RBCC

Full text data of ATRX

ATRX (RAD54L, XH2) [Confidence: low (only semi-automatic identification from reviews)]
Transcriptional regulator ATRX; 3.6.4.12 (ATP-dependent helicase ATRX; X-linked helicase II; X-linked nuclear protein; XNP; Znf-HX)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P46100
ID ATRX_HUMAN Reviewed; 2492 AA.
AC P46100; D3DTE2; P51068; Q15886; Q59FB5; Q59H31; Q5H9A2; Q5JWI4;
read moreAC Q7Z2J1; Q9H0Z1; Q9NTS3;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 5.
DT 22-JAN-2014, entry version 160.
DE RecName: Full=Transcriptional regulator ATRX;
DE EC=3.6.4.12;
DE AltName: Full=ATP-dependent helicase ATRX;
DE AltName: Full=X-linked helicase II;
DE AltName: Full=X-linked nuclear protein;
DE Short=XNP;
DE AltName: Full=Znf-HX;
GN Name=ATRX; Synonyms=RAD54L, XH2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5), VARIANT
RP SER-1860, AND VARIANTS ATRX.
RX PubMed=8968741; DOI=10.1093/hmg/5.12.1899;
RA Picketts D.J., Higgs D.R., Bachoo S., Blake D.J., Quarrell O.W.J.,
RA Gibbons R.J.;
RT "ATRX encodes a novel member of the SNF2 family of proteins: mutations
RT point to a common mechanism underlying the ATR-X syndrome.";
RL Hum. Mol. Genet. 5:1899-1907(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 4), AND VARIANTS PRO-596
RP AND GLY-740.
RX PubMed=9244431; DOI=10.1006/geno.1997.4793;
RA Villard L., Lossi A.-M., Cardoso C., Proud V., Chiaroni P.,
RA Colleaux L., Schwartz C., Fontes M.;
RT "Determination of the genomic structure of the XNP/ATRX gene encoding
RT a potential zinc finger helicase.";
RL Genomics 43:149-155(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF
RP 163-198.
RX PubMed=12777533; DOI=10.1093/molbev/msg134;
RA Kitano T., Schwarz C., Nickel B., Paeaebo S.;
RT "Gene diversity patterns at 10 X-chromosomal loci in humans and
RT chimpanzees.";
RL Mol. Biol. Evol. 20:1281-1289(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6), NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 704-1927 (ISOFORMS 1/2/3/4/5), AND
RP VARIANT GLU-929.
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [6]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 860-2492.
RX PubMed=7874112; DOI=10.1093/hmg/3.11.1957;
RA Stayton C.L., Dabovic B., Gulisano M., Gecz J., Broccoli V.,
RA Giovanazzi S., Bossolasco M., Monaco L., Rastan S., Boncinelli E.,
RA Bianchi M.E., Consalez G.G.;
RT "Cloning and characterization of a new human Xq13 gene, encoding a
RT putative helicase.";
RL Hum. Mol. Genet. 3:1957-1964(1994).
RN [8]
RP PRELIMINARY PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8162050; DOI=10.1093/hmg/3.1.39;
RA Gecz J., Pollard H., Consalez G., Villard L., Stayton C.L.,
RA Millasseau P., Khrestchatisky M., Fontes M.;
RT "Cloning and expression of the murine homologue of a putative human X-
RT linked nuclear protein gene closely linked to PGK1 in Xq13.3.";
RL Hum. Mol. Genet. 3:39-44(1994).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 2401-2492, AND VARIANTS ATRX.
RX PubMed=7697714; DOI=10.1016/0092-8674(95)90287-2;
RA Gibbons R.J., Picketts D.J., Villard L., Higgs D.R.;
RT "Mutations in a putative global transcriptional regulator cause X-
RT linked mental retardation with alpha-thalassemia (ATR-X syndrome).";
RL Cell 80:837-845(1995).
RN [10]
RP INTERACTION WITH EZH2.
RX PubMed=9499421; DOI=10.1093/hmg/7.4.679;
RA Cardoso C., Timsit S., Villard L., Khrestchatisky M., Fontes M.,
RA Colleaux L.;
RT "Specific interaction between the XNP/ATR-X gene product and the SET
RT domain of the human EZH2 protein.";
RL Hum. Mol. Genet. 7:679-684(1998).
RN [11]
RP SUBCELLULAR LOCATION, AND ASSOCIATION WITH PERICENTROMERIC
RP HETEROCHROMATIN.
RX PubMed=10570185; DOI=10.1073/pnas.96.24.13983;
RA McDowell T.L., Gibbons R.J., Sutherland H., O'Rourke D.M.,
RA Bickmore W.A., Pombo A., Turley H., Gatter K., Picketts D.J.,
RA Buckle V.J., Chapman L., Rhodes D., Higgs D.R.;
RT "Localization of a putative transcriptional regulator (ATRX) at
RT pericentromeric heterochromatin and the short arms of acrocentric
RT chromosomes.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:13983-13988(1999).
RN [12]
RP INVOLVEMENT IN MRXSHF1.
RX PubMed=10751095;
RX DOI=10.1002/(SICI)1096-8628(20000306)91:1<83::AID-AJMG15>3.3.CO;2-E;
RA Villard L., Fontes M., Ades L.C., Gecz J.;
RT "Identification of a mutation in the XNP/ATR-X gene in a family
RT reported as Smith-Fineman-Myers syndrome.";
RL Am. J. Med. Genet. 91:83-85(2000).
RN [13]
RP INVOLVEMENT IN ATMDS.
RX PubMed=12858175; DOI=10.1038/ng1213;
RA Gibbons R.J., Pellagatti A., Garrick D., Wood W.G., Malik N.,
RA Ayyub H., Langford C., Boultwood J., Wainscoat J.S., Higgs D.R.;
RT "Identification of acquired somatic mutations in the gene encoding
RT chromatin-remodeling factor ATRX in the alpha-thalassemia
RT myelodysplasia syndrome (ATMDS).";
RL Nat. Genet. 34:446-449(2003).
RN [14]
RP INTERACTION WITH CBX5.
RX PubMed=15882967; DOI=10.1016/j.bbrc.2005.04.016;
RA Lechner M.S., Schultz D.C., Negorev D., Maul G.G., Rauscher F.J. III;
RT "The mammalian heterochromatin protein 1 binds diverse nuclear
RT proteins through a common motif that targets the chromoshadow
RT domain.";
RL Biochem. Biophys. Res. Commun. 331:929-937(2005).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-634 AND SER-1352, AND
RP MASS 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 [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-594; THR-674; SER-675;
RP SER-677; SER-729; SER-731; SER-875; SER-876; SER-1348; SER-1352;
RP SER-1996 AND SER-2220, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-34; TYR-89; SER-112 AND
RP SER-1996, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-967, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-92; THR-591; SER-598;
RP SER-1061; TYR-1063; SER-1348; SER-1352; SER-1527; SER-1992; SER-1996
RP AND SER-2220, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-598; SER-889; SER-1061;
RP SER-1322; SER-1324; SER-1326; SER-1348 AND SER-1352, 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 [24]
RP STRUCTURE BY NMR OF 159-296, AND DOMAIN GATA-TYPE ZINC FINGER.
RX PubMed=17609377; DOI=10.1073/pnas.0704057104;
RA Argentaro A., Yang J.C., Chapman L., Kowalczyk M.S., Gibbons R.J.,
RA Higgs D.R., Neuhaus D., Rhodes D.;
RT "Structural consequences of disease-causing mutations in the ATRX-
RT DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:11939-11944(2007).
RN [25]
RP VARIANT ATRX SER-1713.
RX PubMed=9043863;
RA Villard L., Lacombe D., Fontes M.;
RT "A point mutation in the XNP gene, associated with an ATR-X phenotype
RT without alpha-thalassemia.";
RL Eur. J. Hum. Genet. 4:316-320(1996).
RN [26]
RP VARIANT MRXSHF1 GLN-2131.
RX PubMed=8630485; DOI=10.1038/ng0496-359;
RA Villard L., Gecz J., Mattei J.-F., Fontes M., Saugier-Veber P.,
RA Munnich A., Lyonnet S.;
RT "XNP mutation in a large family with Juberg-Marsidi syndrome.";
RL Nat. Genet. 12:359-360(1996).
RN [27]
RP VARIANTS ATRX.
RX PubMed=9326931; DOI=10.1038/ng1097-146;
RA Gibbons R.J., Bachoo S., Picketts D.J., Aftimos S., Asenbauer B.,
RA Bergoffen J., Berry S.A., Dahl N., Fryer A., Keppler K., Kurosawa K.,
RA Levin M.L., Masuno M., Neri G., Pierpont M.E., Slaney S.F.,
RA Higgs D.R.;
RT "Mutations in transcriptional regulator ATRX establish the functional
RT significance of a PHD-like domain.";
RL Nat. Genet. 17:146-148(1997).
RN [28]
RP VARIANT ATRX LEU-246.
RX PubMed=10660327;
RA Fichera M., Romano C., Castiglia L., Failla P., Ruberto C., Amata S.,
RA Greco D., Cardoso C., Fontes M., Ragusa A.;
RT "New mutations in XNP/ATR-X gene: a further contribution to
RT genotype/phenotype relationship in ATR/X syndrome.";
RL Hum. Mutat. 12:214-214(1998).
RN [29]
RP VARIANT ATRX LYS-1742.
RX PubMed=10417298; DOI=10.1086/302499;
RA Lossi A.-M., Millan J.M., Villard L., Orellana C., Cardoso C.,
RA Prieto F., Fontes M., Martinez F.;
RT "Mutation of the XNP/ATR-X gene in a family with severe mental
RT retardation, spastic paraplegia and skewed pattern of X inactivation:
RT demonstration that the mutation is involved in the inactivation
RT bias.";
RL Am. J. Hum. Genet. 65:558-562(1999).
RN [30]
RP VARIANT MRXSHF1 THR-2050.
RX PubMed=10398237;
RX DOI=10.1002/(SICI)1096-8628(19990730)85:3<249::AID-AJMG12>3.0.CO;2-U;
RA Abidi F., Schwartz C.E., Carpenter N.J., Villard L., Fontes M.,
RA Curtis M.;
RT "Carpenter-Waziri syndrome results from a mutation in XNP.";
RL Am. J. Med. Genet. 85:249-251(1999).
RN [31]
RP VARIANTS ATRX GLU-175; 178-VAL--LYS-198 DEL; SER-190; PRO-219; LEU-246
RP AND CYS-249.
RX PubMed=10204841;
RA Villard L., Bonino M.-C., Abidi F., Ragusa A., Belougne J.,
RA Lossi A.-M., Seaver L., Bonnefont J.-P., Romano C., Fichera M.,
RA Lacombe D., Hanauer A., Philip N., Schwartz C.E., Fontes M.;
RT "Evaluation of a mutation screening strategy for sporadic cases of
RT ATR-X syndrome.";
RL J. Med. Genet. 36:183-186(1999).
RN [32]
RP VARIANTS ATRX SER-179; LEU-190; ILE-194; CYS-246; PHE-1552; SER-1645
RP AND CYS-1847.
RX PubMed=10995512;
RX DOI=10.1002/1096-8628(20000918)94:3<242::AID-AJMG11>3.3.CO;2-B;
RA Wada T., Kubota T., Fukushima Y., Saitoh S.;
RT "Molecular genetic study of Japanese patients with X-linked alpha-
RT thalassemia/mental retardation syndrome (ATR-X).";
RL Am. J. Med. Genet. 94:242-248(2000).
RN [33]
RP VARIANT MRXSHF1 TYR-220.
RX PubMed=11050622;
RX DOI=10.1002/1096-8628(20001023)94:5<383::AID-AJMG7>3.0.CO;2-7;
RA Stevenson R.E., Abidi F., Schwartz C.E., Lubs H.A., Holmes L.B.;
RT "Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome.";
RL Am. J. Med. Genet. 94:383-385(2000).
RN [34]
RP VARIANT ATRX MET-1621.
RX PubMed=12116232; DOI=10.1002/ajmg.10446;
RA Yntema H.G., Poppelaars F.A., Derksen E., Oudakker A.R.,
RA van Roosmalen T., Jacobs A., Obbema H., Brunner H.G., Hamel B.C.J.,
RA van Bokhoven H.;
RT "Expanding phenotype of XNP mutations: mild to moderate mental
RT retardation.";
RL Am. J. Med. Genet. 110:243-247(2002).
RN [35]
RP VARIANT MRXSHF1 GLY-2271.
RX PubMed=16222662; DOI=10.1002/ajmg.a.30990;
RA Leahy R.T., Philip R.K., Gibbons R.J., Fisher C., Suri M., Reardon W.;
RT "Asplenia in ATR-X syndrome: a second report.";
RL Am. J. Med. Genet. A 139:37-39(2005).
RN [36]
RP VARIANT MRXSHF1 SER-409.
RX PubMed=15565397; DOI=10.1007/s10048-004-0190-3;
RA Wieland I., Sabathil J., Ostendorf A., Rittinger O., Roepke A.,
RA Winnepenninckx B., Kooy F., Holinski-Feder E., Wieacker P.;
RT "A missense mutation in the coiled-coil motif of the HP1-interacting
RT domain of ATR-X in a family with X-linked mental retardation.";
RL Neurogenetics 6:45-47(2005).
RN [37]
RP VARIANT ATRX CYS-246.
RX PubMed=16955409; DOI=10.1002/ajmg.a.31400;
RA Badens C., Martini N., Courrier S., DesPortes V., Touraine R.,
RA Levy N., Edery P.;
RT "ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn
RT finger domain and a totally skewed X-inactivation pattern.";
RL Am. J. Med. Genet. A 140:2212-2215(2006).
CC -!- FUNCTION: Could be a global transcriptional regulator. Modifies
CC gene expression by affecting chromatin. May be involved in brain
CC development and facial morphogenesis.
CC -!- CATALYTIC ACTIVITY: ATP + H(2)O = ADP + phosphate.
CC -!- SUBUNIT: Probably binds EZH2. Binds annexin V in a calcium and
CC phosphatidylcholine/phosphatidylserine-dependent manner (By
CC similarity). Interacts directly with CBX5 via the PxVxL motif.
CC -!- INTERACTION:
CC Q9UER7:DAXX; NbExp=3; IntAct=EBI-396461, EBI-77321;
CC -!- SUBCELLULAR LOCATION: Nucleus. Note=Associated with
CC pericentromeric heterochromatin during interphase and mitosis,
CC probably by interacting with HP1.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=4;
CC IsoId=P46100-1; Sequence=Displayed;
CC Name=1;
CC IsoId=P46100-2; Sequence=VSP_000575;
CC Name=2;
CC IsoId=P46100-3; Sequence=VSP_000574;
CC Name=3;
CC IsoId=P46100-4; Sequence=VSP_000576;
CC Name=5;
CC IsoId=P46100-5; Sequence=VSP_000574, VSP_000576;
CC Name=6;
CC IsoId=P46100-6; Sequence=VSP_015499, VSP_015500, VSP_015501;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DOMAIN: Contains one Pro-Xaa-Val-Xaa-Leu (PxVxL) motif, which is
CC required for interaction with chromoshadow domains. This motif
CC requires additional residues -7, -6, +4 and +5 of the central Val
CC which contact the chromoshadow domain.
CC -!- DISEASE: Alpha-thalassemia mental retardation syndrome, X-linked
CC (ATRX) [MIM:301040]: A disorder characterized by severe
CC psychomotor retardation, facial dysmorphism, urogenital
CC abnormalities, and alpha-thalassemia. An essential phenotypic
CC trait are hemoglobin H erythrocyte inclusions. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Mental retardation, X-linked, syndromic, with hypotonic
CC facies 1 (MRXSHF1) [MIM:309580]: A disorder characterized by
CC significantly below average general intellectual functioning
CC associated with impairments in adaptive behavior and manifested
CC during the developmental period. MRXSHF1 is a syndromic mental
CC retardation. Clinical features include severe mental retardation,
CC dysmorphic facies, and a highly skewed X-inactivation pattern in
CC carrier women. Other more variable features include hypogonadism,
CC deafness, renal anomalies, and mild skeletal defects. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Alpha-thalassemia myelodysplasia syndrome (ATMDS)
CC [MIM:300448]: A disorder characterized by hypochromic, microcytic
CC red blood cells, hemoglobin H detected in peripheral blood, and
CC multilineage myelodysplasia. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SNF2/RAD54 helicase family.
CC -!- SIMILARITY: Contains 1 ADD domain.
CC -!- SIMILARITY: Contains 1 GATA-type zinc finger.
CC -!- SIMILARITY: Contains 1 helicase ATP-binding domain.
CC -!- SIMILARITY: Contains 1 helicase C-terminal domain.
CC -!- SIMILARITY: Contains 1 PHD-type zinc finger.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA20872.1; Type=Miscellaneous discrepancy; Note=Many frameshifts and conflits;
CC Sequence=AAC50069.1; Type=Frameshift; Positions=Several;
CC Sequence=BAD92165.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ATRX";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U72937; AAB49970.2; -; mRNA.
DR EMBL; U72938; AAB49971.2; -; mRNA.
DR EMBL; U72935; AAB40698.1; -; Genomic_DNA.
DR EMBL; U72904; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72905; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72907; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72908; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72909; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72910; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72911; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72912; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72913; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72914; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72915; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72916; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72917; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72918; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72919; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72920; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72921; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72922; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72923; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72924; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72925; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72926; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72927; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72928; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72929; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72930; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72931; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72932; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72933; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72934; AAB40698.1; JOINED; Genomic_DNA.
DR EMBL; U72935; AAB40699.1; -; Genomic_DNA.
DR EMBL; U72904; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72907; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72908; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72909; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72910; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72911; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72912; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72913; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72914; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72915; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72916; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72918; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72919; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72920; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72921; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72922; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72923; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72924; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72925; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72926; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72927; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72928; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72929; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72930; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72931; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72932; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72933; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72934; AAB40699.1; JOINED; Genomic_DNA.
