001) in the PSEN1 gene. Family history suggested that
their father was also affected. Neuropathologic examination of both
patients showed numerous cortical plaques and neurofibrillary tangles,
consistent with AD. In addition, both cases showed ballooned neurons and
numerous tau (MAPT; 157140)-immunoreactive Pick bodies in upper
frontotemporal cortical layers and in the hippocampal dentate gyrus.
Halliday et al. (2005) suggested that the M146L mutation may
specifically predispose to both AD and Pick pathology by affecting
multiple intracellular pathways involving tau phosphorylation.

Leverenz et al. (2006) found that 24 (96%) of 25 patients with AD3 had
Lewy body pathology in the amygdala. Most patients also had Lewy body
pathology in other brain regions, including the cingulate gyrus and
neocortex, although there was variability. AD patients with PSEN1
mutations had more frequent Lewy body pathology compared to AD patients
with PSEN2 (600759) mutations. There was no clinical correlation between
age at onset or disease severity onset and Lewy body pathology in either
group, although those with longer disease duration tended to have more
Lewy body pathology.

Piccini et al. (2007) reported a patient who presented at age 28 years
with delusions and lower limb jerks accompanied by intentional myoclonus
and cerebellar ataxia. He had rapid progression with global impairment
of all cognitive functions and became bedridden, anarthric, and
incontinent by age 33. He died of bronchopneumonia at age 35. Postmortem
examination showed severe beta-amyloid deposition in the cerebral and
cerebellar cortices, amyloid angiopathy, and severe loss of Purkinje
cells and fibers in the cerebellum. Neurofibrillary tangles were also
present. Genetic analysis revealed a heterozygous mutation in the PSEN1
gene (S170F; 104311.0036).

- FAD with spastic paraparesis and unusual plaques

In a family with onset of AD in the early forties reported by the
Alzheimer's Disease Collaborative Group (1995), O'Riordan et al. (2002)
described an atypical disease pattern in 3 additional members from the
third generation. One had cognitive impairment, spastic paraparesis, and
white matter abnormalities on MRI. One of his sibs developed dementia
and myoclonus and had white matter abnormalities on MRI. Another sib had
ophthalmoplegia, spastic-ataxic quadriparesis, and cotton-wool plaques
with amyloid angiopathy on brain biopsy (MRI was not performed). The
authors suggested that the MRI findings may reflect an ischemic
leukoencephalopathy due to amyloid angiopathy affecting meningocortical
vessels.

Crook et al. (1998) reported a Finnish pedigree with 17 affected
individuals of both sexes in 3 generations suffering from a novel
variant of Alzheimer disease characterized by progressive dementia that
was in most cases preceded by spastic paraparesis. Neuropathologic
investigations showed numerous distinct, large, round, and eosinophilic
plaques, as well as neurofibrillary tangles and amyloid angiopathy
throughout the cerebral cortex. The predominant plaques resembled
cotton-wool balls and were immunoreactive for A-beta, but lacked a
congophilic dense core or marked plaque-related neuritic pathology.

Matsubara-Tsutsui et al. (2002) reported a Japanese family in which 6
individuals in 2 generations were affected with presenile dementia
preceded by spastic gait. Detailed information was available in 1
patient who had disease onset at age 35 with spasticity, motor apraxia,
and cognitive decline. Neuropathologic examination was not done.

Rogaeva et al. (2003) reported the neuropathologic findings of a patient
with FAD and spastic paraplegia with onset at 52 years of age. The brain
had severe cortical atrophy with neuronal loss, as well as atrophy of
the caudate, hippocampus, amygdala, and entorhinal cortex. The
substantia nigra was pale, depopulated, and had rare tangles and Lewy
bodies. Neurofibrillary tangles and amyloid plaques with a cotton-wool
appearance were identified. Consistent with spastic paraplegia, the
spinal cord was smaller than usual and flattened in its anteroposterior
dimension, and there was degeneration of the corticospinal tracts.