DR EMBL; U72936; AAB49969.1; -; mRNA.
DR EMBL; U72935; AAB40700.1; -; Genomic_DNA.
DR EMBL; U72908; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72909; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72910; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72911; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72912; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72913; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72914; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72915; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72916; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72917; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72918; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72920; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72921; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72922; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72923; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72924; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72925; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72926; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72927; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72928; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72929; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72930; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72931; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72932; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72933; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U72934; AAB40700.1; JOINED; Genomic_DNA.
DR EMBL; U75653; AAC51655.1; -; Genomic_DNA.
DR EMBL; U97103; AAC51657.1; -; Genomic_DNA.
DR EMBL; AF000157; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; AF000158; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; AF000159; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; AF000160; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97080; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97081; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97082; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97083; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97084; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97085; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97086; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97087; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97088; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97089; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97090; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97091; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97092; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97093; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97094; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97095; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97096; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97097; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97098; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97099; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97100; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97101; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; U97102; AAC51657.1; JOINED; Genomic_DNA.
DR EMBL; AB102641; BAC81110.1; -; mRNA.
DR EMBL; AB101681; BAC80270.1; -; Genomic_DNA.
DR EMBL; AB101682; BAC80271.1; -; Genomic_DNA.
DR EMBL; AB101683; BAC80272.1; -; Genomic_DNA.
DR EMBL; AB101685; BAC80274.1; -; Genomic_DNA.
DR EMBL; AB101687; BAC80276.1; -; Genomic_DNA.
DR EMBL; AB101689; BAC80278.1; -; Genomic_DNA.
DR EMBL; AB101691; BAC80280.1; -; Genomic_DNA.
DR EMBL; AB101693; BAC80282.1; -; Genomic_DNA.
DR EMBL; AB101695; BAC80284.1; -; Genomic_DNA.
DR EMBL; AB101700; BAC80289.1; -; Genomic_DNA.
DR EMBL; AB101699; BAC80288.1; -; Genomic_DNA.
DR EMBL; AB101698; BAC80287.1; -; Genomic_DNA.
DR EMBL; AB101697; BAC80286.1; -; Genomic_DNA.
DR EMBL; AB101696; BAC80285.1; -; Genomic_DNA.
DR EMBL; AB101694; BAC80283.1; -; Genomic_DNA.
DR EMBL; AB101692; BAC80281.1; -; Genomic_DNA.
DR EMBL; AB101690; BAC80279.1; -; Genomic_DNA.
DR EMBL; AB101688; BAC80277.1; -; Genomic_DNA.
DR EMBL; AB101686; BAC80275.1; -; Genomic_DNA.
DR EMBL; AB101684; BAC80273.1; -; Genomic_DNA.
DR EMBL; AB208928; BAD92165.1; ALT_INIT; mRNA.
DR EMBL; AB209545; BAD92782.1; -; mRNA.
DR EMBL; AL121874; CAB90351.2; -; Genomic_DNA.
DR EMBL; AL121874; CAI40710.1; -; Genomic_DNA.
DR EMBL; AL109753; CAI40710.1; JOINED; Genomic_DNA.
DR EMBL; Z84487; CAI40710.1; JOINED; Genomic_DNA.
DR EMBL; Z84487; CAI42674.1; -; Genomic_DNA.
DR EMBL; AL109753; CAI42674.1; JOINED; Genomic_DNA.
DR EMBL; AL121874; CAI42674.1; JOINED; Genomic_DNA.
DR EMBL; Z84487; CAI42675.1; -; Genomic_DNA.
DR EMBL; AL109753; CAI42675.1; JOINED; Genomic_DNA.
DR EMBL; AL121874; CAI42675.1; JOINED; Genomic_DNA.
DR EMBL; AL109753; CAI43115.1; -; Genomic_DNA.
DR EMBL; AL121874; CAI43115.1; JOINED; Genomic_DNA.
DR EMBL; Z84487; CAI43115.1; JOINED; Genomic_DNA.
DR EMBL; AL109753; CAI43116.1; -; Genomic_DNA.
DR EMBL; AL121874; CAI43116.1; JOINED; Genomic_DNA.
DR EMBL; Z84487; CAI43116.1; JOINED; Genomic_DNA.
DR EMBL; CH471104; EAW98611.1; -; Genomic_DNA.
DR EMBL; CH471104; EAW98615.1; -; Genomic_DNA.
DR EMBL; U09820; AAC50069.1; ALT_FRAME; mRNA.
DR EMBL; L34363; AAA20872.1; ALT_SEQ; Genomic_DNA.
DR EMBL; X83753; CAA58711.1; -; Genomic_DNA.
DR PIR; I38614; I38614.
DR PIR; I54367; I54367.
DR RefSeq; NP_000480.3; NM_000489.4.
DR RefSeq; NP_612114.2; NM_138270.3.
DR UniGene; Hs.533526; -.
DR UniGene; Hs.653797; -.
DR PDB; 2JM1; NMR; -; A=159-296.
DR PDB; 2LBM; NMR; -; A=163-296.
DR PDB; 2LD1; NMR; -; A=163-296.
DR PDB; 3QL9; X-ray; 0.93 A; A=167-289.
DR PDB; 3QLA; X-ray; 1.60 A; A/D=167-289.
DR PDB; 3QLC; X-ray; 2.50 A; A/B=167-289.
DR PDB; 3QLN; X-ray; 1.90 A; A/B=167-289.
DR PDBsum; 2JM1; -.
DR PDBsum; 2LBM; -.
DR PDBsum; 2LD1; -.
DR PDBsum; 3QL9; -.
DR PDBsum; 3QLA; -.
DR PDBsum; 3QLC; -.
DR PDBsum; 3QLN; -.
DR ProteinModelPortal; P46100; -.
DR SMR; P46100; 159-296.
DR DIP; DIP-31532N; -.
DR IntAct; P46100; 11.
DR MINT; MINT-1186201; -.
DR DrugBank; DB00144; Phosphatidylserine.
DR PhosphoSite; P46100; -.
DR DMDM; 311033500; -.
DR PaxDb; P46100; -.
DR PRIDE; P46100; -.
DR DNASU; 546; -.
DR Ensembl; ENST00000373344; ENSP00000362441; ENSG00000085224.
DR Ensembl; ENST00000395603; ENSP00000378967; ENSG00000085224.
DR GeneID; 546; -.
DR KEGG; hsa:546; -.
DR UCSC; uc004eco.4; human.
DR CTD; 546; -.
DR GeneCards; GC0XM076760; -.
DR H-InvDB; HIX0176765; -.
DR HGNC; HGNC:886; ATRX.
DR HPA; CAB009372; -.
DR HPA; HPA001906; -.
DR MIM; 300032; gene.
DR MIM; 300448; phenotype.
DR MIM; 301040; phenotype.
DR MIM; 309580; phenotype.
DR neXtProt; NX_P46100; -.
DR Orphanet; 847; Alpha thalassemia - X-linked intellectual deficit syndrome.
DR Orphanet; 231401; Alpha-thalassemia - myelodysplastic syndrome.
DR Orphanet; 93973; Carpenter-Waziri syndrome.
DR Orphanet; 93971; Chudley-Lowry-Hoar syndrome.
DR Orphanet; 93970; Holmes-Gang syndrome.
DR Orphanet; 93972; Juberg-Marsidi syndrome.
DR Orphanet; 93974; Smith-Fineman-Myers syndrome.
DR Orphanet; 3423; Vasquez-Hurst-Sotos syndrome.
DR PharmGKB; PA25179; -.
DR eggNOG; COG0553; -.
DR HOVERGEN; HBG000104; -.
DR InParanoid; P46100; -.
DR KO; K10779; -.
DR OMA; NDPANIR; -.
DR OrthoDB; EOG7G4QDQ; -.
DR PhylomeDB; P46100; -.
DR EvolutionaryTrace; P46100; -.
DR GeneWiki; ATRX; -.
DR GenomeRNAi; 546; -.
DR NextBio; 2259; -.
DR PRO; PR:P46100; -.
DR ArrayExpress; P46100; -.
DR Bgee; P46100; -.
DR CleanEx; HS_RAD54L; -.
DR Genevestigator; P46100; -.
DR GO; GO:0005720; C:nuclear heterochromatin; TAS:ProtInc.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0003678; F:DNA helicase activity; TAS:ProtInc.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006306; P:DNA methylation; TAS:ProtInc.
DR GO; GO:0006310; P:DNA recombination; TAS:ProtInc.
DR GO; GO:0006281; P:DNA repair; TAS:ProtInc.
DR GO; GO:0030900; P:forebrain development; IEA:Ensembl.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; TAS:ProtInc.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR025766; ADD.
DR InterPro; IPR014001; Helicase_ATP-bd.
DR InterPro; IPR001650; Helicase_C.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR000330; SNF2_N.
DR InterPro; IPR011011; Znf_FYVE_PHD.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR Pfam; PF00271; Helicase_C; 1.
DR Pfam; PF00176; SNF2_N; 1.
DR SMART; SM00487; DEXDc; 1.
DR SMART; SM00490; HELICc; 1.
DR SMART; SM00184; RING; 1.
DR SUPFAM; SSF52540; SSF52540; 3.
DR SUPFAM; SSF57903; SSF57903; 1.
DR PROSITE; PS51533; ADD; 1.
DR PROSITE; PS51192; HELICASE_ATP_BIND_1; 1.
DR PROSITE; PS51194; HELICASE_CTER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Complete proteome; Disease mutation; DNA damage; DNA repair;
KW DNA-binding; Helicase; Hydrolase; Mental retardation; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Zinc; Zinc-finger.
FT CHAIN 1 2492 Transcriptional regulator ATRX.
FT /FTId=PRO_0000074301.
FT DOMAIN 159 296 ADD.
FT DOMAIN 1581 1768 Helicase ATP-binding.
FT DOMAIN 2025 2205 Helicase C-terminal.
FT ZN_FING 170 206 GATA-type; atypical.
FT ZN_FING 217 272 PHD-type; atypical.
FT NP_BIND 1594 1601 ATP (Potential).
FT MOTIF 581 594 PxVxL motif.
FT MOTIF 1719 1722 DEGH box.
FT COMPBIAS 745 750 Poly-Ser.
FT COMPBIAS 1151 1156 Poly-Ser.
FT COMPBIAS 1166 1169 Poly-Lys.
FT COMPBIAS 1202 1206 Poly-Ser.
FT COMPBIAS 1259 1266 Poly-Asp.
FT COMPBIAS 1443 1466 Poly-Glu.
FT COMPBIAS 1499 1502 Poly-Glu.
FT COMPBIAS 1929 1939 Poly-Lys.
FT COMPBIAS 1941 1948 Poly-Ser.
FT COMPBIAS 2222 2225 Poly-Lys.
FT COMPBIAS 2262 2265 Poly-Glu.
FT COMPBIAS 2420 2425 Poly-Gln.
FT MOD_RES 34 34 Phosphoserine.
FT MOD_RES 89 89 Phosphotyrosine.
FT MOD_RES 92 92 Phosphoserine.
FT MOD_RES 112 112 Phosphoserine.
FT MOD_RES 591 591 Phosphothreonine.
FT MOD_RES 594 594 Phosphoserine.
FT MOD_RES 598 598 Phosphoserine.
FT MOD_RES 634 634 Phosphoserine.
FT MOD_RES 674 674 Phosphothreonine.
FT MOD_RES 675 675 Phosphoserine.
FT MOD_RES 677 677 Phosphoserine.
FT MOD_RES 729 729 Phosphoserine.
FT MOD_RES 731 731 Phosphoserine.
FT MOD_RES 819 819 Phosphoserine (By similarity).
FT MOD_RES 875 875 Phosphoserine.
FT MOD_RES 876 876 Phosphoserine.
FT MOD_RES 889 889 Phosphoserine.
FT MOD_RES 967 967 N6-acetyllysine.
FT MOD_RES 1061 1061 Phosphoserine.
FT MOD_RES 1063 1063 Phosphotyrosine.
FT MOD_RES 1322 1322 Phosphoserine.
FT MOD_RES 1324 1324 Phosphoserine.
FT MOD_RES 1326 1326 Phosphoserine.
FT MOD_RES 1348 1348 Phosphoserine.
FT MOD_RES 1352 1352 Phosphoserine.
FT MOD_RES 1527 1527 Phosphoserine.
FT MOD_RES 1992 1992 Phosphoserine.
FT MOD_RES 1996 1996 Phosphoserine.
FT MOD_RES 2220 2220 Phosphoserine.
FT VAR_SEQ 1 204 Missing (in isoform 1).
FT /FTId=VSP_000575.
FT VAR_SEQ 1 117 Missing (in isoform 2 and isoform 5).
FT /FTId=VSP_000574.
FT VAR_SEQ 124 162 Missing (in isoform 6).
FT /FTId=VSP_015499.
FT VAR_SEQ 124 161 Missing (in isoform 3 and isoform 5).
FT /FTId=VSP_000576.
FT VAR_SEQ 573 601 Missing (in isoform 6).
FT /FTId=VSP_015500.
FT VAR_SEQ 1419 2492 Missing (in isoform 6).
FT /FTId=VSP_015501.
FT VARIANT 175 175 G -> E (in ATRX).
FT /FTId=VAR_012113.
FT VARIANT 178 198 Missing (in ATRX).
FT /FTId=VAR_012114.
FT VARIANT 179 179 N -> S (in ATRX).
FT /FTId=VAR_012115.
FT VARIANT 190 190 P -> A (in ATRX).
FT /FTId=VAR_001226.
FT VARIANT 190 190 P -> L (in ATRX).
FT /FTId=VAR_012116.
FT VARIANT 190 190 P -> S (in ATRX).
FT /FTId=VAR_012117.
FT VARIANT 192 192 L -> F (in ATRX).
FT /FTId=VAR_001227.
FT VARIANT 194 194 V -> I (in ATRX).
FT /FTId=VAR_012118.
FT VARIANT 200 200 C -> S (in ATRX).
FT /FTId=VAR_001228.
FT VARIANT 219 219 Q -> P (in ATRX).
FT /FTId=VAR_012119.
FT VARIANT 220 220 C -> R (in ATRX).
FT /FTId=VAR_001229.
FT VARIANT 220 220 C -> Y (in MRXSHF1).
FT /FTId=VAR_032625.
FT VARIANT 222 222 W -> S (in ATRX).
FT /FTId=VAR_001230.
FT VARIANT 243 243 C -> F (in ATRX).
FT /FTId=VAR_001231.
FT VARIANT 246 246 R -> C (in ATRX).
FT /FTId=VAR_001232.
FT VARIANT 246 246 R -> L (in ATRX).
FT /FTId=VAR_010914.
FT VARIANT 249 249 G -> C (in ATRX).
FT /FTId=VAR_012120.
FT VARIANT 249 249 G -> D (in ATRX).
FT /FTId=VAR_001233.
FT VARIANT 409 409 L -> S (in MRXSHF1).
FT /FTId=VAR_032626.
FT VARIANT 545 545 Q -> E (in dbSNP:rs35738915).
FT /FTId=VAR_055939.
FT VARIANT 596 596 S -> P (in dbSNP:rs1051678).
FT /FTId=VAR_016914.
FT VARIANT 740 740 E -> G (in dbSNP:rs1051680).
FT /FTId=VAR_016915.
FT VARIANT 929 929 Q -> E (in dbSNP:rs3088074).
FT /FTId=VAR_023438.
FT VARIANT 1538 1538 V -> G (in ATRX; unknown pathological
FT significance).
FT /FTId=VAR_012121.
FT VARIANT 1552 1552 V -> F (in ATRX).
FT /FTId=VAR_012122.
FT VARIANT 1609 1609 H -> R (in ATRX).
FT /FTId=VAR_001234.
FT VARIANT 1614 1614 C -> R (in ATRX).
FT /FTId=VAR_001235.
FT VARIANT 1621 1621 T -> M (in ATRX).
FT /FTId=VAR_016916.
FT VARIANT 1645 1645 L -> S (in ATRX).
FT /FTId=VAR_012123.
FT VARIANT 1650 1650 K -> N (in ATRX).
FT /FTId=VAR_001236.
FT VARIANT 1713 1713 P -> S (in ATRX; without alpha-
FT thalassemia).
FT /FTId=VAR_012124.
FT VARIANT 1742 1742 R -> K (in ATRX; atypical; patients
FT presents spastic paraplegia at birth).
FT /FTId=VAR_012125.
FT VARIANT 1847 1847 Y -> C (in ATRX).
FT /FTId=VAR_012126.
FT VARIANT 1860 1860 N -> S (rare polymorphism;
FT dbSNP:rs45439799).
FT /FTId=VAR_001237.
FT VARIANT 2035 2035 D -> V (in ATRX).
FT /FTId=VAR_001238.
FT VARIANT 2050 2050 I -> T (in MRXSHF1; originally reported
FT as Carpenter-Waziri syndrome).
FT /FTId=VAR_012127.
FT VARIANT 2084 2084 Y -> H (in ATRX).
FT /FTId=VAR_001239.
FT VARIANT 2131 2131 R -> Q (in MRXSHF1; originally reported
FT as Juberg-Marsidi syndrome).
FT /FTId=VAR_001240.
FT VARIANT 2163 2163 Y -> C (in ATRX).
FT /FTId=VAR_001241.
FT VARIANT 2271 2271 R -> G (in MRXSHF1).
FT /FTId=VAR_032627.
FT CONFLICT 879 879 A -> R (in Ref. 7; AAC50069).
FT CONFLICT 1286 1286 S -> P (in Ref. 4; BAD92165).
FT CONFLICT 1627 1627 P -> L (in Ref. 7; AAC50069).
FT CONFLICT 1632 1632 L -> F (in Ref. 7; AAC50069).
FT CONFLICT 2280 2280 A -> G (in Ref. 7; AAC50069).
FT CONFLICT 2283 2284 KG -> RV (in Ref. 7; AAC50069).
FT CONFLICT 2436 2436 L -> H (in Ref. 7; AAC50069).
FT CONFLICT 2442 2442 P -> R (in Ref. 7; AAC50069).
FT TURN 172 174
FT STRAND 176 178
FT TURN 179 181
FT TURN 183 185
FT STRAND 186 188
FT TURN 190 192
FT STRAND 195 197
FT HELIX 198 206
FT STRAND 210 212
FT TURN 213 215
FT STRAND 217 219
FT TURN 221 223
FT STRAND 227 231
FT STRAND 233 236
FT STRAND 238 240
FT HELIX 241 247
FT HELIX 250 256
FT STRAND 258 261
FT TURN 266 268
FT HELIX 271 273
FT HELIX 274 284
SQ SEQUENCE 2492 AA; 282586 MW; 637E341F6A4B29C6 CRC64;
MTAEPMSESK LNTLVQKLHD FLAHSSEESE ETSSPPRLAM NQNTDKISGS GSNSDMMENS
KEEGTSSSEK SKSSGSSRSK RKPSIVTKYV ESDDEKPLDD ETVNEDASNE NSENDITMQS
LPKGTVIVQP EPVLNEDKDD FKGPEFRSRS KMKTENLKKR GEDGLHGIVS CTACGQQVNH
FQKDSIYRHP SLQVLICKNC FKYYMSDDIS RDSDGMDEQC RWCAEGGNLI CCDFCHNAFC
KKCILRNLGR KELSTIMDEN NQWYCYICHP EPLLDLVTAC NSVFENLEQL LQQNKKKIKV
DSEKSNKVYE HTSRFSPKKT SSNCNGEEKK LDDSCSGSVT YSYSALIVPK EMIKKAKKLI
ETTANMNSSY VKFLKQATDN SEISSATKLR QLKAFKSVLA DIKKAHLALE EDLNSEFRAM
DAVNKEKNTK EHKVIDAKFE TKARKGEKPC ALEKKDISKS EAKLSRKQVD SEHMHQNVPT
EEQRTNKSTG GEHKKSDRKE EPQYEPANTS EDLDMDIVSV PSSVPEDIFE NLETAMEVQS
SVDHQGDGSS GTEQEVESSS VKLNISSKDN RGGIKSKTTA KVTKELYVKL TPVSLSNSPI
KGADCQEVPQ DKDGYKSCGL NPKLEKCGLG QENSDNEHLV ENEVSLLLEE SDLRRSPRVK
TTPLRRPTET NPVTSNSDEE CNETVKEKQK LSVPVRKKDK RNSSDSAIDN PKPNKLPKSK
QSETVDQNSD SDEMLAILKE VSRMSHSSSS DTDINEIHTN HKTLYDLKTQ AGKDDKGKRK
RKSSTSGSDF DTKKGKSAKS SIISKKKRQT QSESSNYDSE LEKEIKSMSK IGAARTTKKR
IPNTKDFDSS EDEKHSKKGM DNQGHKNLKT SQEGSSDDAE RKQERETFSS AEGTVDKDTT
IMELRDRLPK KQQASASTDG VDKLSGKEQS FTSLEVRKVA ETKEKSKHLK TKTCKKVQDG
LSDIAEKFLK KDQSDETSED DKKQSKKGTE EKKKPSDFKK KVIKMEQQYE SSSDGTEKLP
EREEICHFPK GIKQIKNGTT DGEKKSKKIR DKTSKKKDEL SDYAEKSTGK GDSCDSSEDK
KSKNGAYGRE KKRCKLLGKS SRKRQDCSSS DTEKYSMKED GCNSSDKRLK RIELRERRNL
SSKRNTKEIQ SGSSSSDAEE SSEDNKKKKQ RTSSKKKAVI VKEKKRNSLR TSTKRKQADI
TSSSSSDIED DDQNSIGEGS SDEQKIKPVT ENLVLSSHTG FCQSSGDEAL SKSVPVTVDD
DDDDNDPENR IAKKMLLEEI KANLSSDEDG SSDDEPEEGK KRTGKQNEEN PGDEEAKNQV
NSESDSDSEE SKKPRYRHRL LRHKLTVSDG ESGEEKKTKP KEHKEVKGRN RRKVSSEDSE
DSDFQESGVS EEVSESEDEQ RPRTRSAKKA ELEENQRSYK QKKKRRRIKV QEDSSSENKS
NSEEEEEEKE EEEEEEEEEE EEEEDENDDS KSPGKGRKKI RKILKDDKLR TETQNALKEE
EERRKRIAER EREREKLREV IEIEDASPTK CPITTKLVLD EDEETKEPLV QVHRNMVIKL
KPHQVDGVQF MWDCCCESVK KTKKSPGSGC ILAHCMGLGK TLQVVSFLHT VLLCDKLDFS
TALVVCPLNT ALNWMNEFEK WQEGLKDDEK LEVSELATVK RPQERSYMLQ RWQEDGGVMI
IGYEMYRNLA QGRNVKSRKL KEIFNKALVD PGPDFVVCDE GHILKNEASA VSKAMNSIRS
RRRIILTGTP LQNNLIEYHC MVNFIKENLL GSIKEFRNRF INPIQNGQCA DSTMVDVRVM
KKRAHILYEM LAGCVQRKDY TALTKFLPPK HEYVLAVRMT SIQCKLYQYY LDHLTGVGNN
SEGGRGKAGA KLFQDFQMLS RIWTHPWCLQ LDYISKENKG YFDEDSMDEF IASDSDETSM
SLSSDDYTKK KKKGKKGKKD SSSSGSGSDN DVEVIKVWNS RSRGGGEGNV DETGNNPSVS
LKLEESKATS SSNPSSPAPD WYKDFVTDAD AEVLEHSGKM VLLFEILRMA EEIGDKVLVF
SQSLISLDLI EDFLELASRE KTEDKDKPLI YKGEGKWLRN IDYYRLDGST TAQSRKKWAE
EFNDETNVRG RLFIISTKAG SLGINLVAAN RVIIFDASWN PSYDIQSIFR VYRFGQTKPV
YVYRFLAQGT MEDKIYDRQV TKQSLSFRVV DQQQVERHFT MNELTELYTF EPDLLDDPNS
EKKKKRDTPM LPKDTILAEL LQIHKEHIVG YHEHDSLLDH KEEEELTEEE RKAAWAEYEA
EKKGLTMRFN IPTGTNLPPV SFNSQTPYIP FNLGALSAMS NQQLEDLINQ GREKVVEATN
SVTAVRIQPL EDIISAVWKE NMNLSEAQVQ ALALSRQASQ ELDVKRREAI YNDVLTKQQM
LISCVQRILM NRRLQQQYNQ QQQQQMTYQQ ATLGHLMMPK PPNLIMNPSN YQQIDMRGMY
QPVAGGMQPP PLQRAPPPMR SKNPGPSQGK SM
//

MIM 300032
*RECORD*
*FIELD* NO
300032
*FIELD* TI
*300032 ATR-X GENE; ATRX
;;HELICASE 2, X-LINKED; XH2;;
X-LINKED NUCLEAR PROTEIN GENE; XNP
read more*FIELD* TX

CLONING

Stayton et al. (1994) described the cloning and characterization of a
gene, provisionally called X-linked helicase-2 (XH2), located on
chromosome Xq13. The gene undergoes X inactivation, contains a 4-kb open
reading frame, and encodes a putative NTP-binding nuclear protein
homologous to several members of the helicase II superfamily. In situ
hybridization studies in the mouse revealed precocious, widespread
expression of the murine homolog of XH2 at early stages of
embryogenesis, and more restricted expression during late developmental
stages and at birth. XH2 shares 6 conserved, collinear domains with
other members of the family of proven and putative helicases. In
particular, the XH2 protein shows homology with RAD54. Type II helicases
have been implicated in nucleotide excision repair and initiation of
transcription.

Picketts et al. (1996) established the full-length sequence of the ATRX
cDNA and predicted the structure of the ATRX protein. Their comparative
analysis showed that ATRX is a member of the SNF2-like subgroup of a
superfamily of proteins with similar ATPase and helicase domains (see
300012). The N-terminal region contains a nuclear localization signal
and antibody studies indicated a nuclear localization of the protein.
The C-terminal region is glutamine rich, a common attribute of other
transcription factors. In addition, a 15-amino acid segment (the P
element) in the C-terminal region shows 35 to 50% similarity to
SNF2-like proteins which are involved in gene expression.

Villard et al. (1997) determined that the ATRX gene encodes a predicted
protein of 2,492 amino acids. Three zinc finger motifs were found within
the 5-prime end of the gene. Expression analysis in different tissues
identified an alternative splicing event that involves exon 6. One of
these alternatively spliced transcripts is expressed predominantly in
embryonic tissues.

Gibbons et al. (1998) used the N-terminal sequence of ATRX, as
identified by Picketts et al. (1996), to identify a cysteine-rich motif,
similar to a putative zinc finger domain (cys4-his-cys3), called the PHD
finger. PHD motifs span 50 to 80 amino acids and had been identified in
more than 40 proteins, many of which are implicated in
chromatin-mediated transcriptional control.

Picketts et al. (1998) showed that the mouse Atrx gene shows structural
features similar to those of the human gene. Two highly conserved and
functionally important regions were identified: a potential finger
domain at the N terminus and a catalytic domain at the C terminus.

Gibbons and Higgs (2000) stated that the XH2 gene encodes at least 2
alternatively spliced mRNA transcripts that differ at the 5-prime ends
and give rise to slightly different proteins of 265 and 280 kD,
respectively.

GENE STRUCTURE

Stayton et al. (1994) determined that the genomic length of XH2 is more
than 220 kb. Picketts et al. (1996) determined that the XH2 gene
contains 36 exons and spans approximately 300 kb. Using a vectorette
strategy, Villard et al. (1997) identified and sequenced the intron/exon
boundaries of the ATRX gene.

MAPPING

Stayton et al. (1994) mapped the XH2 gene to chromosome Xq13, between
the gene for Menkes disease (MNK; 309400) and DXS56. They showed that
the murine homolog maps to the homologous genetic interval between Pgk1
and Xist.

GENE FUNCTION

Gibbons et al. (1995) showed that mutations in the XH2 gene cause the
alpha-thalassemia/mental retardation syndrome (ATR-X; 301040), an
X-linked disorder comprising severe psychomotor retardation,
characteristic facial features, genital abnormalities, and
alpha-thalassemia. XH2 is a member of a subgroup of the helicase
superfamily that includes proteins involved in a wide range of cellular
functions, including DNA recombination and repair (e.g., ERCC6; 609413)
and transcription regulation. Because of the complex ATR-X phenotype,
Gibbons et al. (1995) suggested that a mutation in the XH2 gene results
in transcriptional downregulation of several genes, including the
alpha-globin genes.

Picketts et al. (1996) suggested that ATRX is most likely involved in
the regulation of gene expression, a known function of helicases. They
noted that ATRX downregulates alpha-globin (141800) but not beta-globin
(141900). They postulated that this may be due to the fact that alpha-
and beta-globin are contained within different chromosomal environments
and are regulated differently because of the interaction of regulatory
factors and chromatin.

The SNF2-like family comprises numerous members involved in a broad
range of biologic functions: transcriptional regulation, DNA repair, and
chromosome segregation. Since experiments on fibroblasts from ATR-X
patients provided no evidence for either a DNA repair defect or abnormal
chromosome breakage segregation, Cardoso et al. (1998) suspected that
the XNP protein is somehow involved in regulation of gene expression.
Genetic and biochemical studies had led to the emerging concept that
SNF2-like proteins are components of a large protein complex that may
exert its functions by modulating chromatin structure. Cardoso et al.
(1998) performed a yeast 2-hybrid analysis with XNP and several human
heterochromatin-associated proteins. They found a specific interaction
between XNP and the EZH2 (601573) proteins. In light of these
observations, they discussed how the XNP protein may regulate gene
transcription at the chromatin level.

Using indirect immunofluorescence and confocal microscopy, McDowell et
al. (1999) showed that ATRX protein is associated with pericentromeric
heterochromatin during interphase and mitosis. By coimmunofluorescence,
they found that ATRX localizes with a mouse homolog of the Drosophila
heterochromatic protein HP1 in vivo, consistent with a previous 2-hybrid
screen identifying this interaction. From the analysis of a trap assay
for nuclear proteins, McDowell et al. (1999) showed that the
localization of ATRX to heterochromatin is encoded by its N-terminal
region, which contains a conserved plant homeodomain-like finger and a
coiled-coil domain. In addition to its association with heterochromatin,
at metaphase ATRX clearly binds to the short arms of human acrocentric
chromosomes, where the arrays of ribosomal DNA are located. The
unexpected association of a putative transcriptional regulator with
highly repetitive DNA provides a potential explanation for the
variability in phenotype of patients with identical mutations in the
ATRX gene.

Berube et al. (2000) demonstrated that the association of the ATRX
protein with chromosomes at mitosis is concomitant with phosphorylation
and its association with HP1-alpha (604478). The authors proposed a dual
role for ATRX, possibly involving gene regulation at interphase as well
as chromosomal segregation at mitosis.

XY patients with deletions or mutations in the ATRX gene display varying
degrees of sex reversal, implicating ATRX in the development of the
human testis (Reardon et al., 1995). To explore further the role of ATRX
in mammalian sex differentiation, Pask et al. (2000) cloned and
characterized the homologous gene in a marsupial. To their surprise,
active homologs of ATRX were detected on the marsupial Y as well as the
X chromosome. The Y-borne copy (ATRY) displayed testis-specific
expression. This, as well as the sex reversal of ATRX patients,
suggested that ATRY is involved in testis development in marsupials and
may represent an ancestral testis-determining mechanism that predated
the evolution of SRY (480000) as the primary mammalian male
sex-determining gene. The authors found no evidence for a Y-borne ATRX
homolog in mouse or human, implying that this gene has been lost in
eutherians and its role supplanted by the evolution of SRY from SOX3
(313430) as the dominant determiner of male differentiation.

Gibbons et al. (2003) stated that like other members of the SWI2/SNF2
family of proteins, multiprotein complexes isolated by ATRX antibodies
have ATP-dependent nucleosome remodeling and DNA translocase activities
in vitro. ATRX is a nuclear protein that localizes to nuclear
subcompartments called PML bodies and to pericentromeric
heterochromatin, where it interacts with a known component of
heterochromatin, HP1.

Nan et al. (2007) found that ATRX interacts with MECP2 (300005), a
methyl-CpG-binding protein that is mutated in Rett syndrome (RTT;
312750) and some forms of mental retardation. Studies in cultured mouse
cells showed that MECP2 targeted the C-terminal helicase domain of ATRX
to heterochromatic foci. The heterochromatic localization of ATRX was
disturbed in neurons from Mecp2-null mice. The findings suggested that
disruption of MECP2-ATRX interaction leads to pathologic changes that
contribute to mental retardation.

By immunofluorescence using ATRX deletion constructs in HeLa cells,
Berube et al. (2008) identified 2 nuclear localization signals and 2
C-terminal domains that targeted ATRX to nuclear speckles, including to
promyelocytic leukemia (PML) nuclear bodies. The PML-targeting domain
appeared to play a role in chromatin remodeling and subnuclear
targeting. Mutant ATRX proteins with mutations in the C-terminal domain
resulted an approximately 80% reduction in the number of transfected
cells with ATRX colocalization to nuclear speckles. The findings showed
that mutations have an effect on subnuclear targeting to PML nuclear
bodies and can cause a loss of ATRX protein function, which may result
in aberrant gene regulation.

Law et al. (2010) examined the genomewide distribution of ATRX protein
and found that it was enriched at telomeres and subtelomeric regions of
human chromosomes. Chromatin immunoprecipitation and sequence analysis
identified 917 ATRX targets in primary human erythroid cells and 1,305
targets in mouse embryonic stem cells. The most prominent feature of the
targets in both human and mouse is the presence of variable number
tandem repeats, many of which are G and C rich, contain a high
proportion of CpG dinucleotides, and/or have the potential to form
G-quadruplex structures, particularly when single stranded. A
subtelomeric region of chromosome 16 (16p13.3) contains 2 ATRX targets,
alpha-globin and NME4 (601818), and each has the potential to form
G-quadruplex structures. The beta-globin locus does not contain likely
ATRX target sequences. Quantitative PCR analysis showed that all peaks
of ATRX binding localized at or very close to regions of G-rich tandemly
repetitive DNA, and the degree of downregulation of each alpha-like
globin gene was related to its proximity to the major peak of ATRX
binding 1 kb upstream from the hemoglobin mu gene (HBM; 609639).
Gel-shift assays confirmed that ATRX bound G-quadruplex DNA in vitro.
Law et al. (2010) noted that a number of ATRX targets are highly
polymorphic, suggesting that the degree to which gene expression is
altered by ATRX may relate to the size of the tandem repeat. This
variability in ATRX targets may also explain incomplete penetrance of
alpha-thalassemia in individuals with identical ATRX mutations.

MOLECULAR GENETICS

In patients with the ATR-X syndrome (301040), an X-linked disorder
comprising severe psychomotor retardation, characteristic facial
features, genital abnormalities, and alpha-thalassemia, Gibbons et al.
(1995) identified mutations in the XH2 gene (300032.0001-300032.0009).
They identified 2 premature in-frame stop mutations, 7 missense
mutations, and a small deletion that reduced expression of the gene in
ATR-X patients to less than 1% of that of controls. A clue to the
presence of mutations in XH2 associated with ATR-X syndrome was the
absence of a hybridization signal with an XH2 probe in the patient with
the deletion. The 9 other mutations were identified by single-strand
conformation polymorphism analysis followed by sequencing.

Picketts et al. (1996) screened 52 individuals with ATR-X syndrome and
identified 4 novel splicing defects in the ATRX gene. They reported
sites of mutation in 27 different cases of ATR-X. Picketts et al. (1996)
noted that mutations associated with the severe urogenital abnormalities
which may occur in ATR-X have primarily been mutations that lead to
severe truncation of the protein with loss of the C-terminal region,
which includes both the P element and the polyglutamine tract.

In a family with Juberg-Marsidi syndrome (309580), Villard et al. (1996)
demonstrated a mutation in the ATRX gene (300032.0011). The findings
indicated that X-linked alpha-thalassemia/mental retardation syndrome
and Juberg-Marsidi syndrome are the same disorder.

Villard et al. (1997) searched for mutations in the 5-prime region of
the ATRX gene in ATR-X patients who did not have mutations in the
3-prime region. In 1 patient, they found that part of exon 7 was removed
from the XNP transcript as a result of a mutation creating a novel
splice site that was substituted for the natural splice site
(300032.0013). The new splicing event removed 1 zinc finger motif,
suggesting that mutations in both the helicase and zinc finger regions
result in disease manifestations.

Extending the mutation analysis of the ATRX gene to include the PHD zinc
finger region, Gibbons et al. (1998) identified 10 different mutations
within a 294-bp segment (see, e.g., 300032.0014; 300032.0015). Family
studies confirmed de novo mutations at 4 of these sites. In 15 unrelated
individuals, a C-to-T transition at a single CpG dinucleotide,
presumably a deamination 'hotspot,' changed arg to cys, which had the
potential to disrupt the putative zinc finger. Similarly, 3 mutations
affected conserved cys residues, which could coordinate zinc binding in
this region. Finally, in 4 unrelated individuals, an identical splice
site mutation removed 21 amino acids, which would disrupt the putative
zinc finger located upstream of the PHD-like domain. Although the
clinical phenotype of particular ATRX mutations was similar, there was a
wide range in the perturbation of alpha-globin expression as reflected
by the proportion of cells with Hb H inclusions, suggesting that the
effect of ATRX protein on gene expression, as for other
chromatin-associated regulators, may be modified by other genetic
factors. Variation was observed even within the same family.

Villard et al. (1999) reported mutation analysis of the XNP gene using
direct sequencing of PCR products derived from primers amplifying the
300-bp zinc finger coding region spanning exons 7, 8, and 9. In 21
mentally retarded male patients with facial appearance typical of ATR-X,
but not necessarily having urogenital abnormalities or hemoglobin H
inclusions, 6 mutations (28%) were detected. Villard et al. (1999)
concluded that this method was suitable for screening individuals in
this population.

Bachoo and Gibbons (1999) identified 2 women who were each mosaic for an
ATRX mutation. One of them, whose mutation was undetectable in
peripheral blood and buccal cells, had 2 affected sons and was therefore
presumed to be a germline mosaic. In the other woman, the ATRX mutation
was weakly detectable in the peripheral blood, but only 1 of her 3
children who shared the disease-associated haplotype carried the
mutation. Therefore, the authors concluded that she represented a
gonosomal mosaic. These cases provided the first molecular evidence for
the occurrence of postzygotic mutations in ATR-X syndrome.

Gibbons et al. (2000) demonstrated that mutations in the ATRX gene give
rise to changes in the methylation pattern of several highly repeated
sequences, including the rDNA arrays, a Y-specific satellite, and
subtelomeric repeats. Using methylation-sensitive restriction
endonucleases, they noted differences in the pattern of rDNA methylation
by comparing genomic DNA from EBV-transformed B cells or the peripheral
blood of normal individuals with that from patients with ATRX syndrome.
In normal individuals, approximately 20% of rDNA repeats were methylated
within most CpG-rich regions. In ATRX patients, rDNA genes were
substantially unmethylated. These differences were present in a variety
of tissues from the fetal stage of development onwards. The Y-specific
repeat DYZ2 makes up 10 to 20% of the Y chromosome, distributed along
the entire heterochromatic band Yq12. Gibbons et al. (2000) discovered
that approximately 6% of DYZ2 repeats were unmethylated on the Y
chromosomes in the peripheral blood of normal individuals, but almost
all were methylated in ATRX patients. These results differed from those
identified in the rDNA repeats, suggesting that the effect of ATRX
mutations on Y-chromosome repeats is different from their effect on rDNA
repeats. Gibbons et al. (2000) concluded that their findings provide a
potential link between the processes of chromatin remodeling, DNA
methylation, and gene expression in mammalian development.

In a study of 8 unrelated Japanese families, Wada et al. (2000) found 7
missense mutations, including 6 novel mutations, as the cause of the
ATR-X syndrome. One mutation, arg246-to-cys (300032.0018), was found in
2 unrelated patients. All mutations were located either in the
N-terminal region corresponding to the putative zinc finger domain or in
the C-terminal region corresponding to the helicase domain. The clinical
manifestations were the same with mutations of either group, suggesting
that the putative zinc finger and helicase domains have similar
functional significance for the ATRX gene.

Using a broad range denaturing gel gradient electrophoresis (DGGE)
method for single-step mutation scanning of the entire open reading
frame and canonical splice sites of the ATRX gene, Borgione et al.
(2003) identified 5 novel sequence changes: 4 missense mutations and 1
polymorphism.

Rarely, alpha-thalassemia occurs as an acquired abnormality in
individuals with various types of multilineage myelodysplasia, the
so-called ATMDS syndrome (300448) (Weatherall et al., 1978; Higgs et
al., 1983). Gibbons et al. (2003) stated that 71 individuals with the
ATMDS syndrome had been identified, of whom 62 (87%) were males who had
a de novo, acquired form of alpha-thalassemia with hypochromic
microcytic anemia. In these individuals, a reduction in alpha-globin
expression leads to an excess of beta-globin chains, which form an
abnormal hemoglobin (HbH, or beta-4) that is readily detectable in
peripheral blood. In the most severely affected individuals, alpha-chain
synthesis is almost abolished, implying that all 4 alpha genes are
downregulated. This degree of alpha-thalassemia would be lethal during
development if it resulted from an inherited mutation. No structural
abnormalities in cis to the alpha-globin genes had been detected, and
the downregulation of alpha-globin appeared to be associated with a
trans-acting mutation. ATRX was a plausible candidate for harboring
mutations associated with this syndrome. Because of the large size of
the gene (300 kb) and the failure of previous direct mutational
searches, Gibbons et al. (2003) chose microarray analysis to search for
genes whose expression might be perturbed in ATMDS. In purified
granulocytes from the peripheral blood they found that ATRX expression
was 3 to 4% of that in normal controls. In contrast, there was no
significant reduction in ATRX expression in 13 individuals with
myelodysplasia syndrome with alpha-thalassemia. Sequence analysis
identified a G-to-A mutation in the canonic splice donor site (GT) of
intron 1 of ATRX (300032.0020). This mutation was present in
granulocytes but absent in DNA from both buccal cells and a
lymphoblastoid cell line derived from the patient. The finding suggested
that this pleiotropic cofactor is an essential component rather than a
mere facilitator of globin gene expression. For many important genes,
inherited null mutations are lethal early in development. The only
viable manifestations of such mutations in these genes will be seen in
diseases associated with acquired somatic mutations. Other examples of
this, in addition to ATRX, include mutations of PIGA (311770) in
paroxysmal nocturnal hemoglobinuria (300818), and GNAS1 (139320) in
McCune-Albright syndrome (174800).