Moretti et al. (2004) reported 2 sibs with early-onset dementia and
spastic paraparesis. Their father, paternal grandfather, and paternal
great-grandfather reportedly died in their thirties of a dementing
illness associated with severe progressive gait impairment. The proband
developed memory problems at age 28 years. At age 31, he had mild
bilateral limb apraxia, dystonia, mild dementia, and hypometabolism of
the temporoparietal association cortex on PET scan. By age 34, he was
profoundly demented, with dysarthria, dysphagia, and spasticity of the
arms and legs. Postmortem examination showed moderate brain atrophy with
amyloid plaques and neurofibrillary tangles consistent with AD
throughout the neocortex, limbic regions, and striatum, as well as large
eosinophilic cotton-wool plaques. His sister had a similar disease
course. Moretti et al. (2004) identified a heterozygous 6-bp insertion
in the PSEN1 gene (104311.0029) in both sibs.

Marrosu et al. (2006) reported a family in which 4 members had memory
loss and personality changes ranging in onset from 32 to 45 years of age
followed by a rapidly progressive disease course resulting in dementia,
spastic tetraparesis, and anarthria in the most severely affected
patients. Brain imaging showed multiple white matter lesions reminiscent
of those seen in multiple sclerosis (see 126200). Genetic analysis
confirmed a heterozygous mutation in the PSEN1 gene.

MAPPING

St. George-Hyslop et al. (1992), Van Broeckhoven et al. (1992), and
Mullan et al. (1992) presented evidence of linkage of early-onset FAD to
chromosome 14q.

In 2 Belgian families with early-onset autosomal dominant AD, Van
Broeckhoven et al. (1987) excluded linkage to the APP locus on
chromosome 21q. One pedigree contained 36 patients in 6 generations, and
the second had 22 patients spanning 5 generations. By linkage analysis
of the 2 Belgian families studied by Van Broeckhoven et al. (1987), Van
Broeckhoven et al. (1992) found linkage to chromosome 14q. They narrowed
the candidate region to an 8.9-cM area between D14S42 and D14S53,
flanking D14S43 on both sides.

Mullan et al. (1992) placed the gene proximal to that for
alpha-1-antichymotrypsin (AACT; 107280), thus excluding AACT, which is a
component of plaque cores and a protease inhibitor, as a possible
candidate gene for AD.

In 9 non-Volga German kindreds with autosomal dominant AD, Schellenberg
et al. (1992) found linkage to chromosome 14: a total lod score of 9.15
at theta = 0.01 was obtained with the marker D14S43 at 14q24.3. A single
early-onset family yielded a lod score of 4.89 (theta = 0.0). When no
assumptions were made about age-dependent penetrance, significant
results were still obtained (maximum lod = 5.94 at theta = 0.0) despite
the loss of power. Results for several Volga German families were either
negative or nonsignificant for markers in this region of chromosome 14.

Schellenberg et al. (1993) explored the role of chromosome 14 in
late-onset FAD. They studied 49 families with a mean age of onset of 60
years or more. No evidence of linkage was obtained, and strong evidence
against linkage to chromosome 3 markers was found. Evidence of linkage
to D14S52 was found for a subgroup of families of intermediate age of
onset, namely, older than 60 but less than 70 years of age. They
concluded that the chromosome 14 locus was not responsible for Alzheimer
disease in most late-onset FAD kindreds.

In 2 large early-onset FAD pedigrees, Nechiporuk et al. (1993) found
tight linkage to D14S43 and D14S53. In a large pedigree with early-onset
FAD, Campion et al. (1995) observed a lod score of 5.48 at a
recombination fraction of theta = 0.0 with the genetic marker D14S43,
confirming the location of the responsible gene on chromosome 14q24.3.

MOLECULAR GENETICS

Sherrington et al. (1995) identified 5 different missense mutations in
the PSEN1 gene that cosegregated with early-onset familial Alzheimer
disease type 3 (104311.0001-104311.0005).

Lopera et al. (1997) stated that affected members of a large Colombian
kindred with early-onset AD had a glu280-to-ala mutation in the PSEN1
gene (E280A; 104311.0009). By genotype analysis of 109 carriers of the
E280A PSEN1 mutation, including 52 individuals with AD, Pastor et al.
(2003) found that those with at least 1 APOE4 (see 107741) allele were
more likely to develop AD at an earlier age than those without an APOE4
allele, indicating an epistatic effect.