- Partial Duplication of the ATRX Gene

Thienpont et al. (2007) reported 3 patients, including 2 sibs, with the
ATRX syndrome due to partial duplications of the ATRX gene. In 1 family,
the duplication included exons 2 to 35; in the other family, exons 2 to
29. Further analysis showed that both mothers carried the duplication
and both had skewed X inactivation. In 1 patient, ATRX mRNA levels were
about 3% of normal values. Thienpont et al. (2007) noted that the
duplications were not identified by sequence analysis and suggested that
quantitative analysis to detect copy numbers of the ATRX gene may be
required in some cases.

Cohn et al. (2009) reported a family in which 3 males had ATRX syndrome
due to a partial intragenic duplication of the ATRX gene that spanned
exons 2 to 31. Northern blot analysis failed to identify a full-length
transcript, but cDNA sequencing was consistent with some level of
expression. The authors noted that complete loss of ATRX is most likely
lethal, suggesting that the mutation was likely hypomorphic and
associated with some residual protein function. Unaffected obligate
carrier females in the family had highly skewed X inactivation. The
phenotype was typical for the disorder, although the facial features
were not as readily apparent in the 2 older affected individuals. The
proband was identified from 2 larger cohorts comprising 300 males with
mental retardation. Cohn et al. (2009) did not find ATRX duplications in
29 additional males with ATRX syndrome who were negative on sequence
analysis, suggesting that duplications are a rare cause of the disorder.

PATHOGENESIS

- Pancreatic Neuroendocrine Tumors

Jiao et al. (2011) explored the genetic basis of pancreatic
neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10
nonfamilial PanNETs and then screened the most commonly mutated genes in
58 additional PanNETs. The most frequently mutated genes specify
proteins implicated in chromatin remodeling: 44% of the tumors had
somatic inactivating mutations in MEN1 (613733), and 43% had mutations
in genes encoding either of the 2 subunits of a transcription/chromatin
remodeling complex consisting of DAXX (death domain-associated protein,
603186) and ATRX. Clinically, mutations in the MEN1 and DAXX/ATRX genes
were associated with better prognosis. Jiao et al. (2011) also found
mutations in genes in the mTOR (601231) pathway in 14% of the tumors, a
finding that could potentially be used to stratify patients for
treatments with mTOR inhibitors.

Heaphy et al. (2011) evaluated telomere status in PanNETs in which ATRX
and DAXX mutational status had been determined through Sanger
sequencing. Telomere-specific FISH revealed that 25 of 41 (61%) PanNETs
displayed large, ultrabright telomere FISH signals, a nearly universal
feature of the telomerase-independent telomere maintenance mechanism
termed alternative lengthening of telomeres. ATRX and DAXX gene
mutations both were significantly correlated with ALT positivity (P less
than 0.008 for each gene). All 19 (100%) PanNETs with ATRX or DAXX gene
mutations were ALT-positive, whereas 6 of 20 cases without detectable
mutations were ALT-positive. To ascertain whether ATRX and DAXX gene
mutations might be more generally associated with the ALT phenotype,
Heaphy et al. (2011) examined 439 tumors of other types and found a
strong correlation between inactivation of ATRX or DAXX and the ALT
phenotype in unrelated tumor types.

- Pediatric Glioblastoma

Schwartzentruber et al. (2012) sequenced the exomes of 48 pediatric
glioblastoma (137800) samples. Somatic mutations in the H3.3-ATRX-DAXX
chromatin remodeling pathway were identified in 44% of tumors (21 of
48). Recurrent mutations in H3F3A (601128), which encodes the
replication-independent histone-3 variant H3.3, were observed in 31% of
tumors, and led to amino acid substitutions at 2 critical positions
within the histone tail (K27M, G34R/G34V) involved in key regulatory
posttranslational modifications. Mutations in ATRX and DAXX, encoding 2
subunits of a chromatin remodeling complex required for H3.3
incorporation at pericentric heterochromatin and telomeres, were
identified in 31% of samples overall, and in 100% of tumors harboring a
G34R or G34V H3.3 mutation. Somatic TP53 (191170) mutations were
identified in 54% of all cases, and in 86% of samples with H3F3A and/or
ATRX mutations. Screening of a large cohort of gliomas of various grades
and histologies (n = 784) showed H3F3A mutations to be specific to
glioblastoma multiforme and highly prevalent in children and young
adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was
strongly associated with alternative lengthening of telomeres and
specific gene expression profiles. Schwartzentruber et al. (2012) stated
that this was the first report to highlight recurrent mutations in a
regulatory histone in humans, and that their data suggested that defects
of the chromatin architecture underlie pediatric and young adult
glioblastoma multiforme pathogenesis.

GENOTYPE/PHENOTYPE CORRELATIONS

In a review article, Gibbons and Higgs (2000) noted that mutations
resulting in the loss of the C terminal domain are associated with the
most severe urogenital abnormalities. However, at other sites, there is
no obvious link between genotype and phenotype, and there is
considerable variation in the degree of abnormalities seen in
individuals with the same mutation.

Among 22 ATRX patients from 16 families, Badens et al. (2006) found that
those with mutations in the PHD-like domain of the ATRX protein had
significantly more severe and permanent psychomotor retardation and
significantly more severe urogenital anomalies compared to those with
mutations in the helicase domain.

Extreme skewing of X-chromosome inactivation (XCI) is rare in the normal
female population but is observed frequently in carriers of some
X-linked mutations. Plenge et al. (2002) showed that various forms of
X-linked mental retardation (XLMR) have a strong association with skewed
XCI in female carriers. The ATRX syndrome is one such disorder;
phenotypically normal female carriers virtually all have highly skewed
XCI biased against the X chromosome that harbors the mutant allele.
Muers et al. (2007) used a mouse model to understand the processes
causing skewed XCI. In female mice heterozygous for a null Atrx allele,
they found that XCI is balanced early in embryogenesis but becomes
skewed over the course of development, because of selection favoring
cells expressing the wildtype Atrx allele. Unexpectedly, selection did
not appear to be the result of general cellular viability defects in
Atrx-deficient cells, since it was restricted to specific stages of
development and was not ongoing throughout the life of the animal.
Instead, there was evidence that selection results from independent
tissue-specific effects.

ANIMAL MODEL

Although the ATRX protein is a member of the SWI/SNF family of chromatin
remodeling proteins, little is known about the biochemical activity of
the ATRX protein or its in vivo function during development. Berube et
al. (2002) demonstrated that ATRX is part of a large multiprotein
complex similar in size to the SWI/SNF complex. Overexpression of ATRX
in transgenic mice was associated with growth retardation, neural tube
defects, and a high incidence of embryonic death. Moreover, brains from
E10.5 transgenic embryos displayed abnormal growth and organization of
the ventricular zone that was highly convoluted in the most severely
affected embryos. Transgenic mice that survived to birth exhibited a
high incidence of perinatal death as well as seizures, mild craniofacial
anomalies, and abnormal behavior. The authors concluded that ATRX dosage
is crucial for normal development and organization of the cortex.

By immunostaining for Atrx in mouse brain, Berube et al. (2005) found
that Atrx expression was nuclear in all cells and coincided with regions
of intense DAPI staining, consistent with a heterochromatin
colocalization. The temporal pattern of Atrx expression followed the
process of neuroprogenitor differentiation. To circumvent early
lethality in Atrx-null mice, Berube et al. (2005) developed mice with
forebrain-targeted conditional loss of Atrx expression. Targeted loss of
Atrx caused widespread hypocellularity in the neocortex and hippocampus
and a pronounced reduction in forebrain size. Neuronal 'birthdating'
confirmed that fewer neurons reached the superficial cortical layers,
despite normal progenitor cell proliferation. The loss of cortical mass
resulted from a 12-fold increase in neuronal apoptosis during early
stages of corticogenesis in the mutant animals. Cultured cortical
progenitor cells isolated from Atrx-null mice underwent enhanced
apoptosis upon differentiation. Berube et al. (2005) concluded that Atrx
is a critical mediator of cell survival during early neuronal
differentiation and that neuronal loss may contribute to the mental
retardation observed in ATR-X syndrome patients.

Medina et al. (2009) surveyed ATR-X syndrome clinical findings and noted
that ocular defects were present in 47 (23%) of 202 patients. They
showed that Atrx was expressed in the neuroprogenitor pool in embryonic
mouse retina and in all cell types of adult mouse retina except rod
photoreceptors. Conditional inactivation of Atrx in mouse retina during
embryogenesis resulted in loss of only 2 types of neurons, amacrine and
horizontal cells. This defect did not arise from a failure to specify
these cells, but rather a defect in interneuron differentiation and
survival postnatally. The timing of cell loss was concomitant with
light-dependent changes in synaptic organization in mouse retina and
with a change in Atrx subnuclear localization within these interneurons.
The interneuron defects were associated with functional deficits as
demonstrated by reduced b-wave amplitudes upon electroretinogram
analysis. Medina et al. (2009) proposed a role for Atrx in interneuron
survival and differentiation.

*FIELD* AV
.0001
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, HIS750ARG

In a patient with the ATR-X syndrome (301040), Gibbons et al. (1995)
identified a 2302A-G transition in the XH2 gene, resulting in a
his750-to-arg (H750R) substitution.

.0002
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, CYS755ARG

In a patient with the ATR-X syndrome (301040), Gibbons et al. (1995)
identified a 2316T-C transition in the XH2 gene, resulting in a
cys755-to-arg (C755R) amino acid change.

.0003
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, LYS792ASN

In a patient with the ATR-X syndrome (301040), Gibbons et al. (1995)
identified a 2429G-T transversion in the XH2 gene, resulting in a
lys792-to-asn (K792N) amino acid change.

.0004
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, ASN1002SER

In a patient with the ATR-X syndrome (301040), Gibbons et al. (1995)
identified a 3058A-G transition in the XH2 gene, resulting in an
asn1002-to-ser (N1002S) amino acid change.

.0005
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, ASP1177VAL

In a patient with the ATR-X syndrome (301040), Gibbons et al. (1995)
identified a 3583A-T transversion in the XH2 gene, leading to an
asp1177-to-val (D1177V) amino acid change.

.0006
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, TYR1226HIS

In a patient with the ATR-X syndrome (301040), Gibbons et al. (1995)
identified a 3729T-C transition in the XH2 gene, leading to a
tyr1226-to-his (Y1226H) amino acid change.

.0007
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, TYR1305CYS

In a patient with the ATR-X syndrome (301040), Gibbons et al. (1995)
identified a 3967A-G transition in the XH2 gene, leading to a
tyr1305-to-cys (Y1305C) amino acid change.

.0008
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, ARG1528TER

In a patient with the ATR-X syndrome (301040), Gibbons et al. (1995)
identified a 4635C-T transition in the XH2 gene, leading to premature
termination of the polypeptide at codon 1528 (R1528X).

.0009
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, GLU1530TER

In a patient with the ATR-X syndrome (301040), Gibbons et al. (1995)
identified a 4641G-T transversion in the XH2 gene, resulting in a
glu1530-to-ter (E1530X) substitution.

.0010
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, IVSAS, T-A, -10

In affected members of a family with ATR-X syndrome (301040), Villard et
al. (1996) identified a T-to-A transversion in the XH2 gene in the
consensus splice acceptor site at position -10 on the upstream side of
the deleted 176-bp exon, resulting in a premature stop codon and a
shortened protein with 638 amino acids. In 2 first cousins presenting
the classic ATR-X phenotype with alpha-thalassemia and Hb H inclusions,
only the abnormal transcript was expressed. In a distant cousin
presenting with a similar dysmorphic mental retardation phenotype, but
without thalassemia, they found that approximately 30% of the XH2
transcripts were normal. These data suggested that the mode of action of
the XH2 gene product on globin expression is distinct from its mode of
action in brain development and facial morphogenesis. The mothers of the
patients were found to be heterozygotes. It appeared that the mutated
splice site could be used with varying efficiency in different
individuals. Kiesewetter et al. (1993) reported the same missense
mutation in the cystic fibrosis gene, in which it leads to different
phenotypes, depending on the genetic background in which the mutation
was segregating.

.0011
MENTAL RETARDATION-HYPOTONIC FACIES SYNDROME, X-LINKED
ATRX, ARG1272GLN

In affected members of a large family with Juberg-Marsidi syndrome
(309580) reported by Mattei et al. (1983), Villard et al. (1996)
identified a mutation in the XH2 gene, resulting in an arg1272-to-gln
(R1272Q) substitution in the highly conserved helicase V domain. The
helicase V domain was known to be involved in transcriptional control in
yeast. Furthermore, the change of amino acid arg1272, which is highly
conserved among species from yeast to human, alters the overall charge
of the domain. In the family studied, the mutant X chromosome was
consistently inactivated in carriers as it is in the ATR-X syndrome.
This suggested to the authors that the XNP protein either plays a role
in a fundamental cellular process, such as X inactivation or cell
division, or has a nonspecific deleterious effect with clonal selection
of the normal XNP allele.

.0012
MENTAL RETARDATION-HYPOTONIC FACIES SYNDROME, X-LINKED
ATRX, PRO852SER

In a proband and a maternal uncle with X-linked mental
retardation-hypotonic face syndrome (309580), Villard et al. (1996)
identified a pro852-to-ser (P852S) substitution in the ATRX gene in a
highly-conserved region of helicase domain II.

.0013
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, 751A-G

In a sporadic case presenting with a typical ATR-X phenotype (301040),
Villard et al. (1997) found that the 2 alternatively spliced transcripts
of ATRX were smaller than expected. DNA sequencing identified a 751A-G
transition in the ATRX gene. This mutation created an effective splicing
site with a consensus value (Shapiro and Senapathy, 1987) of 0.9, which
is a higher value than that for the usual donor splicing site (0.85) or
the nonmutated cryptic site (0.77), probably allowing it to be more
efficiently used in vivo than the normal donor site. The event leads to
a potential protein missing 21 amino acids. The missing part of the
transcript corresponded to the first zinc finger of the gene.

.0014
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, PRO73ALA

In a patient with ATR-X syndrome (301040), Gibbons et al. (1998)
identified a 901C-G transversion in the XH2 gene, resulting in a
pro73-to-ala (P73A) substitution.

.0015
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, ARG129CYS

In affected members of 15 unrelated families with ATR-X syndrome
(301040), Gibbons et al. (1998) identified a 1069C-T transition in the
XH2 gene, resulting in an arg129-to-cys (R129C) substitution. The
mutation was de novo in 3 cases. The proportion of cells with Hb H
inclusions ranged from 0.006 to 14% in these individuals with an
identical mutation. The mutation occurred in a CpG dinucleotide.

.0016
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, ARG1742LYS

In affected patients from a family with ATR-X syndrome (301040) reported
by Martinez et al. (1998), Lossi et al. (1999) identified a 5459G-A
transition in the XH2 gene, resulting in an arg1742-to-lys (R1742K)
substitution in the conserved helicase domain III. Affected patients
showed hypertonia from birth and spasticity, which are unusual findings
in ATR-X syndrome. Haplotype analysis identified 2 females who shared
the disease-associated haplotype, spanning both the ATRX gene and the
X-inactivation center, but lacking the R1742K mutation. Lossi et al.
(1999) deduced that the mutation arose de novo in the germline of 1
member of the founding couple. Furthermore, the fact that females in the
nonmutated branch of the family did not exhibit a skewed pattern of X
inactivation demonstrated that the skewing in carrier females was
directly linked to the presence of the mutation in the gene. Lossi et
al. (1999) stated that this was the first reported instance in which
negative selection against the cells expressing an abnormal gene product
in females did not imply a male lethal condition.

.0017
MENTAL RETARDATION-HYPOTONIC FACIES SYNDROME, X-LINKED
ATRX, IVS34, A-G, -2

Villard et al. (2000) demonstrated that 2 brothers reported by Ades et
al. (1991) as having the Smith-Fineman-Myers type of mental retardation
(309580) had a mutation in the ATRX gene: the acceptor splice site of
intron 34 was affected, causing a frameshift and the replacement of the
92 amino acids encoded by exon 35 in the wildtype transcript by 46
different amino acids. Three previous mutations had been reported to
affect this last exon of the gene. In 2 of the 3, the affected patients
presented severe urogenital anomalies which led to female gender
assignment. The brothers reported by Ades et al. (1991) and Villard et
al. (2000) had bilateral cryptorchidism.

.0018
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, ARG246CYS

In 2 presumably unrelated Japanese patients with ATR-X syndrome
(301040), Wada et al. (2000) identified a mutation in the ATRX gene,
resulting in an arg246-to-cys (R246C) substitution.

Badens et al. (2006) reported a 4-year-old girl with typical features of
the ATR-X syndrome. Molecular studies showed a totally skewed
X-inactivation pattern with the active chromosome carrying a
heterozygous R246C mutation, resulting from a 951C-T transition in the
zinc finger domain-coding region of the ATRX gene. Neither parent had
the mutation in peripheral blood leukocytes, but SNP analysis indicated
that the mutation occurred on the maternal chromosome. The child was
conceived with assisted reproduction technologies (ART) due to
micropolycystic ovaries and endometriosis in the mother. Badens et al.
(2006) suggested that some aspect of ART may have disturbed imprinting
in this patient.

.0019
ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED
ATRX, THR1621MET

Yntema et al. (2002) identified a thr1621-to-met (T1621M) missense
mutation in the ATRX gene in a patient from a family in which most
affected members had only mild mental retardation and no obvious facial
dysmorphisms. Linkage analysis showed a maximum lod score of 3.9 at
theta = 0.0 for linkage to the ATRX locus. Subsequent analysis of red
blood cells revealed hemoglobin H inclusion bodies. Furthermore,
X-inactivation studies revealed extreme skewing of X-inactivation in
carrier females. In retrospect, facial hypotonia was recognized in
pictures taken in childhood, a usual finding in the ATR-X syndrome
(301040), but this feature was not seen in adulthood.

.0020
ALPHA-THALASSEMIA MYELODYSPLASIA SYNDROME, SOMATIC
ATRX, IVS1DS, G-A, +1

In a case of alpha-thalassemia myelodysplasia syndrome (300448), Gibbons
et al. (2003) identified a G-to-A transition in the canonic splice donor
site (GT) of intron 1 of the ATRX gene. The mutation was present in
granulocytes but absent in DNA from both buccal cells and a
lymphoblastoid cell line derived from the patient. Because ATMDS is a
clonal disorder affecting myeloid progenitors, DNA isolated from the
unfractionated white cells (granulocytes and lymphocytes) in peripheral
blood had a mixture of mutant and wildtype sequences.

.0021
ALPHA-THALASSEMIA MYELODYSPLASIA SYNDROME, SOMATIC
ATRX, SER79TER

In bone marrow cDNA from a patient with alpha-thalassemia myelodysplasia
syndrome (300448), Gibbons et al. (2003) found a C-to-G transversion in
exon 4 of the ATRX gene, resulting in a ser79-to-ter (S79X)
substitution. A mixture of mutant and wildtype sequence in DNA from bone
marrow and peripheral blood was found.