In affected members of 24 of 31 families with early-onset AD, Raux et
al. (2005) identified mutations in the PSEN1 gene. The mean age of
disease onset was 41.7 years. Combined with earlier studies, the authors
estimated that 66% of families with early-onset AD are attributable to
mutations in the PSEN1 gene.

- FAD with Spastic Paraparesis and Unusual Plaques

In a family with FAD with onset in the early forties, O'Riordan et al.
(2002) identified a mutation in the PSEN1 gene (E280G; 104311.0010).
Three additional members with the same mutation also had spastic
paraparesis and unusual plaques. In a patient with FAD, spastic
paraplegia, and cotton-wool plaques, Rogaeva et al. (2003) identified
the E280G mutation. The authors noted that the E280G mutation had been
found in patients with classic FAD, suggesting that genetic modifiers
may exist.

In a Finnish family with FAD with spastic paraparesis and unusual
plaques, Crook et al. (1998) identified a mutation in the PSEN1 gene
that caused deletion of exon 9 (104311.0012). They stated that it was
the only known structural mutation in the PSEN1 gene; previously
identified mutations had been missense mutations.

In a Japanese patient with early-onset FAD, spasticity, and apraxia,
Matsubara-Tsutsui et al. (2002) identified a mutation in the PSEN1 gene
(104311.0022).

POPULATION GENETICS

Yescas et al. (2006) identified a heterozygous mutation in the PSEN1
gene (A431E; 104311.0033) in affected members of 9 Mexican families with
early-onset Alzheimer disease, All families were from the state of
Jalisco in western Mexico, and haplotype analysis indicated a founder
effect. The A431E mutation was found in 19 (32%) of 60 apparently
unaffected family members, suggesting either a presymptomatic state or
reduced penetrance. Murrell et al. (2006) found the A431E mutation in 20
individuals with AD3 from 15 families identified in Guadalajara,
southern California, and Chicago. Age at disease onset ranged from 33 to
44 years, and spasticity was a common clinical feature. Fourteen
families were of Mexican mestizo descent, and of these families, 9
traced the illness to ancestors from the state of Jalisco in Mexico. The
remaining proband had a more remote Mexican ancestry. The findings
further supported a founder effect for the A431E mutation.

HISTORY

Early-onset Alzheimer disease with spastic paraparesis was first
reported by Barrett (1913).

Ettinger et al. (1994) proposed that familial Alzheimer disease is
associated with chromosomal instability and breakage at nonrandom sites.
Using a novel gene cotransfer technique involving X-linked markers, they
found decreased cotransfer of markers in FAD fibroblasts compared to
controls, suggesting increased chromosomal breakage. The authors
hypothesized a role for the trifunctional protein C(1)-THF synthase
(172460), which maps to 14q24, in the generation of chromosomal
instability in FAD.

*FIELD* SA
Tanzi et al. (1991)
*FIELD* RF
1. Alzheimer's Disease Collaborative Group: The structure of the
presenilin 1 (S182) gene and identification of six novel mutations
in early onset AD families. Nature Genet. 11: 219-222, 1995.

2. Ataka, S.; Tomiyama, T.; Takuma, H.; Yamashita, T.; Shimada, H.;
Tsutada, T.; Kawabata, K.; Mori, H.; Miki, T.: A novel presenilin-1
mutation (leu85pro) in early-onset Alzheimer disease with spastic
paraparesis. Arch. Neurol. 61: 1773-1776, 2004.

3. Barrett, A. M.: A case of Alzheimer's disease with unusual neurological
disturbances. J. Nerv. Ment. Dis. 4: 361-374, 1913.

4. Campion, D.; Brice, A.; Hannequin, D.; Tardieu, S.; Dubois, B.;
Calenda, A.; Brun, E.; Penet, C.; Tayot, J.; Martinez, M.; Bellis,
M.; Mallet, J.; Agid, Y.; Clerget-Darpoux, F.: A large pedigree with
early-onset Alzheimer's disease: clinical, neuropathologic, and genetic
characterization. Neurology 45: 80-85, 1995.

5. Crook, R.; Verkkoniemi, A.; Perez-Tur, J.; Mehta N.; Baker, M.;
Houlden, H.; Farrer, M.; Hutton, M.; Lincoln, S.; Hardy, J.; Gwinn,
K.; Somer, M.; Paetau, A.; Kalimo, H.; Ylikoski, R.; Poyhonen, M.;
Kucera, S.; Haltia, M.: A variant of Alzheimer's disease with spastic
paraparesis and unusual plaques due to deletion of exon 9 of presenilin
1. Nature Med. 4: 452-455, 1998.

6. Ettinger, S.; Weksler, M. E.; Zhou, X.; Blass, J.; Szabo, P.:
Chromosomal fragility associated with familial Alzheimer's disease. Ann.
Neurol. 36: 190-199, 1994.

7. Godbolt, A. K.; Beck, J. A.; Collinge, J.; Garrard, P.; Warren,
J. D.; Fox, N. C.; Rossor, M. N.: A presenilin 1 R278I mutation presenting
with language impairment. Neurology 63: 1702-1704, 2004.

8. Halliday, G. M.; Song, Y. J. C.; Lepar, G.; Brooks, W. S.; Kwok,
J. B.; Kersaitis, C.; Gregory, G.; Shepherd, C. E.; Rahimi, F.; Schofield,
P. R.; Kril, J. J.: Pick bodies in a family with presenilin-1 Alzheimer's
disease. Ann. Neurol. 57: 139-143, 2005.

9. Hull, M.; Fiebich, B. L.; Dykierek, P.; Schmidtke, K.; Nitzsche,
E.; Orszagh, M.; Deuschl, G.; Moser, E.; Schumacher, M.; Lucking,
C.; Berger, M.; Bauer, J.: Early-onset Alzheimer's disease due to
mutations of the presenilin-1 gene on chromosome 14: a 7-year follow-up
of a patient with a mutation at codon 139. Europ. Arch. Psychiat.
Clin. Neurosci. 248: 123-129, 1998.

10. Leverenz, J. B.; Fishel, M. A.; Peskind, E. R.; Montine, T. J.;
Nochlin, D.; Steinbart, E.; Raskind, M. A.; Schellenberg, G. D.; Bird,
T. D.; Tsuang, D.: Lewy body pathology in familial Alzheimer disease:
evidence for disease- and mutation-specific pathologic phenotype. Arch.
Neurol. 63: 370-376, 2006.

11. Lopera, F.; Ardilla, A.; Martinez, A.; Madrigal, L.; Arango-Viana,
J. C.; Lemere, C. A.; Arango-Lasprilla, J. C.; Hincapie, L.; Arcos-Burgos,
M.; Ossa, J. E.; Behrens, I. M.; Norton, J.; Lendon, C.; Goate, A.
M.; Ruiz-Linares, A.; Rosselli, M.; Kosik, K. S.: Clinical features
of early-onset Alzheimer disease in a large kindred with an E280A
presenilin-1 mutation. JAMA 277: 793-799, 1997.

12. Marrosu, M. G.; Floris, G.; Costa, G.; Schirru, L.; Spinicci,
G.; Cherchi, M. V.; Mura, M.; Mascia, M. G.; Cocco, E.: Dementia,
pyramidal system involvement, and leukoencephalopathy with a presenilin
1 mutation. Neurology 66: 108-111, 2006.

13. Matsubara-Tsutsui, M.; Yasuda, M.; Yamagata, H.; Nomura, T.; Taguchi,
K.; Kohara, K.; Miyoshi, K.; Miki, T.: Molecular evidence of presenilin
1 mutation in familial early onset dementia. Am. J. Med. Genet. 114:
292-298, 2002.

14. Moretti, P.; Lieberman, A. P.; Wilde, E. A.; Giordani, B. I.;
Kluin, K. J.; Koeppe, R. A.; Minoshima, S.; Kuhl, D. E.; Seltzer,
W. K.; Foster, N. L.: Novel insertional presenilin 1 mutation causing
Alzheimer disease with spastic paraparesis. Neurology 62: 1865-1868,
2004.

15. Mullan, M.; Houlden, H.; Windelspecht, M.; Fidani, L.; Lombardi,
C.; Diaz, P.; Rossor, M.; Crook, R.; Hardy, J.; Duff, K.; Crawford,
F.: A locus for familial early-onset Alzheimer's disease on the long
arm of chromosome 14, proximal to the alpha-1-antichymotrypsin gene. Nature
Genet. 2: 340-342, 1992.