.0022
MENTAL RETARDATION-HYPOTONIC FACIES SYNDROME, X-LINKED
ATRX, ARG37TER

In 4 male cousins with the X-linked mental retardation-hypotonic facies
syndrome (309580), Guerrini et al. (2000) identified a 109C-T transition
in exon 2 of the ATRX gene, resulting in an arg37-to-ter (R37X)
substitution. Two patients had moderate to profound mental retardation
and the typical facial features of the syndrome, whereas the other 2
patients presented with mild mental retardation and epilepsy, but
without the characteristic facial dysmorphism.

Howard et al. (2004) found that human embryonic kidney cells carrying
the R37X mutation expressed approximately 20% of a slightly shortened
ATRX protein compared to controls. Analysis of the 5-prime end of the
ATRX gene revealed a downstream AUG start codon at residue 40,
suggesting an alternative initiation event. Howard et al. (2004)
suggested that 'phenotypic rescue' due to the expression of a truncated
ATRX protein using the alternative downstream initiation site underlies
the relatively mild phenotype seen in some patients with the R37X
mutation.

Abidi et al. (2005) identified the R37X mutation in 3 affected males
originally reported by Chudley et al. (1988) as having Chudley-Lowry
syndrome. Western blot and immunocytochemical analyses using a specific
monoclonal antibody directed against ATRX showed the protein to be
present in lymphoblastoid cells, despite the premature stop codon. Abidi
et al. (2005) suggested that the less severe phenotype was due to the
presence of some residual ATRX protein. The phenotypic variation between
patients with the same mutation suggested that the ATRX gene may
influence the expression of several genes in multiple tissues during
development.

.0023
MENTAL RETARDATION-HYPOTONIC FACIES SYNDROME, X-LINKED
ATRX, LEU409SER

In several members of a family with X-linked mental
retardation-hypotonic facies syndrome (301040), Wieland et al. (2005)
identified a 1226T-C transition in the ATRX gene, resulting in a
leu409-to-ser (L409S) substitution in a conserved residue within the
coiled-coil motif of the heterochromatin protein-1 (HP1;
604478)-interacting domain of the ATRX protein.

.0024
MENTAL RETARDATION-HYPOTONIC FACIES SYNDROME, X-LINKED
ATRX, ILE2052THR

In affected members of a family with X-linked mental retardation and
facial abnormalities originally reported by Carpenter et al. (1988,
1999) (309580), Abidi et al. (1999) identified a 6356T-C transition in
the ATRX gene, resulting in an ile2052-to-thr (I2052T) substitution in
the helicase IV domain. Abidi et al. (1999) referred to the disorder as
the Carpenter-Waziri syndrome.

.0025
MENTAL RETARDATION-HYPOTONIC FACIES SYNDROME, X-LINKED
ATRX, CYS220TYR

In 2 obligate carriers from a family with XLMR-hypotonic facies syndrome
(309580) originally reported by Holmes and Gang (1984), Stevenson et al.
(2000) identified an 866G-A transition in the XH2 gene, resulting in a
cys220-to-tyr (C220Y) substitution in the second zinc finger domain.
Carriers in this family, who had no clinical manifestations, showed the
typical marked skewing of X inactivation, consistent with a mutation in
the XH2 gene.

.0026
MENTAL RETARDATION-HYPOTONIC FACIES SYNDROME, X-LINKED
ATRX, ARG2271GLY

In a 3-year-old boy with XLMR-hypotonic facies syndrome (309580), a
history of hypotonia followed by hypertonia, and asplenia, Leahy et al.
(2005) identified a 6811A-G transition in exon 32 of the ATRX gene,
resulting in an arg2271-to-gly (R2271G) substitution. The mother was a
carrier of the mutation.

*FIELD* RF
1. Abidi, F.; Schwartz, C. E.; Carpenter, N. J.; Villard, L.; Fontes,
M.; Curtis, M.: Carpenter-Waziri syndrome results from a mutation
in XNP. (Letter) Am. J. Hum. Genet. 85: 249-251, 1999.

2. Abidi, F. E.; Cardoso, C.; Lossi, A.-M.; Lowry, R. B.; Depetris,
D.; Mattei, M.-G.; Lubs, H. A.; Stevenson, R. E.; Fontes, M.; Chudley,
A. E.; Schwartz, C. E.: Mutation in the 5-prime alternatively spliced
region of the XNP/ATR-X gene causes Chudley-Lowry syndrome. Europ.
J. Hum. Genet. 13: 176-183, 2005.

3. Ades, L. C.; Kerr, B.; Turner, G.; Wise, G.: Smith-Fineman-Myers
syndrome in two brothers. Am. J. Med. Genet. 40: 467-470, 1991.

4. Bachoo, S.; Gibbons, R. J.: Germline and gonosomal mosaicism in
the ATR-X syndrome. Europ. J. Hum. Genet. 7: 933-936, 1999.

5. Badens, C.; Lacoste, C.; Philip, N.; Martini, N.; Courrier, S.;
Giuliano, F.; Verloes, A.; Munnich, A.; Leheup, B.; Burglen, L.; Odent,
S.; Van Esch, H.; Levy, N.: Mutations in PHD-like domain of the ATRX
gene correlate with severe psychomotor impairment and severe urogenital
abnormalities in patients with ATRX syndrome. Clin. Genet. 70: 57-62,
2006.

6. Badens, C.; Martini, N.; Courrier, S.; DesPortes, V.; Touraine,
R.; Levy, N.; Edery, P.: ATRX syndrome in a girl with a heterozygous
mutation in the ATRX Zn finger domain and a totally skewed X-inactivation
pattern. Am. J. Med. Genet. 140A: 2212-2215, 2006.

7. Berube, N. G.; Healy, J.; Medina, C. F.; Wu, S.; Hodgson, T.; Jagla,
M.; Picketts, D. J.: Patient mutations alter ATRX targeting to PML
nuclear bodies. Europ. J. Hum. Genet. 16: 192-201, 2008.

8. Berube, N. G.; Jagla, M.; Smeenk, C.; De Repentigny, Y.; Kothary,
R.; Picketts, D. J.: Neurodevelopmental defects resulting from ATRX
overexpression in transgenic mice. Hum. Molec. Genet. 11: 253-261,
2002.

9. Berube, N. G.; Mangelsdorf, M.; Jagla, M.; Vanderluit, J.; Garrick,
D.; Gibbons, R. J.; Higgs, D. R.; Slack, R. S.; Picketts, D. J.:
The chromatin-remodeling protein ATRX is critical for neuronal survival
during corticogenesis. J. Clin. Invest. 115: 258-267, 2005.

10. Berube, N. G.; Smeenk, C. A.; Picketts, D. J.: Cell cycle-dependent
phosphorylation of the ATRX protein correlates with changes in nuclear
matrix and chromatin association. Hum. Molec. Genet. 9: 539-547,
2000.

11. Borgione, E.; Sturnio, M.; Spalletta, A.; Lo Giudice, M. A.; Castiglia,
L.; Galesi, O.; Ragusa, A.; Fichera, M.: Mutational analysis of the
ATRX gene by DGGE: a powerful diagnostic approach for the ATRX syndrome. Hum.
Mutat. 21: 529-534, 2003.

12. Cardoso, C.; Timsit, S.; Villard, L.; Khrestchatisky, M.; Fontes,
M.; Colleaux, L.: Specific interaction between the XNP/ATR-X gene
product and the SET domain of the human EZH2 protein. Hum. Molec.
Genet. 7: 679-684, 1998.

13. Carpenter, N. J.; Qu, Y.; Curtis, M.; Patil, S. R.: X-linked
mental retardation syndrome with characteristic 'coarse' facial appearance,
brachydactyly, and short stature maps to proximal Xq. Am. J. Med.
Genet. 85: 230-235, 1999.

14. Carpenter, N. J.; Waziri, M.; Liston, J.; Patil, S. R.: Studies
on X-linked mental retardation: evidence for a gene in the region
Xq11-q22. (Abstract) Am. J. Hum. Genet. 43 (suppl.): A139 only,
1988.

15. Chudley, A. E.; Lowry, R. B.; Hoar, D. I.: Mental retardation,
distinct facial changes, short stature, obesity, and hypogonadism:
a new X-linked mental retardation syndrome. Am. J. Med. Genet. 31:
741-751, 1988.

16. Cohn, D. M.; Pagon, R. A.; Hudgins, L.; Schwartz, C. E.; Stevenson,
R. E.; Friez, M. J.: Partial ATRX gene duplication causes ATR-X syndrome.
(Letter) Am. J. Med. Genet. 149A: 2317-2320, 2009.

17. Gibbons, R. J.; Bachoo, S.; Picketts, D. J.; Aftimos, S.; Asenbauer,
B.; Bergoffen, J.; Berry, S. A.; Dahl, N.; Fryer, A.; Keppler, K.;
Kurosawa, K.; Levin, M. L.; Masuno, M.; Neri, G.; Pierpont, M. E.;
Slaney, S. F.; Higgs, D. R.: Mutations in transcriptional regulator
ATRX establish the functional significance of a PHD-like domain. (Letter) Nature
Genet. 17: 146-148, 1998.

18. Gibbons, R. J.; Higgs, D. R.: Molecular-clinical spectrum of
the ATR-X syndrome. Am. J. Med. Genet. 97: 204-212, 2000.

19. Gibbons, R. J.; McDowell, T. L.; Raman, S.; O'Rourke, D. M.; Garrick,
D.; Ayyub, H.; Higgs, D. R.: Mutations in ATRX, encoding a SWI/SNF-like
protein, cause diverse changes in the pattern of DNA methylation. Nature
Genet. 24: 368-371, 2000.

20. Gibbons, R. J.; Pellagatti, A.; Garrick, D.; Wood, W. G.; Malik,
N.; Ayyub, H.; Langford, C.; Boultwood, J.; Wainscoat, J. S.; Higgs,
D. R.: Identification of acquired somatic mutations in the gene encoding
chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia
syndrome (ATMDS). Nature Genet. 34: 446-449, 2003.

21. Gibbons, R. J.; Picketts, D. J.; Villard, L.; Higgs, D. R.: Mutations
in a putative global transcriptional regulator cause X-linked mental
retardation with alpha-thalassemia (ATR-X syndrome). Cell 80: 837-845,
1995.

22. Guerrini, R.; Shanahan, J. L.; Carrozzo, R.; Bonanni, P.; Higgs,
D. R.; Gibbons, R. J.: A nonsense mutation of the ATRX gene causing
mild mental retardation and epilepsy. Ann. Neurol. 47: 117-121,
2000.

23. Heaphy, C. M.; de Wilde, R. F.; Jiao, Y.; Klein, A. P.; Edil,
B. H.; Shi, C.; Bettegowda, C.; Rodriguez, F. J.; Eberhart, C. G.;
Hebbar, S.; Offerhaus, G. J.; McLendon, R.; and 13 others: Altered
telomeres in tumors with ATRX and DAXX mutations. Science 333: 425
only, 2011.

24. Higgs, D. R.; Wood, W. G.; Barton, C.; Weatherall, D. J.: Clinical
features and molecular analysis of acquired hemoglobin H disease. Am.
J. Med. 75: 181-191, 1983.

25. Holmes, L. B.; Gang, D. L.: An X-linked mental retardation syndrome
with craniofacial abnormalities, microcephaly and club foot. Am.
J. Med. Genet. 17: 375-382, 1984.

26. Howard, M. T.; Malik, N.; Anderson, C. B.; Voskuil, J. L. A.;
Atkins, J. F.; Gibbons, R. J.: Attenuation of an amino-terminal premature
stop codon mutation in the ATRX gene by an alternative mode of translational
initiation. (Letter) J. Med. Genet. 41: 951-956, 2004.

27. Jiao, Y.; Shi, C.; Edil, B. H.; de Wilde, R. F.; Klimstra, D.
S.; Maitra, A.; Schulick, R. D.; Tang, L. H.; Wolfgang, C. L.; Choti,
M. A.; Velculescu, V. E.; Diaz, L. A., Jr.; Vogelstein, B.; Kinzler,
K. W.; Hruban, R. H.; Papadopoulos, N.: DAXX/ATRX, MEN1, and mTOR
pathway genes are frequently altered in pancreatic neuroendocrine
tumors. Science 331: 1199-1203, 2011.

28. Kiesewetter, S.; Macek, M., Jr.; Davis, C.; Curristin, S. M.;
Chu, C.-S.; Graham, C.; Shrimpton, A. E.; Cashman, S. M.; Tsui, L.-C.;
Mickle, J.; Amos, J.; Highsmith, W. E.; Shuber, A.; Witt, D. R.; Crystal,
R. G.; Cutting, G. R.: A mutation in CFTR produces different phenotypes
depending on chromosomal background. Nature Genet. 5: 274-278, 1993.

29. Law, M. J.; Lower, K. M.; Voon, H. P. J.; Hughes, J. R.; Garrick,
D.; Viprakasit, V.; Mitson, M.; De Gobbi, M.; Marra, M.; Morris, A.;
Abbott, A.; Wilder, S. P.; and 10 others: ATR-X syndrome protein
targets tandem repeats and influences allele-specific expression in
a size-dependent manner. Cell 143: 367-378, 2010.

30. Leahy, R. T.; Philip, R. K.; Gibbons, R. J.; Fisher, C.; Suri,
M.; Reardon, W.: Asplenia in ATR-X syndrome: a second report. Am.
J. Med. Genet. 139A: 37-39, 2005.

31. Lossi, A. M.; Millan, J. M.; Villard, L.; Orellana, C.; Cardoso,
C.; Prieto, F.; Fontes, M.; Martinez, F.: Mutation of the XNP/ATR-X
gene in a family with severe mental retardation, spastic paraplegia
and skewed pattern of X inactivation: demonstration that the mutation
is involved in the inactivation bias. (Letter) Am. J. Hum. Genet. 65:
558-562, 1999.

32. Martinez, F.; Tomas, M.; Millan, J. M.; Fernandez, A.; Palau,
F.; Prieto, F.: Genetic localisation of mental retardation with spastic
diplegia to the pericentromeric region of the X chromosome: X inactivation
in female carriers. J. Med. Genet. 35: 284-287, 1998.

33. Mattei, J. F.; Collignon, P.; Ayme, S.; Giraud, F.: X-linked
mental retardation, growth retardation, deafness and microgenitalism:
a second familial report. Clin. Genet. 23: 70-74, 1983.

34. McDowell, T. L.; Gibbons, R. J.; Sutherland, H.; O'Rourke, D.
M.; Bickmore, W. A.; Pombo, A.; Turley, H.; Gatter, K.; Picketts,
D. J.; Buckle, V. J.; Chapman, L.; Rhodes, D.; Higgs, D. R.: Localization
of a putative transcriptional regulator (ATRX) at pericentromeric
heterochromatin and the short arms of acrocentric chromosomes. Proc.
Nat. Acad. Sci. 96: 13983-13988, 1999.

35. Medina, C. F.; Mazerolle, C.; Wang, Y.; Berube, N. G.; Coupland,
S.; Gibbons, R. J.; Wallace, V. A.; Picketts, D. J.: Altered visual
function and interneuron survival in Atrx knockout mice: inference
for the human syndrome. Hum. Molec. Genet. 18: 966-977, 2009.

36. Muers, M. R.; Sharpe, J. A.; Garrick, D.; Sloane-Stanley, J.;
Nolan, P. M.; Hacker, T.; Wood, W. G.; Higgs, D. R.; Gibbons, R. J.
: Defining the cause of skewed X-chromosome inactivation in X-linked
mental retardation by use of a mouse model. Am. J. Hum. Genet. 80:
1138-1149, 2007.

37. Nan, X.; Hou, J.; Maclean, A.; Nasir, J.; Lafuente, M. J.; Shu,
X.; Kriaucionis, S.; Bird, A.: Interaction between chromatin proteins
MECP2 and ATRX is disrupted by mutations that cause inherited mental
retardation. Proc. Nat. Acad. Sci. 104: 2709-2714, 2007.

38. Pask, A.; Renfree, M. B.; Graves, J. A. M.: The human sex-reversing
ATRX gene has a homologue on the marsupial Y chromosome, ATRY: implications
for the evolution of mammalian sex determination. Proc. Nat. Acad.
Sci. 97: 13198-13202, 2000.

39. Picketts, D. J.; Higgs, D. R.; Bachoo, S.; Blake, D. J.; Quarrell,
O. W. J.; Gibbons, R. J.: ATRX encodes a novel member of the SNF2
family of proteins: mutations point to a common mechanism underlying
the ATR-X syndrome. Hum. Molec. Genet. 5: 1899-1907, 1996.

40. Picketts, D. J.; Tastan, A. O.; Higgs, D. R.; Gibbons, R. J.:
Comparison of the human and murine ATRX gene identifies highly conserved,
functionally important domains. Mammalian Genome 9: 400-403, 1998.

41. Plenge, R. M.; Stevenson, R. A.; Lubs, H. A.; Schwartz, C. E.;
Willard, H. F.: Skewed X-chromosome inactivation is a common feature
of X-linked mental retardation disorders. Am. J. Hum. Genet. 71:
168-173, 2002.

42. Reardon, W.; Gibbons, R. J.; Winter, R. M.; Baraitser, M.: Male
pseudohermaphroditism in sibs with the alpha-thalassemia/mental retardation
(ATR-X) syndrome. Am. J. Med. Genet. 55: 285-287, 1995.

43. Schwartzentruber, J.; Korshunov, A; Liu, X.-Y.; Jones, D. T. W.;
Pfaff, E.; Jacob, K.; Sturm, D.; Fontebasso, A. M.; Quang, D.-A. K.;
Tonjes, M.; Hovestadt, V.; Albrecht, S.; and 50 others: Driver
mutations in histone H3.3 and chromatin remodelling genes in paediatric
glioblastoma. Nature 482: 226-231, 2012. Note: Erratum: Nature 484:
130 only, 2012.

44. Shapiro, M. B.; Senapathy, P.: RNA splice junctions of different
classes of eukaryotes: sequence statistics and functional implications
in gene expression. Nucleic Acids Res. 15: 7155-7174, 1987.

45. Stayton, C. L.; Dabovic, B.; Gulisano, M.; Gecz, J.; Broccoli,
V.; Giovanazzi, S.; Bossolasco, M.; Monaco, L.; Rastan, S.; Boncinelli,
E.; Bianchi, M. E.; Consalez, G. G.: Cloning and characterization
of a new human Xq13 gene, encoding a putative helicase. Hum. Molec.
Genet. 3: 1957-1964, 1994.

46. Stevenson, R. E.; Abidi, F.; Schwartz, C. E.; Lubs, H. A.; Holmes,
L. B.: Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome.
(Letter) Am. J. Med. Genet. 94: 383-385, 2000.

47. Thienpont, B.; de Ravel, T.; Van Esch, H.; Van Schoubroeck, D.;
Moerman, P.; Vermeesch, J. R.; Fryns, J.-P.; Froyen, G.; Lacoste,
C.; Badens, C.; Devriendt, K.: Partial duplications of the ATRX gene
cause the ATR-X syndrome. Europ. J. Hum. Genet. 15: 1094-1097, 2007.

48. Villard, L.; Bonino, M.-C.; Abidi, F.; Ragusa, A.; Belougne, J.;
Lossi, A.-M.; Seaver, L.; Bonnefont, J.-P.; Romano, C.; Fichera, M.;
Lacombe, D.; Hanauer, A.; Philip, N.; Schwartz, C.; Fontes, M.: Evaluation
of a mutation screening strategy for sporadic cases of ATR-X syndrome. J.
Med. Genet. 36: 183-186, 1999.

49. Villard, L.; Fontes, M.; Ades, L. C.; Gecz, J.: Identification
of a mutation in the XNP/ATR-X gene in a family reported as Smith-Fineman-Myers
syndrome. (Letter) Am. J. Med. Genet. 91: 83-85, 2000.

50. Villard, L.; Gecz, J.; Mattei, J. F.; Fontes, M.; Saugier-Veber,
P.; Munnich, A.; Lyonnet, S.: XNP mutation in a large family with
Juberg-Marsidi syndrome. (Letter) Nature Genet. 12: 359-360, 1996.