16. Murrell, J.; Ghetti, B.; Cochran, E.; Macias-Islas, M. A.; Medina,
L.; Varpetian, A.; Cummings, J. L.; Mendez, M. F.; Kawas, C.; Chui,
H.; Ringman, J. M.: The A431E mutation in PSEN1 causing familial
Alzheimer's disease originating in Jalisco state, Mexico: an additional
fifteen families. (Letter) Neurogenetics 7: 277-279, 2006.

17. Nechiporuk, A.; Fain, P.; Kort, E.; Nee, L. E.; Frommelt, E.;
Polinsky, R. J.; Korenberg, J. R.; Pulst, S.-M.: Linkage of familial
Alzheimer disease to chromosome 14 in two large early-onset pedigrees:
effects of marker allele frequencies on lod scores. Am. J. Med. Genet. 48:
63-66, 1993.

18. O'Riordan, S.; McMonagle, P.; Janssen, J. C.; Fox, N. C.; Farrell,
M.; Collinge, J.; Rossor, M. N.; Hutchinson, M.: Presenilin-1 mutation
(E280G), spastic paraparesis, and cranial MRI white-matter abnormalities. Neurology 59:
1108-1110, 2002.

19. Pastor, P.; Roe, C. M.; Villegas, A.; Bedoya, G.; Chakraverty,
S.; Garcia, G.; Tirado, V.; Norton, J.; Rios, S.; Martinez, M.; Kosik,
K. S.; Lopera, F.; Goate, A. M.: Apolipoprotein E-epsilon-4 modifies
Alzheimer's disease onset in an E280A PS1 kindred. Ann. Neurol. 54:
163-169, 2003.

20. Piccini, A.; Zanusso, G.; Borghi, R.; Noviello, C.; Monaco, S.;
Russo, R.; Damonte, G.; Armirotti, A.; Gelati, M.; Giordano, R.; Zambenedetti,
P.; Russo, C.; Ghetti, B.; Tabaton, M.: Association of a presenilin
1 S170F mutation with a novel Alzheimer disease molecular phenotype. Arch.
Neurol. 64: 738-745, 2007.

21. Raux, G.; Guyant-Marechal, L.; Martin, C.; Bou, J.; Penet, C.;
Brice, A.; Hannequin, D.; Frebourg, T.; Campion, D.: Molecular diagnosis
of autosomal dominant early onset Alzheimer's disease: an update.
(Letter) J. Med. Genet. 42: 793-795, 2005.

22. Rippon, G. A.; Crook, R.; Baker, M.; Halvorsen, E.; Chin, S.;
Hutton, M.; Houlden, H.; Hardy, J.; Lynch, T.: Presenilin 1 mutation
in an African American family presenting with atypical Alzheimer dementia. Arch.
Neurol. 60: 884-888, 2003.

23. Rogaeva, E.; Bergeron, C.; Sato, C.; Moliaka, I.; Kawarai, T.;
Toulina, A.; Song, Y.-Q.; Kolesnikova, T.; Orlacchio, A.; Bernardi,
G.; St. George-Hyslop, P. H.: PS1 Alzheimer's disease family with
spastic paraplegia: the search for a gene modifier. Neurology 61:
1005-1007, 2003.

24. Schellenberg, G. D.; Bird, T. D.; Wijsman, E. M.; Orr, H. T.;
Anderson, L.; Nemens, E.; White, J. A.; Bonnycastle, L.; Weber, J.
L.; Alonso, M. E.; Potter, H.; Heston, L. L.; Martin, G. M.: Genetic
linkage evidence for a familial Alzheimer's disease locus on chromosome
14. Science 258: 668-671, 1992.

25. Schellenberg, G. D.; Payami, H.; Wijsman, E. M.; Orr, H. T.; Goddard,
K. A. B.; Anderson, L.; Nemens, E.; White, J. A.; Alonso, M. E.; Ball,
M. J.; Kaye, J.; Morris, J. C.; Chui, H.; Sadovnick, A. D.; Heston,
L. L.; Martin, G. M.; Bird, T. D.: Chromosome 14 and late-onset familial
Alzheimer disease (FAD). Am. J. Hum. Genet. 53: 619-628, 1993.