51. Villard, L.; Lacombe, D.; Fontes, M.: A point mutation in the
XNP gene, associated with an ATR-X phenotype without alpha-thalassemia. Europ.
J. Hum. Genet. 4: 316-320, 1996.

52. Villard, L.; Lossi, A.-M.; Cardoso, C.; Proud, V.; Chiaroni, P.;
Colleaux, L.; Schwartz, C.; Fontes, M.: Determination of the genomic
structure of the XNP/ATRX gene encoding a potential zinc finger helicase. Genomics 43:
149-155, 1997.

53. Villard, L.; Toutain, A.; Lossi, A.-M.; Gecz, J.; Houdayer, C.;
Moraine, C.; Fontes, M.: Splicing mutation in the ATR-X gene can
lead to a dysmorphic mental retardation phenotype without alpha-thalassemia. Am.
J. Hum. Genet. 58: 499-505, 1996.

54. Wada, T.; Kubota, T.; Fukushima, Y.; Saitoh, S.: Molecular genetic
study of Japanese patients with X-linked alpha-thalassemia/mental
retardation syndrome (ATR-X). Am. J. Med. Genet. 94: 242-248, 2000.

55. Weatherall, D. J.; Old, J.; Longley, J.; Wood, W. G.; Clegg, J.
B.; Pollock, A.; Lewis, M. J.: Acquired haemoglobin H disease in
leukaemia: pathophysiology and molecular basis. Brit. J. Haemat. 38:
305-322, 1978.

56. Wieland, H.; Sabathil, J.; Ostendorf, A.; Rittinger, O.; Ropke,
A.; Winnepenninckx, B.; Kooy, F.; Holinski-Feder, E.; Wieacker, P.
: A missense mutation in the coiled-coil motif of the HP1-interacting
domain of ATR-X in a family with X-linked mental retardation. Neurogenetics 6:
45-47, 2005.

57. Yntema, H. G.; Poppelaars, F. A.; Derksen, E.; Oudakker, A. R.;
van Roosmalen, T.; Jacobs, A.; Obbema, H.; Brunner, H. G.; Hamel,
B. C. J.; van Bokhoven, H.: Expanding phenotype of XNP mutations:
mild to moderate mental retardation. Am. J. Med. Genet. 110: 243-247,
2002.

*FIELD* CN
Ada Hamosh - updated: 3/7/2012
Ada Hamosh - updated: 9/2/2011
Ada Hamosh - updated: 6/6/2011
Patricia A. Hartz - updated: 2/17/2011
Cassandra L. Kniffin - updated: 10/13/2010
Cassandra L. Kniffin - updated: 1/26/2010
George E. Tiller - updated: 8/12/2009
Cassandra L. Kniffin - updated: 10/16/2007
Victor A. McKusick - updated: 5/23/2007
Cassandra L. Kniffin - updated: 4/27/2007
Cassandra L. Kniffin - updated: 12/18/2006
Cassandra L. Kniffin - updated: 8/24/2006
Marla J. F. O'Neill - updated: 11/17/2005
Cassandra L. Kniffin - updated: 6/23/2005
Cassandra L. Kniffin - updated: 5/12/2005
Victor A. McKusick - updated: 4/11/2005
Patricia A. Hartz - updated: 2/25/2005
Cassandra L. Kniffin - updated: 1/25/2005
Victor A. McKusick - updated: 7/30/2003
Victor A. McKusick - updated: 6/11/2003
George E. Tiller - updated: 9/19/2002
Victor A. McKusick - updated: 7/2/2002
Victor A. McKusick - updated: 1/3/2001
George E. Tiller - updated: 4/14/2000
Ada Hamosh - updated: 3/29/2000
Victor A. McKusick - updated: 3/1/2000
Victor A. McKusick - updated: 2/16/2000
Victor A. McKusick - updated: 12/8/1999
Michael J. Wright - updated: 11/3/1999
Victor A. McKusick - updated: 10/6/1998
Victor A. McKusick - updated: 5/8/1998
Victor A. McKusick - updated: 4/20/1998
Victor A. McKusick - updated: 1/21/1998
Moyra Smith - updated: 1/24/1997

*FIELD* CD
Victor A. McKusick: 2/25/1996

*FIELD* ED
carol: 04/11/2012
alopez: 3/12/2012
terry: 3/7/2012
alopez: 9/2/2011
terry: 9/2/2011
alopez: 6/14/2011
terry: 6/6/2011
carol: 6/1/2011
alopez: 3/30/2011
mgross: 3/14/2011
terry: 2/17/2011
wwang: 10/20/2010
ckniffin: 10/13/2010
mgross: 7/1/2010
wwang: 2/5/2010
ckniffin: 1/26/2010
wwang: 8/24/2009
terry: 8/12/2009
carol: 6/13/2008
carol: 10/17/2007
ckniffin: 10/16/2007
alopez: 5/23/2007
terry: 5/23/2007
wwang: 5/9/2007
ckniffin: 4/27/2007
wwang: 12/21/2006
ckniffin: 12/18/2006
wwang: 9/1/2006
ckniffin: 8/24/2006
wwang: 11/23/2005
terry: 11/17/2005
ckniffin: 7/19/2005
carol: 7/15/2005
ckniffin: 6/23/2005
ckniffin: 5/12/2005
wwang: 4/28/2005
wwang: 4/20/2005
terry: 4/11/2005
mgross: 2/25/2005
tkritzer: 1/27/2005
ckniffin: 1/25/2005
alopez: 1/23/2004
carol: 12/15/2003
ckniffin: 12/11/2003
tkritzer: 10/13/2003
alopez: 9/17/2003
alopez: 8/11/2003
alopez: 7/31/2003
terry: 7/30/2003
tkritzer: 6/24/2003
terry: 6/11/2003
cwells: 9/19/2002
ckniffin: 8/28/2002
cwells: 7/15/2002
terry: 7/2/2002
mcapotos: 1/10/2001
mcapotos: 1/9/2001
terry: 1/3/2001
carol: 10/4/2000
terry: 10/4/2000
alopez: 4/14/2000
terry: 4/14/2000
carol: 4/4/2000
mgross: 3/29/2000
carol: 3/29/2000
mgross: 3/1/2000
mgross: 2/16/2000
terry: 12/8/1999
alopez: 11/10/1999
terry: 11/3/1999
carol: 9/14/1999
carol: 8/4/1999
carol: 10/9/1998
terry: 10/6/1998
dkim: 9/10/1998
carol: 8/18/1998
carol: 5/9/1998
terry: 5/8/1998
carol: 5/6/1998
terry: 4/20/1998
mark: 1/25/1998
terry: 1/21/1998
mark: 1/25/1997
terry: 1/24/1997
mark: 1/24/1997
mark: 4/9/1996
terry: 4/5/1996
mark: 3/8/1996
mark: 3/7/1996
terry: 3/4/1996
joanna: 2/25/1996

MIM 300448
*RECORD*
*FIELD* NO
300448
*FIELD* TI
#300448 ALPHA-THALASSEMIA MYELODYSPLASIA SYNDROME; ATMDS
;;HEMOGLOBIN H DISEASE, ACQUIRED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
phenotype is caused in many cases by mutation in the
chromatin-remodeling factor ATRX (300032), which is mutant in the
alpha-thalassemia/mental retardation syndrome (301040) and in certain
other X-linked mental retardation syndromes.

CLINICAL FEATURES

Alpha-thalassemia is a common inherited form of anemia that usually
results from deletion of 1 or more of the duplicated alpha-globin genes
on chromosome 16 (Higgs et al., 1989). A mild form of alpha-thalassemia
is also associated with a variety of developmental abnormalities in a
rare, severe form of X-linked mental retardation (301040).

In the alpha-thalassemia myelodysplasia syndrome, alpha-thalassemia
occurs as an acquired abnormality in association with a multilineage
myelodysplasia. Gibbons et al. (2003) stated that 71 such individuals
had been identified, of whom 62 (87%) were males who had a de novo,
acquired form of alpha-thalassemia with hypochromic microcytic anemia. A
reduction in alpha-globin expression leads to an excess of beta-globin
chains, which form an abnormal hemoglobin, HbH (beta-4), which is
readily detectable in peripheral blood.

Gibbons et al. (2003) demonstrated by gene expression studies using a
microarray technique and RT-PCR that ATRX (300032) expression in
granulocytes was 3 to 4% of that in normal controls.

MOLECULAR GENETICS

Inherited mutations of specific genes have elucidated the normal roles
of the proteins they encode by relating specific mutations to particular
phenotypes. However, many potentially informative mutations in such
genes are lethal early in development. Consequently, inherited mutations
may not reflect all the functional roles of such proteins. Acquired,
somatic defects reflect a wider spectrum of mutations because they are
not prone to negative selection in development. It had been difficult to
identify such mutations; microarray analysis provided a new opportunity
to identify mutations and was the method used by Gibbons et al. (2003)
in studying the relationship to the large (300 kb) ATRX gene in
myelodysplasia associated with alpha-thalassemia (ATMDS). The ATRX gene
encodes a member of the SWI2/SNF2 family of proteins. Like other members
of this group, multiprotein complexes isolated by ATRX antibodies have
ATP-dependent nucleosome-remodeling and DNA translocase activities in
vitro. ATRX is a nuclear protein that localizes to nuclear
subcompartments called PML bodies and to pericentromeric
heterochromatin, where it interacts with a component of heterochromatin,
HP1. Sequence analysis identified specific somatic mutations in the ATRX
gene in granulocytes or bone marrow cells that were absent in buccal
cells and a lymphoblastoid cell line.

*FIELD* SA
Weatherall et al. (1978)
*FIELD* RF
1. Gibbons, R. J.; Pellagatti, A.; Garrick, D.; Wood, W. G.; Malik,
N.; Ayyub, H.; Langford, C.; Boultwood, J.; Wainscoat, J. S.; Higgs,
D. R.: Identification of acquired somatic mutations in the gene encoding
chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia
syndrome (ATMDS). Nature Genet. 34: 446-449, 2003.

2. Higgs, D. R.; Vickers, M. A.; Wilkie, A. O. M.; Pretorius, I.-M.;
Jarman, A. P.; Weatherall, D. J.: A review of the molecular genetics
of the human alpha-globin gene cluster. Blood 73: 1081-1104, 1989.

3. Weatherall, D. J.; Old, J.; Longley, J.; Wood, W. G.; Clegg, J.
B.; Pollock, A.; Lewis, M. J.: Acquired haemoglobin H disease in
leukemia: pathophysiology and molecular basis. Brit. J. Haemat. 38:
305-322, 1978.

*FIELD* CN
Victor A. McKusick - updated: 01/22/2004

*FIELD* CD
Victor A. McKusick: 8/8/2003

*FIELD* ED
terry: 01/22/2004
tkritzer: 1/22/2004
tkritzer: 10/3/2003
alopez: 9/17/2003
alopez: 8/20/2003

MIM 301040
*RECORD*
*FIELD* NO
301040
*FIELD* TI
#301040 ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED; ATRX
;;ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, NONDELETION TYPE;;
read moreATR-X SYNDROME;;
ATR, NONDELETION TYPE
*FIELD* TX
A number sign (#) is used with this entry because the phenotype is
caused by mutation in the ATRX gene (300032).

The 'deletion' type of alpha-thalassemia/mental retardation syndrome
(141750) is a contiguous gene syndrome due to a deletion in chromosome
16p that involves the hemoglobin alpha-1 (HBA1; 141800) and alpha-2
(HBA2; 141850) genes.

The X-linked mental retardation-hypotonic facies syndrome (309580) is
also caused by mutation in the ATRX gene.

CLINICAL FEATURES

Weatherall et al. (1981) reported the association of hemoglobin H
disease (Hb H; see alpha-thalassemias, 141800) and mental retardation in
3 unrelated patients of northern European descent.

Wilkie et al. (1990) reported 5 unrelated patients, 2 of whom were
reported by Weatherall et al. (1981), with mental retardation and
alpha-thalassemia without molecular abnormalities of the alpha-globin
gene complex on chromosome 16p. The patients showed a strikingly uniform
phenotype comprising severe mental handicap, characteristic dysmorphic
facies, genital abnormalities, and an unusual, mild form of hemoglobin H
disease. Facial features included microcephaly, hypertelorism,
epicanthus, a small triangular upturned nose, and flat face. The degree
of red blood cell hypochromia and Hb H levels, which varied from 0.7 to
6.7%, were milder than usually found in alpha-thalassemia. Although
several approaches failed to find a defect in the alpha-globin genes, 3
patients tested had markedly reduced total mRNA levels of both HBA1 and
HBA2. The authors suggested that the responsible locus encoded a
trans-acting factor involved in the normal regulation of alpha-globin
expression.

Harvey et al. (1990) described the syndrome in a 21-year-old male and
his brother who had died earlier, suggesting X-linked inheritance. DNA
analysis showed no deletions within the alpha-globin gene cluster. Hb H
bodies were present at a low level (1.6%).

Porteous and Burn (1990) described a 6-year-old boy who had a maternal
uncle with an X-linked mental retardation syndrome, and suggested that
their case resembled 2 brothers previously thought to have an atypical
form of the Coffin-Lowry syndrome (303600) (illustrated in Smith's
Recognizable Patterns of Human Malformation, Jones, 1988). However,
Wilkie et al. (1991) found that there were hematologic signs of the
nondeletion ATR syndrome in the patient reported by Porteous and Burn
(1990). In addition, Wilkie et al. (1991) reported that hematologic
evaluation of 1 of the brothers reported in Smith's book showed that he
had nondeletion ATR and that a male first-cousin through the maternal
line had the same condition. Wilkie et al. (1991) suggested that this
condition be called 'X-linked alpha-thalassemia/mental retardation'
(ATR-X) to distinguish it from the deletion form.

In a review, Gibbons et al. (1991) noted that some patients with ATR-X
syndrome have normal or only mildly abnormal hematologic indices; thus
normal hemoglobin levels and red cell indices do not necessarily exclude
the condition.

Cole et al. (1991) described an affected boy whose maternal uncle was
also affected. The boy had right-sided renal agenesis with left-sided
hydronephrosis and hydroureter. He had recurrent hypochromic, microcytic
anemia. His otherwise unaffected sister had had recurrent urinary tract
infections and persistent renal impairment in the absence of any
identifiable renal tract anomaly. Kurosawa et al. (1996) described a boy
with self-induced vomiting followed by rumination and noted that Cole et
al. (1991) made the same observation in a man and his nephew.

Donnai et al. (1991) described 4 brothers with this syndrome in whom the
diagnosis was first suspected because of their characteristic clinical
features and was confirmed in each case by the demonstration of Hb H
inclusions in a proportion of their red blood cells. Very rare Hb H
inclusions were found in the red blood cells of the mother and one
sister who both shared some facial features with the affected boys; they
were presumed to be carriers of the disorder.

Gorlin (1993) examined patients with typical features of the ATR-X
syndrome, but without hemoglobin H. The facies were identical and
mapping studies in several families suggested location of the mutation
in the site on the X chromosome involved in ATR-X. The facies of this
syndrome, which is often confused with that of Coffin-Lowry syndrome,
were marked by telecanthus, epicanthic folds, flat nasal bridge, midface
hypoplasia, a carp-shaped mouth with full lips, and small triangular
nose with anteverted nostrils. Gorlin (1993) noted that the alae of the
nose extended lower than the columella and septum. All developmental
milestones, especially walking, were delayed and speech was almost
absent. On further investigation, Gibbons (1994) found that the patients
of Gorlin (1993) did have alpha-thalassemia, as indicated by the
presence of hemoglobin H inclusions after use of 1% brilliant cresyl
blue staining overnight in buffered solution at room temperature. With
the staining, the Hb H inclusions give the erythrocytes the appearance
of golf balls.

Logie et al. (1994) reported a pedigree with 6 affected males in 4
sibships spanning 2 generations. Two affected cousins were described in
detail, one of whom had an unusually mild hematologic phenotype. Hb H
inclusions, the hallmark of the disorder, were detected in the
peripheral red blood cells only after repeated observations. The cousins
had strikingly similar facies with telecanthus, anteverted nares,
carp-shaped mouth, and large tongue. Gibbons et al. (1995) showed that
the hematologic findings in ATR-X may vary widely; indeed, in some
cases, the manifestation of alpha-thalassemia may be subtle and missed
without repeated examinations. McPherson et al. (1995) described a
kindred with 4 affected members. The hematologic abnormality was not
detected on routine hematologic studies, including hemoglobin
electrophoresis, but the patients were found to have hemoglobin H
inclusions on brilliant cresyl blue staining of peripheral smears.

Reardon et al. (1995) reported 2 phenotypic females with a 46,XY
karyotype who had abnormalities of the external genitalia resulting in
male pseudohermaphroditism. They pointed out that 1 of the 5 original
patients described in defining the ATR-X syndrome was a phenotypic
female with a 46,XY karyotype (Wilkie et al., 1990). McPherson et al.
(1995) described genital anomalies that led to a female sex of rearing
in 3 of 4 affected members of a family. Gibbons et al. (1995) emphasized
the progressive coarsening of the facial appearance. Kuno et al. (1997)
described a 5-year-old Japanese boy with this condition. He had an
abnormal hemoglobin which was found to consist exclusively of a beta
subunit. Severe mental retardation and hypoplastic penis and testes were
present. Anemia was only mild (hematocrit 35.8%). The family history was
unremarkable.

Martinez et al. (1998) reported 2 brothers and 1 maternal cousin with
severe mental retardation, microcephaly, short stature, cryptorchidism,
and spastic diplegia. Some facial dysmorphic features were present.
Martinez et al. (1998) pointed out the similarity in phenotype between
their family and that described by Sutherland et al. (1988) (see
309500). They suggested that the greater phenotypic severity in their
family was due to allelic heterogeneity. X-inactivation analysis of 1
potential and 3 obligate carriers showed nonrandom inactivation of the
disease-linked variant. On further analysis of this family, Lossi et al.
(1999) found that 3% of the patients' erythrocytes showed Hb H
inclusions, consistent with ATR-X. Lossi et al. (1999) also reported
dysmorphic facial features, including 'carp-like' triangular mouth,
hypertelorism, small triangular nose, and broad nasal root. The
hypertonia and spasticity were unusual findings in this family. A
mutation was found in the ATRX gene in affected individuals
(300032.0016).

Gibbons and Higgs (2000) provided a review of the clinical spectrum of
syndromes caused by mutation in the XH2 gene.

Martucciello et al. (2006) described male 3-year-old dizygotic twins
with ATRX who exhibited gastrointestinal problems including severe
regurgitation of food, vomiting, dysphagia, irritability, respiratory
disorders, meteorism, and chronic constipation. Barium studies in both
twins showed gastric pseudovolvulus, and 24-hour pH monitoring showed
severe gastroesophageal reflux. Enzymo-histochemical studies of
full-thickness colonic biopsies revealed a complex dysganglionosis:
ultrashort Hirschsprung disease (see 142623) associated with
hypoganglionosis. Martucciello et al. (2006) reviewed the
gastrointestinal phenotype of 128 confirmed cases of ATRX and found that
drooling was reported in 36% of cases, gastroesophageal reflux was
present in 72%, and constipation in 30%. Fundoplication was performed in
10% of cases, and 9% were fed by gastrostomy. Upper GI bleeding was
reported in 10% of cases. Fatal aspiration of vomitus occurred in 3
patients; volvulus was seen in 4 patients, 2 of whom died after
intestinal infarction; and 4 patients had recurrent hospitalizations for
ileus or pseudoobstruction. Martucciello et al. (2006) also noted that
there were numerous anecdotal reports from parents describing prolonged
episodes of patient distress with refusal to eat or drink.

Jezela-Stanek et al. (2009) reported a patient with ATRX confirmed by
genetic analysis. He had hypertelorism, epicanthal folds, strabismus,
short nose with flat bridge and triangular upturned tip, and tented
upper lip with everted lower lip. Other features included hypotonia,
psychomotor retardation, and hemoglobin H inclusions. The patient also
had undescended testes and ambiguous genitalia, which the authors
referred to as male pseudohermaphroditism. Laboratory studies showed
increased FSH and decreased testosterone. A deceased sib was believed to
have been affected and reportedly had ambiguous external genitalia.
Jezela-Stanek et al. (2009) postulated that the distinctive facial
features in ATRX result from facial hypotonia and can be confused with
Coffin-Lowry syndrome (CLS; 303600) or SLO syndromes (SLOS; 270400).

- Carrier Females

Studying 7 pedigrees that included individuals with the ATR-X syndrome,
Gibbons et al. (1992) concluded that intellectually normal female
carriers could be identified by the presence of rare cells containing Hb
H inclusions in their peripheral blood and by an extremely skewed
pattern of X inactivation in cells from a variety of tissues. McPherson
et al. (1995) used a combination of skewed X inactivation and haplotype
analysis at Xq12-q21.3 to establish carrier status.

Wada et al. (2005) found skewed X-inactivation patterns (greater than
90:10) in 6 of 7 unaffected Japanese female ATR-X carriers; the 1
carrier with non-skewed X inactivation (72:28) demonstrated moderate
mental retardation. The woman did not have dysmorphic features or
hemoglobin inclusions. Wada et al. (2005) concluded that mutations in
the ATRX gene may cause mental retardation in females if the chromosome
carrying the mutation is not properly inactivated.

Badens et al. (2006) reported a 4-year-old girl with typical features of
the ATR-X syndrome. Molecular studies showed a totally skewed
X-inactivation pattern, with the active chromosome carrying a
heterozygous mutation in the ATRX gene (300032.0018). Neither parent had
the mutation in peripheral blood leukocytes, but SNP analysis indicated
that the mutation occurred on the maternal chromosome. The child was
conceived with assisted reproduction technologies (ART) due to
micropolycystic ovaries and endometriosis in the mother. Badens et al.
(2006) suggested that some aspect of ART may have disturbed imprinting
in this patient.

MAPPING

By linkage analysis of 7 affected pedigrees, Gibbons et al. (1992)
mapped the ATR-X locus to an 11-cM interval on chromosome Xq12-q21.31
between markers DXS106 and DXYS1X (peak lod score of 5.4 at theta = 0 at
DXS72).

In a 3-generation ATR-X family with 3 affected males, Houdayer et al.
(1993) demonstrated a maximum lod score of 2.09 at a recombination
fraction of zero for linkage with DXS453 located at the boundary
Xq12-q13.1. The nearest flanking loci demonstrating recombination with
the disease locus were the androgen receptor (AR; 313700) at Xq11.2-q12
on the centromeric side and DXS72 at Xq21.1 on the telomeric side.
Houdayer et al. (1993) interpreted their results as compatible with a
distal boundary at Xq21.1 instead of Xq21.31 as previously held.

Gibbons et al. (1995) performed linkage analysis in 9 families with
ATR-X syndrome and identified key recombinants that reduced the area of
interest to 1.4 cM (estimated to be 15 Mb) between DXS454 and DXS72
within Xq13.1-q21.1 (Wang et al., 1994).

MOLECULAR GENETICS

In patients with the ATR-X syndrome, Gibbons et al. (1995) identified
mutations in the ATRX gene (300032.0001-300032.0009).

In affected members of a family with ATR-X syndrome, Villard et al.
(1996) identified a splice site mutation in the ATRX gene (300032.0010).
In 2 first cousins presenting the classic ATR-X phenotype with
alpha-thalassemia and Hb H inclusions, only the abnormal transcript was
expressed. In a distant cousin presenting with a similar dysmorphic
mental retardation phenotype, but without thalassemia, they found that
approximately 30% of the ATRX transcripts were normal. These data
suggested that the mode of action of the ATRX gene product on globin
expression is distinct from its mode of action in brain development and
facial morphogenesis, and that the mutated splice site could be used
with varying efficiency in different individuals.

Hendrich and Bickmore (2001) reviewed human disorders that share in
common defects of chromatin structure or modification, including the
ATR-X spectrum of disorders, ICF syndrome (242860), Rett syndrome
(312750), Rubinstein-Taybi syndrome (180849), and Coffin-Lowry syndrome.

- Partial Duplication of the ATRX Gene

Thienpont et al. (2007) reported 3 patients, including 2 sibs, with the
ATRX syndrome due to partial duplications of the ATRX gene. In 1 family,
the duplication included exons 2 to 35; in the other family, exons 2 to
29. Further analysis showed that both mothers carried the duplication
and both had skewed X inactivation. In 1 patient, ATRX mRNA levels were
about 3% of normal values. Thienpont et al. (2007) noted that the
duplications were not identified by sequence analysis and suggested that
quantitative analysis to detect copy numbers of the ATRX gene may be
required in some cases.

Cohn et al. (2009) reported a family in which 3 males had ATRX syndrome
due to a partial intragenic duplication of the ATRX gene that spanned
exons 2 to 31. Northern blot analysis failed to identify a full-length
transcript, but cDNA sequencing was consistent with some level of
expression. The authors noted that complete loss of ATRX is most likely
lethal, suggesting that the mutation was likely hypomorphic and
associated with some residual protein function. Unaffected obligate
carrier females in the family had highly skewed X inactivation. The
phenotype was typical for the disorder, although the facial features
were not as readily apparent in the 2 older affected individuals. The
proband was identified from 2 larger cohorts comprising 300 males with
mental retardation. Cohn et al. (2009) did not find ATRX duplications in
29 additional males with ATRX syndrome who were negative on sequence
analysis, suggesting that duplications are a rare cause of the disorder.

GENOTYPE/PHENOTYPE CORRELATIONS

In a review article, Gibbons and Higgs (2000) noted that mutations in
the ATRX gene resulting in the loss of the C terminal domain are
associated with the most severe urogenital abnormalities. However, at
other sites, there is no obvious link between genotype and phenotype,
and there is considerable variation in the degree of abnormalities seen
in individuals with the same mutation.

Among 22 ATRX patients from 16 families, Badens et al. (2006) found that
those with mutations in the PHD-like domain of the ATRX protein had
significantly more severe and permanent psychomotor retardation and
significantly more severe urogenital anomalies compared to those with
mutations in the helicase domain.

ANIMAL MODEL

Medina et al. (2009) surveyed ATR-X syndrome clinical findings and noted
that ocular defects were present in 47 (23%) of 202 patients. They
showed that Atrx was expressed in the neuroprogenitor pool in embryonic
mouse retina and in all cell types of adult mouse retina except rod
photoreceptors. Conditional inactivation of Atrx in mouse retina during
embryogenesis resulted in loss of only 2 types of neurons, amacrine and
horizontal cells. This defect did not arise from a failure to specify
these cells, but rather a defect in interneuron differentiation and
survival postnatally. The timing of cell loss was concomitant with
light-dependent changes in synaptic organization in mouse retina and
with a change in Atrx subnuclear localization within these interneurons.
The interneuron defects were associated with functional deficits as
demonstrated by reduced b-wave amplitudes upon electroretinogram
analysis. Medina et al. (2009) proposed a role for Atrx in interneuron
survival and differentiation.

*FIELD* RF
1. Badens, C.; Lacoste, C.; Philip, N.; Martini, N.; Courrier, S.;
Giuliano, F.; Verloes, A.; Munnich, A.; Leheup, B.; Burglen, L.; Odent,
S.; Van Esch, H.; Levy, N.: Mutations in PHD-like domain of the ATRX
gene correlate with severe psychomotor impairment and severe urogenital
abnormalities in patients with ATRX syndrome. Clin. Genet. 70: 57-62,
2006.

2. Badens, C.; Martini, N.; Courrier, S.; DesPortes, V.; Touraine,
R.; Levy, N.; Edery, P.: ATRX syndrome in a girl with a heterozygous
mutation in the ATRX Zn finger domain and a totally skewed X-inactivation
pattern. Am. J. Med. Genet. 140A: 2212-2215, 2006.

3. Cohn, D. M.; Pagon, R. A.; Hudgins, L.; Schwartz, C. E.; Stevenson,
R. E.; Friez, M. J.: Partial ATRX gene duplication causes ATR-X syndrome.
(Letter) Am. J. Med. Genet. 149A: 2317-2320, 2009.

4. Cole, T. R. P.; May, A.; Hughes, H. E.: Alpha-thalassaemia/mental
retardation syndrome (non-deletional type): report of a family supporting
X linked inheritance. J. Med. Genet. 28: 734-737, 1991.

5. Donnai, D.; Clayton-Smith, J.; Gibbons, R. J.; Higgs, D. R.: The
non-deletion alpha-thalassaemia/mental retardation syndrome: further
support for X linkage. J. Med. Genet. 28: 742-745, 1991.

6. Gibbons, R.: Personal Communication. Oxford, England 11/7/1994.

7. Gibbons, R. J.; Brueton, L.; Buckle, V. J.; Burn, J.; Clayton-Smith,
J.; Davison, B. C. C.; Gardner, R. J. M.; Homfray, T.; Kearney, L.;
Kingston, H. M.; Newbury-Ecob, R.; Porteous, M. E. P.; Wilkie, A.
O. M.; Higgs, D. R.: Clinical and hematologic aspects of the X-linked
alpha-thalassemia/mental retardation syndrome (ATR-X). Am. J. Med.
Genet. 55: 288-299, 1995.

8. Gibbons, R. J.; Higgs, D. R.: Molecular-clinical spectrum of the
ATR-X syndrome. Am. J. Med. Genet. 97: 204-212, 2000.

9. Gibbons, R. J.; Picketts, D. J.; Villard, L.; Higgs, D. R.: Mutations
in a putative global transcriptional regulator cause X-linked mental
retardation with alpha-thalassemia (ATR-X syndrome). Cell 80: 837-845,
1995.

10. Gibbons, R. J.; Suthers, G. K.; Wilkie, A. O. M.; Buckle, V. J.;
Higgs, D. R.: X-linked alpha-thalassemia/mental retardation (ATR-X)
syndrome: localization to Xq12-q21.31 by X inactivation and linkage
analysis. Am. J. Hum. Genet. 51: 1136-1149, 1992.

11. Gibbons, R. J.; Wilkie, A. O. M.; Weatherall, D. J.; Higgs, D.
R.: A newly defined X linked mental retardation syndrome associated
with alpha-thalassaemia. J. Med. Genet. 28: 729-733, 1991.

12. Gorlin, R. J.: Personal Communication. Minneapolis, Minn.
5/29/1993.

13. Harvey, M. P.; Kearney, A.; Smith, A.; Trent, R. J.: Occurrence
of the alpha-thalassaemia-mental retardation syndrome (non-deletional
type) in an Australian male. J. Med. Genet. 27: 577-581, 1990.

14. Hendrich, B.; Bickmore, W.: Human diseases with underlying defects
in chromatin structure and modification. Hum. Molec. Genet. 10:
2233-2242, 2001.

15. Houdayer, C.; Toutain, A.; Ronce, N.; Lefort, G.; Sarda, P.; Taib,
J.; Briault, S.; Lambert, J. C.; Moraine, C.: X-linked alpha-thalassemia/mental
retardation syndrome: linkage analysis in a new family further supports
localization in proximal Xq. Ann. Genet. 36: 194-199, 1993.

16. Jezela-Stanek, A.; Fisher, C.; Szarras-Czapnik, M.; Olczak-Kowalczyk,
D.; Gibbons, R. J.; Slowikowska-Hilczer, J.; Krajewska-Walasek, M.
: X-linked alpha thalassaemia/mental retardation syndrome: a case
with gonadal dysgenesis, caused by a novel mutation in ATRX gene. Clin.
Dysmorph. 18: 168-171, 2009.

17. Jones, K. L.: Smith's Recognizable Patterns of Human Malformation.
Philadelphia: W. B. Saunders (pub.) (4th ed.): 1988. P. 237.

18. Kuno, T.; Ideguchi, H.; Yoshida, N.; Masuyama, T.; Ohta, M.; Nishimura,
S.; Tasaki, H.; Miyazaki, S.; Hara, H.; Matsumoto, K.: A case of
X-linked alpha-thalassemia/mental retardation syndrome: analysis of
hemoglobin by an automated glycated hemoglobin analyzer. Acta Paediat.
Jpn. 39: 615-618, 1997.

19. Kurosawa, K.; Akatsuka, A.; Ochiai, Y.; Ikeda, J.; Maekawa, K.
: Self-induced vomiting in X-linked alpha-thalassemia/mental retardation
syndrome. (Letter) Am. J. Med. Genet. 63: 505-506, 1996.

20. Logie, L. J.; Gibbons, R. J.; Higgs, D. R.; Brown, J. K.; Porteous,
M. E. M.: Alpha thalassaemia mental retardation (ATR-X): an atypical
family. Arch. Dis. Child. 70: 439-440, 1994.

21. Lossi, A. M.; Millan, J. M.; Villard, L.; Orellana, C.; Cardoso,
C.; Prieto, F.; Fontes, M.; Martinez, F.: Mutation of the XNP/ATR-X
gene in a family with severe mental retardation, spastic paraplegia
and skewed pattern of X inactivation: demonstration that the mutation
is involved in the inactivation bias. (Letter) Am. J. Hum. Genet. 65:
558-562, 1999.

22. Martinez, F.; Tomas, M.; Millan, J. M.; Fernandez, A.; Palau,
F.; Prieto, F.: Genetic localisation of mental retardation with spastic
diplegia to the pericentromeric region of the X chromosome: X inactivation
in female carriers. J. Med. Genet. 35: 284-287, 1998.

23. Martucciello, G.; Lombardi, L.; Savasta, S.; Gibbons, R. J.:
Gastrointestinal phenotype of ATR-X syndrome. Am. J. Med. Genet. 140A:
1172-1176, 2006.

24. McPherson, E. W.; Clemens, M. M.; Gibbons, R. J.; Higgs, D. R.
: X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome:
a new kindred with severe genital anomalies and mild hematologic expression. Am.
J. Med. Genet. 55: 302-306, 1995.

25. Medina, C. F.; Mazerolle, C.; Wang, Y.; Berube, N. G.; Coupland,
S.; Gibbons, R. J.; Wallace, V. A.; Picketts, D. J.: Altered visual
function and interneuron survival in Atrx knockout mice: inference
for the human syndrome. Hum. Molec. Genet. 18: 966-977, 2009.

26. Porteous, M. E. M.; Burn, J.: Unknown syndrome. A possible new
X linked retardation syndrome: dysmorphic facies, microcephaly, hypotonia,
and small genitalia. J. Med. Genet. 27: 339-340, 1990.

27. Reardon, W.; Gibbons, R. J.; Winter, R. M.; Baraitser, M.: Male
pseudohermaphroditism in sibs with the alpha-thalassemia/mental retardation
(ATR-X) syndrome. Am. J. Med. Genet. 55: 285-287, 1995.

28. Sutherland, G. R.; Gedeon, A. K.; Haan, E. A.; Woodroffe, P.;
Mulley, J. C.: Linkage studies with the gene for an X-linked syndrome
of mental retardation, microcephaly and spastic diplegia. Am. J.
Med. Genet. 30: 493-508, 1988.

29. Thienpont, B.; de Ravel, T.; Van Esch, H.; Van Schoubroeck, D.;
Moerman, P.; Vermeesch, J. R.; Fryns, J.-P.; Froyen, G.; Lacoste,
C.; Badens, C.; Devriendt, K.: Partial duplications of the ATRX gene
cause the ATR-X syndrome. Europ. J. Hum. Genet. 15: 1094-1097, 2007.

30. Villard, L.; Toutain, A.; Lossi, A.-M.; Gecz, J.; Houdayer, C.;
Moraine, C.; Fontes, M.: Splicing mutation in the ATR-X gene can
lead to a dysmorphic mental retardation phenotype without alpha-thalassemia. Am.
J. Hum. Genet. 58: 499-505, 1996.

31. Wada, T.; Sugie, H.; Fukushima, Y.; Saitoh, S.: Non-skewed X-inactivation
may cause mental retardation in a female carrier of X-linked alpha-thalassemia/mental
retardation syndrome (ATR-X): X-inactivation study of nine female
carriers of ATR-X. Am. J. Med. Genet. 138A: 18-20, 2005.

32. Wang, L. H.; Collins, A.; Lawrence, S.; Keats, B. J.; Morton,
N. E.: Integration of gene maps: chromosome X. Genomics 22: 590-604,
1994.

33. Weatherall, D. J.; Higgs, D. R.; Bunch, C.; Old, J. M.; Hunt,
D. M.; Pressley, L.; Clegg, J. B.; Bethlenfalvay, N. C.; Sjolin, S.;
Koler, R. D.; Magenis, E.; Francis, J. L.; Bebbington, D.: Hemoglobin
H disease and mental retardation: a new syndrome or a remarkable coincidence? New
Eng. J. Med. 305: 607-612, 1981.

34. Wilkie, A. O. M.; Pembrey, M. E.; Gibbons, R. J.; Higgs, D. R.;
Porteous, M. E. M.; Burn, J.; Winter, R. M.: The non-deletion type
of alpha thalassaemia/mental retardation: a recognisable dysmorphic
syndrome with X linked inheritance. (Letter) J. Med. Genet. 28:
724 only, 1991.

35. Wilkie, A. O. M.; Zeitlin, H. C.; Lindenbaum, R. H.; Buckle, V.
J.; Fischel-Ghodsian, N.; Chui, D. H. K.; Gardner-Medwin, D.; MacGillivray,
M. H.; Weatherall, D. J.; Higgs, D. R.: Clinical features and molecular
analysis of the alpha-thalassemia/mental retardation syndromes. II.
Cases without detectable abnormality of the alpha-globin complex. Am.
J. Hum. Genet. 46: 1127-1140, 1990.