26. Sherrington, R.; Rogaev, E. I.; Liang, Y.; Rogaeva, E. A.; Levesque,
G.; Ikeda, M.; Chi, H.; Lin, C.; Li, G.; Holman, K.; Tsuda, T.; Mar,
L.; Foncin, J.-F.; Bruni, A. C.; Montesi, M. P.; Sorbi, S.; Rainero,
I.; Pinessi, L.; Nee, L.; Chumakov, I.; Pollen, D.; Brookes, A.; Sanseau,
P.; Polinsky, R. J.; Wasco, W.; Da Silva, H. A. R.; Haines, J. L.;
Pericak-Vance, M. A.; Tanzi, R. E.; Roses, A. D.; Fraser, P. E.; Rommens,
J. M.; St George-Hyslop, P. H.: Cloning of a gene bearing mis-sense
mutations in early-onset familial Alzheimer's disease. Nature 375:
754-760, 1995.

27. St. George-Hyslop, P.; Haines, J.; Rogaev, E.; Mortilla, M.; Vaula,
G.; Pericak-Vance, M.; Foncin, J.-F.; Montesi, M.; Bruni, A.; Sorbi,
S.; Rainero, I.; Pinessi, L.; Pollen, D.; Polinsky, R.; Nee, L.; Kennedy,
J.; Macciardi, F.; Rogaeva, E.; Liang, Y.; Alexandrova, N.; Lukiw,
W.; Schlumpf, K.; Tanzi, R.; Tsuda, T.; Farrer, L.; Cantu, J.-M.;
Duara, R.; Amaducci, L.; Bergamini, L.; Gusella, J.; Roses, A.; Crapper
McLachlan, D.: Genetic evidence for a novel familial Alzheimer's
disease locus on chromosome 14. Nature Genet. 2: 330-334, 1992.

28. Tanzi, R. E.; St. George-Hyslop, P. H.; Gusella, J. F.: Molecular
genetics of Alzheimer disease amyloid. J. Biol. Chem. 266: 20579-20582,
1991.

29. Van Broeckhoven, C.; Backhovens, H.; Cruts, M.; De Winter, G.;
Bruyland, M.; Cras, P.; Martin, J.-J.: Mapping of a gene predisposing
to early-onset Alzheimer's disease to chromosome 14q24.3. Nature
Genet. 2: 335-339, 1992.

30. Van Broeckhoven, C.; Genthe, A. M.; Vandenberghe, A.; Horsthemke,
B.; Backhovens, H.; Raeymaekers, P.; Van Hul, W.; Wehnert, A.; Gheuens,
J.; Cras, P.; Bruyland, M.; Martin, J. J.; Salbaum, M.; Multhaup,
G.; Masters, C. L.; Beyreuther, K.; Gurling, H. M. D.; Mullan, M.
J.; Holland, A.; Barton, A.; Irving, N.; Williamson, R.; Richards,
S. J.; Hardy, J. A.: Failure of familial Alzheimer's disease to segregate
with the A4-amyloid gene in several European families. Nature 329:
153-155, 1987.

31. Yescas, P.; Huertas-Vazquez, A.; Villarreal-Molina, M. T.; Rasmussen,
A.; Tusie-Luna, M. T.; Lopez, M.; Canizales-Quinteros, S.; Alonso,
M. E.: Founder effect for the ala431glu mutation of the presenilin
1 gene causing early-onset Alzheimer's disease in Mexican families. Neurogenetics 7:
195-200, 2006.

*FIELD* CS
INHERITANCE:
Autosomal dominant

ABDOMEN:
[Gastrointestinal];
Dysphagia

NEUROLOGIC:
[Central nervous system];
Alzheimer disease, early-onset;
Dementia, progressive;
Memory loss;
Loss of language ability;
Gait disturbances;
Spastic quadriparesis;
Myoclonus;
Dystonia;
Extrapyramidal signs;
Hyperreflexia in lower limbs;
Extensor plantar responses;
Seizures;
Apraxia;
Dysarthria;
Dysphagia;
Constructional apraxia (in a subset of patients);
Visuospatial agnosia (in a subset of patients);
Optic ataxia (in a subset of patients);
Cortical and subcortical regions involved;
Neurofibrillary tangles;
Amyloid plaques;
Eosinophilic 'cotton wool' plaques without dense congophilic core
in various brain regions;
Cortical atrophy;
[Behavioral/psychiatric manifestations];
Loss of attention;
Loss of executive functions;
Behavioral changes;
Personality changes;
Social withdrawal

MISCELLANEOUS:
Onset in late twenties to thirties;
A subset of patients have a 'visual variant';
Rapidly progressive;
Severe phenotype;
Later onset has been reported

MOLECULAR BASIS:
Caused by mutation in the presenilin-1 gene (PSEN1, 104311.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 6/17/2005

*FIELD* CD
Cassandra L. Kniffin: 2/18/2005

*FIELD* ED
ckniffin: 01/29/2008
joanna: 12/9/2005
ckniffin: 6/17/2005
joanna: 5/12/2005
ckniffin: 2/18/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 4/15/2008
Cassandra L. Kniffin - updated: 2/19/2007
Cassandra L. Kniffin - updated: 12/6/2006
Cassandra L. Kniffin - updated: 8/29/2006
Cassandra L. Kniffin - updated: 4/7/2006
Cassandra L. Kniffin - updated: 12/28/2005
Cassandra L. Kniffin - updated: 11/3/2005
Cassandra L. Kniffin - updated: 7/25/2005
Cassandra L. Kniffin - updated: 6/17/2005
Cassandra L. Kniffin - updated: 5/13/2005
Cassandra L. Kniffin - updated: 2/18/2005
Cassandra L. Kniffin - updated: 2/6/2004
Cassandra L. Kniffin - updated: 1/7/2004
Cassandra L. Kniffin - updated: 8/8/2003

*FIELD* CD
Cassandra L. Kniffin: 5/23/2003

*FIELD* ED
terry: 06/03/2009
wwang: 4/17/2008
ckniffin: 4/15/2008
alopez: 6/4/2007
wwang: 2/22/2007
ckniffin: 2/19/2007
wwang: 12/7/2006
ckniffin: 12/6/2006
wwang: 9/7/2006
ckniffin: 8/29/2006
wwang: 4/11/2006
ckniffin: 4/7/2006
carol: 2/10/2006
ckniffin: 12/28/2005
terry: 12/20/2005
ckniffin: 12/19/2005
wwang: 11/10/2005
ckniffin: 11/3/2005
wwang: 7/26/2005
ckniffin: 7/25/2005
ckniffin: 6/17/2005
wwang: 5/27/2005
ckniffin: 5/13/2005
ckniffin: 5/12/2005
wwang: 2/23/2005
ckniffin: 2/18/2005
tkritzer: 2/18/2004
ckniffin: 2/6/2004
tkritzer: 1/14/2004
ckniffin: 1/7/2004
ckniffin: 8/8/2003
ckniffin: 5/29/2003
carol: 5/28/2003
ckniffin: 5/27/2003

MIM 613694
*RECORD*
*FIELD* NO
613694
*FIELD* TI
#613694 CARDIOMYOPATHY, DILATED, 1U; CMD1U
*FIELD* TX
A number sign (#) is used with this entry because dilated
read morecardiomyopathy-1U is caused by heterozygous mutation in the PSEN1 gene
(104311) on chromosome 14q24.3.

For a general phenotypic description and a discussion of genetic
heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

CLINICAL FEATURES

Li et al. (2006) described an African American family with dilated
cardiomyopathy segregating with mutation in the PSEN1 gene (CMD1U).
Affected members were identified in 3 generations. Onset of dilated
cardiomyopathy and heart failure ranged from age 24 to 69 years.
Mortality from progressive heart failure usually followed within a few
years of diagnosis. The index patient presented with symptomatic heart
failure due to idiopathic dilated cardiomyopathy at age 52 years.
Another family member, who presented with idiopathic dilated
cardiomyopathy and heart failure at the age of 51 years, required
cardiac transplantation at age 62 years. Extensive hospital records
showed that the affected member in the first generation received the
diagnoses of heart failure and nonischemic dilated cardiomyopathy at age
69 years and of dementia at the age of 71 years. Both the cardiomyopathy
and dementia progressed and resulted in repeated hospitalizations until
the patient's death at age 78 years, in advanced heart failure.

MOLECULAR GENETICS

While familial Alzheimer disease (see 607822) can be caused by
presenilin mutations, these genes are also expressed in the heart and
are critical to cardiac development. Li et al. (2006) hypothesized that
mutations in presenilin may also be associated with dilated
cardiomyopathy (DCM; see 115200) and that their discovery could provide
new insight into the pathogenesis of DCM and heart failure. They
evaluated a total of 315 index patients with DCM for sequence variation
in PSEN1 and PSEN2. Families positive for mutations underwent additional
clinical, genetic, and functional studies. Li et al. (2006) identified a
novel heterozygous PSEN1 missense mutation (D333G; 104311.0034) in 1
family and a single heterozygous PSEN2 missense mutation (600759.0008)
in 2 other families. The PSEN1 mutation was associated with complete
penetrance and progressive disease that resulted in the necessity of
cardiac transplantation or in death. The PSEN2 mutation showed partial
penetrance, milder disease, and a more favorable prognosis. Calcium
signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2
mutation carriers.

*FIELD* RF
1. Li, D.; Parks, S. B.; Kushner, J. D.; Nauman, D.; Burgess, D.;
Ludwigsen, S.; Partain, J.; Nixon, R. R.; Allen, C. N.; Irwin, R.
P.; Jakobs, P. M.; Litt, M.; Hershberger, R. E.: Mutations of presenilin
genes in dilated cardiomyopathy and heart failure. Am. J. Hum. Genet. 79:
1030-1039, 2006.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Cardiomyopathy, dilated;
Ejection fraction decreased;
Heart failure;
Syncope

MOLECULAR BASIS:
Caused by mutation in the presenilin-1 gene (PSEN1, 104311.0034)

*FIELD* CD
Marla J. F. O'Neill: 1/14/2011

*FIELD* ED
joanna: 12/31/2011
alopez: 1/14/2011

*FIELD* CD
Anne M. Stumpf: 1/14/2011

*FIELD* ED
alopez: 01/14/2011
alopez: 1/14/2011

MIM 613737
*RECORD*
*FIELD* NO
613737
*FIELD* TI
#613737 ACNE INVERSA, FAMILIAL, 3; ACNINV3
*FIELD* TX
A number sign (#) is used with this entry because familial acne
read moreinversa-3 (ACNINV3) is caused by heterozygous mutation in the PSEN1 gene
(104311) on chromosome 14q24.3. Heterozygous mutation in the PSEN1 gene
can also result in early-onset Alzheimer disease (607822).

DESCRIPTION

Acne inversa is a chronic inflammatory disease of the hair follicles
whose characteristic features include draining sinuses, painful skin
abscesses, and disfiguring scars. Manifestations typically appear after
puberty. Familial acne inversa is genetically heterogeneous (summary by
Wang et al., 2010).

For a general phenotypeic description and a discussion of genetic
heterogeneity of familial acne inversa, see 142690.

MOLECULAR GENETICS

In a 3-generation Chinese family segregating autosomal dominant acne
inversa, Wang et al. (2010) identified heterozygosity for a frameshift
mutation in the PSEN1 gene in affected individuals (104311.0038). Wang
et al. (2010) noted that all Alzheimer disease/dementia-causing PSEN
mutations reported to that time had been missense mutations or in-frame
deletions or insertions. No affected individual 50 years old or older
had symptoms of Alzheimer disease or dementias.

*FIELD* RF
1. Wang, B.; Yang, W.; Wen, W.; Sun, J.; Su, B.; Liu, B.; Ma, D.;
Lv, D.; Wen, Y.; Qu, T.; Chen, M.; Sun, M.; Shen, Y.; Zhang, X.:
Gamma-secretase gene mutations in familial acne inversa. Science 330:
1065 only, 2010.

*FIELD* CD
Ada Hamosh: 2/8/2011

*FIELD* ED
carol: 11/08/2013
carol: 12/12/2011
alopez: 2/16/2011
carol: 2/9/2011
alopez: 2/8/2011

RBCC Red Blood Cell Collection

Full text data of PSEN1