*FIELD* CS
INHERITANCE:
X-linked dominant

GROWTH:
[Other];
Postnatal growth deficiency

HEAD AND NECK:
[Head];
Microcephaly;
Absent frontal sinuses;
[Face];
Mid-face hypoplasia;
[Ears];
Small ears;
Low-set ears;
Posteriorly rotated ears;
Sensorineural hearing loss (less common);
[Eyes];
Hypertelorism;
Epicanthal folds;
[Nose];
Low nasal bridge;
Small triangular nose;
Anteverted nares;
[Mouth];
'Carp-like' mouth;
Full lips;
Protruding tongue;
[Teeth];
Widely-spaced upper incisors

CARDIOVASCULAR:
[Heart];
Perimembranous ventricular septal defect

ABDOMEN:
[External features];
Umbilical hernia;
[Gastrointestinal];
Constipation;
Gastroesophageal reflux

GENITOURINARY:
[External genitalia, male];
Shawl scrotum;
Small penis;
Hypospadias;
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Renal agenesis;
Hydronephrosis

SKELETAL:
[Spine];
Kyphoscoliosis;
Hemivertebra;
[Pelvis];
Coxa valga;
[Hands];
Tapering fingers;
Clinodactyly;
[Feet];
Talipes equinovarus

NEUROLOGIC:
[Central nervous system];
Mental retardation;
Delayed developmental milestones;
Expressive speech absent;
Hypotonia early;
Spasticity later;
Seizures (in 35%);
Cerebral atrophy

HEMATOLOGY:
Mild hypochromic microcytic anemia;
Mild form of hemoglobin H (Hb H) disease

LABORATORY ABNORMALITIES:
Hb H erythrocyte inclusions

MISCELLANEOUS:
Variable phenotype;
X-linked mental retardation-hypotonic facies syndrome (309580) is
an allelic disorder without alpha-thalassemia

MOLECULAR BASIS:
Caused by mutation in the ATR-X gene (ATRX, 300032.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 6/23/2005
Kelly A. Przylepa - revised: 8/22/2000

*FIELD* ED
joanna: 12/09/2008
joanna: 12/12/2005
ckniffin: 6/23/2005
joanna: 3/15/2005
joanna: 3/14/2005
joanna: 9/4/2001
kayiaros: 8/22/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 10/13/2010
George E. Tiller - updated: 8/24/2009
Cassandra L. Kniffin - updated: 7/31/2009
Cassandra L. Kniffin - updated: 12/18/2006
Marla J. F. O'Neill - updated: 10/11/2006
Cassandra L. Kniffin - updated: 8/24/2006
Cassandra L. Kniffin - updated: 9/19/2005
Cassandra L. Kniffin - reorganized: 7/14/2005
Cassandra L. Kniffin - updated: 6/23/2005
Victor A. McKusick - updated: 1/22/2004
George E. Tiller - updated: 2/12/2002
Victor A. McKusick - updated: 10/3/2000

*FIELD* CD
Victor A. McKusick: 11/7/1991

*FIELD* ED
alopez: 07/25/2011
wwang: 10/20/2010
ckniffin: 10/13/2010
terry: 5/12/2010
wwang: 8/24/2009
wwang: 8/5/2009
ckniffin: 7/31/2009
wwang: 12/21/2006
ckniffin: 12/18/2006
wwang: 10/12/2006
terry: 10/11/2006
wwang: 9/1/2006
ckniffin: 8/24/2006
wwang: 11/23/2005
wwang: 10/3/2005
wwang: 9/30/2005
ckniffin: 9/19/2005
carol: 7/14/2005
ckniffin: 6/23/2005
ckniffin: 6/15/2005
ckniffin: 5/12/2005
terry: 1/22/2004
cwells: 2/18/2002
cwells: 2/12/2002
mcapotos: 10/6/2000
mcapotos: 10/5/2000
terry: 10/3/2000
carol: 8/4/1999
mark: 2/12/1998
mark: 3/27/1997
mark: 6/25/1996
terry: 6/14/1996
mark: 3/7/1996
terry: 3/4/1996
mark: 4/8/1995
terry: 1/20/1995
carol: 10/6/1994
davew: 8/22/1994
warfield: 4/19/1994

MIM 309580
*RECORD*
*FIELD* NO
309580
*FIELD* TI
#309580 MENTAL RETARDATION-HYPOTONIC FACIES SYNDROME, X-LINKED, 1; MRXHF1
;;SMITH-FINEMAN-MYERS SYNDROME 1; SFM1;;
read moreSFMS;;
XLMR-HYPOTONIC FACIES SYNDROME;;
CARPENTER-WAZIRI SYNDROME;;
CHUDLEY-LOWRY SYNDROME;;
JUBERG-MARSIDI SYNDROME; JMS;;
HOLMES-GANG SYNDROME;;
MENTAL RETARDATION, X-LINKED, WITH GROWTH RETARDATION, DEAFNESS, AND
MICROGENITALISM
*FIELD* TX
A number sign (#) is used with this entry because the phenotype is
caused by mutation in the ATRX gene (300032).

DESCRIPTION

The term 'X-linked mental retardation-hypotonic facies syndrome'
comprises several syndromes previously reported separately. These
include Juberg-Marsidi, Carpenter-Waziri, Holmes-Gang, and
Smith-Fineman-Myers syndromes as well as 1 family with X-linked mental
retardation with spastic paraplegia. All these syndromes were found to
be caused by mutation in the XH2 gene and are characterized primarily by
severe mental retardation, dysmorphic facies, and a highly skewed
X-inactivation pattern in carrier women (Abidi et al., 2005). Other more
variable features include hypogonadism, deafness, renal anomalies, and
mild skeletal defects.

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X; 301040)
is an allelic disorder with a similar phenotype with the addition of
alpha-thalassemia and Hb H inclusion bodies in erythrocytes.

CLINICAL FEATURES

Smith et al. (1980) described 2 brothers with a combination of mental
retardation, microcephaly, short stature, and unusual facial appearance,
including slanted palpebral fissures, narrow face with maxillary
overjet, alternating exotropia, and ptosis. Muscle tone was hypotonic,
but 1 patient had hyperreflexia. The authors quoted Frota-Pessoa et al.
(1968) as citing a prior probability of about 30% for autosomal
recessive inheritance and about 70% for X-linked inheritance, when 2
brothers are affected. Stephenson and Johnson (1985) reported a third
case of what they referred to as 'Smith-Fineman-Myers syndrome' in an
unrelated male residing in the same institution as the 2 brothers of
Smith et al. (1980). Ades et al. (1991) described 2 brothers who had
findings similar to those in the patients of Smith et al. (1980) and
Stephenson and Johnson (1985), including patulous lower lip and
prominent, widely spaced upper central incisors. One of the brothers had
asplenia, and both had bilateral cryptorchidism. Hypotonia was present
early and hypertonia later. Hall (1992) suggested that these brothers in
fact had the X-linked alpha-thalassemia/mental retardation syndrome.
Ades (1992) responded that study of the blood of both boys, their
phenotypically normal sister, and both parents showed absence of
hemoglobin H inclusions in all specimens. Guion-Almeida et al. (1998)
suggested that Smith-Fineman-Myers syndrome was the disorder in 2 boys
thought to be monozygotic twins. Features were an unusual facial
appearance, cortical atrophy, dolichocephaly, short stature, cleft
palate, micrognathia, prominent upper central incisors, bilateral Sidney
line, minor foot deformities, instability in walking, early hypotonia,
hyperreflexia, hyperactivity, psychomotor retardation, and severe delay
in language development.

Juberg and Marsidi (1980) described a mental retardation syndrome in a
4-year-old boy and 2 of his maternal uncles. Growth was less than the
third percentile, with delayed bone age. The affected males had
deafness, flat nasal bridge, several ocular abnormalities, and a
rudimentary scrotum with cryptorchidism. One had a small penis. The
proband also had onychodystrophy. One uncle died at age 9 and the second
at age 10 months. The fragile site at Xq28 was not found on chromosome
study of the proband. These authors rejected the pedigree of Vasquez et
al. (1979) as being similarly affected, although both showed mental
retardation, hypogonadism, micropenis, and short stature, and both
originated in Ohio but were apparently not related (see 309585). Mattei
et al. (1983) presented a second family with Juberg-Marsidi syndrome
affecting 7 males in 5 sibships. The patients had deafness, severe
mental retardation, facial dysmorphism, and genital abnormalities,
including small penis, hypospadias, and cryptorchidism. Renier et al.
(1982) described a kindred in which 3 brothers and 2 of their maternal
uncles had microcephaly with severe mental retardation, spasticity,
epilepsy, and deafness. Some heterozygous women had subnormal
intelligence and microcephaly. Renier et al. (1982) concluded that their
family probably had the same disorder as that in the family of Juberg
and Marsidi (1980). Tsukahara et al. (1995) reported a 2-year-old boy
with Juberg-Marsidi syndrome. He had mental retardation, short stature,
micropenis, and cryptorchidism. His Leydig cells responded to
administration of human chorionic gonadotropin, and there were positive
responses to luteinizing hormone (152780) and follicle-stimulating
hormone (136530) with the administration of luteinizing
hormone-releasing hormone (152760). He showed normal weight gain and
head circumference, which had not been described previously. Hematologic
and molecular studies of the patient excluded the thalassemia trait or
Hb H disease.

Holmes and Gang (1984) reported a family in which 3 males had an
X-linked mental retardation syndrome with microcephaly, epicanthal
folds, short nose with anteverted nostrils, short upper lip and
equinovarus deformity. One patient had bilateral renal hypoplasia. The 3
affected boys died in infancy or early childhood, 1 of pneumonia, 1 of
'encephalitis,' and 1 of unknown cause during febrile illness.

Chudley et al. (1988) described a 3-year-old boy and his 2 maternal
uncles with moderate to severe mental retardation, short stature, mild
obesity, hypogonadism, a low total finger ridge count, and a distinctive
face characterized by bitemporal narrowness, almond-shaped palpebral
fissures, depressed nasal bridge, anteverted nares, short and
inverted-V-shaped upper lip, and macrostomia. In this family, 2 other
males with similar facial and other features had died in early infancy
and mid-childhood. Preliminary studies with DNA probes were consistent
with X-linkage, and permitted exclusion of distal Xp and Xq regions as
the site of the mutation. Cole et al. (1991) suggested that the family
reported by Chudley et al. (1988) might have the ATR-X syndrome.
However, Chudley and Lowry (1992) reported that follow-up showed normal
hematologic indices and no detectable hemoglobin H. Furthermore, their
patients appeared to be less severely retarded than the patients
reported by Cole et al. (1991). Because of the possibility of an
X-chromosome contiguous gene syndrome with different sized deletions,
they performed high resolution chromosome analyses but found no
deletions.

Carpenter et al. (1988) reported a family in which 6 males were affected
with X-linked mental retardation. Clinical features included short
stature, prominent lips, bushy eyebrows, depressed nasal bridge with
widening of the tip of the nose, widely-spaced teeth, and brachydactyly.
Genetic analysis excluded fragile X syndrome, and radiographic analysis
excluded Coffin-Lowry syndrome. Linkage studies identified a locus at
Xq11-q22. In a follow-up study of the same family, Carpenter et al.
(1999) found that obligate carrier females showed completely skewed
X-inactivation. Carpenter et al. (1999) noted that the patients did not
have alpha-thalassemia or genital abnormalities.

Villard et al. (1996) reported a male patient and maternal uncle with
X-linked mental retardation-hypotonic face syndrome and a mutation in
the XH2 gene (300032.0012). At age 4, the proband had severe mental
retardation with hypotonia and absence of speech. Facial features
included epicanthic folds, telecanthus, midface hypoplasia, flat nasal
bridge, small triangular nose with anteverted nostrils and with
columella not extending below the nasal alae, carp-shaped mouth,
hypoplastic lower central incisors, apparently low-set and posteriorly
angulated ears, and protrusion of the tongue. The fingers were short and
tapering and the toes overlapping. There were no signs of hematologic
abnormality. The maternal uncle was severely mentally retarded, could
not speak, and died at 7 years of age. The authors stated that
photographs of the uncle showed the same facial dysmorphism as was found
in his nephew.

Gibbons and Higgs (2000) provided a review of the clinical spectrum of
syndromes caused by mutation in the XH2 gene.

MAPPING

In the kindred with Juberg-Marsidi syndrome reported by Mattei et al.
(1983), Saugier-Veber et al. (1993) mapped the disease locus to Xq12-q21
by linkage to a probe at the DXS441 locus; maximum lod = 3.24 at theta =
0.0. Multipoint linkage analysis placed the JMS gene within the interval
defined by DXS159 and DXYS1X.

By linkage analysis, Carpenter et al. (1988) found that the XLMR
syndrome in the family they reported showed linkage to a locus at
Xq11-q22. In a follow-up study of the same family, Carpenter et al.
(1999) refined the disease locus to a region between Xp11.3 and Xq23
(maximum lod score of 2.53 at several markers).

MOLECULAR GENETICS

In 1 surviving affected member and many heterozygous carriers of a
family previously reported by Mattei et al. (1983) as having
Juberg-Marsidi syndrome, Villard et al. (1996) identified a mutation in
the ATRX gene (300032.0011).

In affected males in the family reported by Carpenter et al. (1988,
1999), Abidi et al. (1999) identified a mutation in the ATRX gene
(300032.0024). The authors referred to the disorder as the
'Carpenter-Waziri syndrome.'

Villard et al. (2000) found that the patients reported by Ades et al.
(1991) as having Smith-Fineman-Myers syndrome had a mutation in the ATRX
gene (300032.0017).

In 2 obligate carriers from the family reported by Holmes and Gang
(1984), Stevenson et al. (2000) identified a mutation in the ATRX gene
(300032.0025). Carriers in this family, who had no clinical
manifestations, showed the typical marked skewing of X inactivation,
consistent with a mutation in the ATRX gene. Stevenson et al. (2000)
referred to this disorder as the 'XLMR-hypotonic face syndrome.'

In affected males in the original family with Chudley-Lowry syndrome
(Chudley et al., 1988), Abidi et al. (2005) identified a mutation in the
ATRX gene (300032.0022)

Leahy et al. (2005) reported a 3-year-old boy with mental retardation,
dysmorphic facial features, early hypotonia followed by hypertonia, and
asplenia, in whom they identified a missense mutation in the ATRX gene
(300032.0026). They stated that this was the second reported patient
with mental retardation and asplenia with a mutation in the ATRX gene,
the first being the patient reported by Ades et al. (1991). Neither
patient had HbH inclusion bodies on staining with brilliant cresyl blue.

*FIELD* RF
1. Abidi, F.; Schwartz, C. E.; Carpenter, N. J.; Villard, L.; Fontes,
M.; Curtis, M.: Carpenter-Waziri syndrome results from a mutation
in XNP. (Letter) Am. J. Med. Genet. 85: 249-251, 1999.

2. Abidi, F. E.; Cardoso, C.; Lossi, A.-M.; Lowry, R. B.; Depetris,
D.; Mattei, M.-G.; Lubs, H. A.; Stevenson, R. E.; Fontes, M.; Chudley,
A. E.; Schwartz, C. E.: Mutation in the 5-prime alternatively spliced
region of the XNP/ATR-X gene causes Chudley-Lowry syndrome. Europ.
J. Hum. Genet. 13: 176-183, 2005.

3. Ades, L. C.: Reply to Dr. Hall. (Letter) Am. J. Med. Genet. 44:
251 only, 1992.

4. Ades, L. C.; Kerr, B.; Turner, G.; Wise, G.: Smith-Fineman-Myers
syndrome in two brothers. Am. J. Med. Genet. 40: 467-470, 1991.

5. Carpenter, N. J.; Qu, Y.; Curtis, M.; Patil, S. R.: X-linked mental
retardation syndrome with characteristic 'coarse' facial appearance,
brachydactyly, and short stature maps to proximal Xq. Am. J. Med.
Genet. 85: 230-235, 1999.

6. Carpenter, N. J.; Waziri, M.; Liston, J.; Patil, S. R.: Studies
on X-linked mental retardation: evidence for a gene in the region
Xq11-q22. (Abstract) Am. J. Hum. Genet. 43 (suppl.): A139 only,
1988.

7. Chudley, A. E.; Lowry, R. B.: X linked alpha thalassaemia/mental
retardation (ATR-X) syndrome. (Letter) J. Med. Genet. 29: 357-360,
1992.

8. Chudley, A. E.; Lowry, R. B.; Hoar, D. I.: Mental retardation,
distinct facial changes, short stature, obesity, and hypogonadism:
a new X-linked mental retardation syndrome. Am. J. Med. Genet. 31:
741-751, 1988.

9. Cole, T. R. P.; May, A.; Hughes, H. E.: Alpha-thalassaemia/mental
retardation syndrome (non-deletion type): report of a family supporting
X linked inheritance. J. Med. Genet. 28: 734-737, 1991.

10. Frota-Pessoa, O.; Opitz, J. M.; Leroy, J. G.; Patau, K.: Counseling
in diseases produced either by autosomal or X-linked recessive mutations. Acta
Genet. Statist. Med. 18: 521-533, 1968.

11. Gibbons, R. J.; Higgs, D. R.: Molecular-clinical spectrum of
the ATR-X syndrome. Am. J. Med. Genet. 97: 204-212, 2000.

12. Guion-Almeida, M. L.; Tabith, A., Jr.; Kokitsu-Nakata, N. M.;
Zechi, R. M.: Smith-Fineman-Myers syndrome in apparently monozygotic
twins. Am. J. Med. Genet. 79: 205-208, 1998.

13. Hall, B. D.: Alpha-thalassemia/mental retardation syndrome often
confused with other disorders. (Letter) Am. J. Med. Genet. 44: 250
only, 1992.

14. Holmes, L. B.; Gang, D. L.: An X-linked mental retardation syndrome
with craniofacial abnormalities, microcephaly and club foot. Am.
J. Med. Genet. 17: 375-382, 1984.

15. Juberg, R. C.; Marsidi, I.: A new form of X-linked mental retardation
with growth retardation, deafness, and microgenitalism. Am. J. Hum.
Genet. 32: 714-722, 1980.

16. Leahy, R. T.; Philip, R. K.; Gibbons, R. J.; Fisher, C.; Suri,
M.; Reardon, W.: Asplenia in ATR-X syndrome: a second report. Am.
J. Med. Genet. 139A: 37-39, 2005.

17. Mattei, J. F.; Collignon, P.; Ayme, S.; Giraud, F.: X-linked
mental retardation, growth retardation, deafness and microgenitalism:
a second familial report. Clin. Genet. 23: 70-74, 1983.

18. Renier, W. O.; Gabreels, F. J. M.; Jasper, H. H. J.; Hustinx,
T. W. J.; Geelen, J. A. G.; van Haelst, U. J. G.: An X-linked syndrome
with microcephaly, severe mental retardation, spasticity, epilepsy
and deafness. J. Ment. Defic. Res. 26: 27-40, 1982.

19. Saugier-Veber, P.; Abadie, V.; Moncla, A.; Mathieu, M.; Piussan,
C.; Turleau, C.; Mattei, J.-F.; Munnich, A.; Lyonnet, S.: The Juberg-Marsidi
syndrome maps to the proximal long arm of the X chromosome (Xq12-q21). Am.
J. Hum. Genet. 52: 1040-1045, 1993.

20. Smith, R. D.; Fineman, R. M.; Myers, G. G.: Short stature, psychomotor
retardation, and unusual facial appearance in two brothers. Am. J.
Med. Genet. 7: 5-9, 1980.

21. Stephenson, L. D.; Johnson, J. P.: Smith-Fineman-Myers syndrome:
report of a third case. Am. J. Med. Genet. 22: 301-304, 1985.

22. Stevenson, R. E.; Abidi, F.; Schwartz, C. E.; Lubs, H. A.; Holmes,
L. B.: Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome.
(Letter) Am. J. Med. Genet. 94: 383-385, 2000.

23. Tsukahara, M.; Nasu, T.; Takihara, H.; Hattori, Y.; Nakane, H.;
Kamata, K.; Mitsui, H.; Hayashida, S.: Juberg-Marsidi syndrome: report
of an additional case. Am. J. Med. Genet. 58: 353-355, 1995.

24. Vasquez, S. B.; Hurst, D. L.; Sotos, J. F.: X-linked hypogonadism,
gynecomastia, mental retardation, short stature, and obesity--a new
syndrome. J. Pediat. 94: 56-60, 1979.

25. Villard, L.; Fontes, M.; Ades, L. C.; Gecz, J.: Identification
of a mutation in the XNP/ATR-X gene in a family reported as Smith-Fineman-Myers
syndrome. (Letter) Am. J. Med. Genet. 91: 83-85, 2000.

26. Villard, L.; Gecz, J.; Mattei, J. F.; Fontes, M.; Saugier-Veber,
P.; Munnich, A.; Lyonnet, S.: XNP mutation in a large family with
Juberg-Marsidi syndrome. (Letter) Nature Genet. 12: 359-360, 1996.

27. Villard, L.; Lacombe, D.; Fontes, M.: A point mutation in the
XNP gene, associated with an ATR-X phenotype without alpha-thalassemia. Europ.
J. Hum. Genet. 4: 316-320, 1996.

*FIELD* CS
INHERITANCE:
X-linked recessive

GROWTH:
[Height];
Short stature;
[Weight];
Obesity, mild (rare);
[Other];
Growth retardation

HEAD AND NECK:
[Head];
Microcephaly;
Dolichocephaly;
[Face];
Midface hypoplasia;
Bitemporal narrowing;
Small philtrum;
Micrognathia;
Coarse facial features;
[Ears];
Low-set ears;
Small ears;
Everted ears;
Posteriorly rotated ears;
Hyperfolded ears;
Sensorineural hearing impairment (less common);
[Eyes];
Epicanthal folds;
Hypertelorism;
Upslanting palpebral fissures;
Exotropia (less common);
Ptosis;
Optic atrophy;
[Nose];
Flat, broad nasal bridge;
Depressed nasal bridge;
Triangular nasal tip;
Anteverted nostrils;
[Mouth];
'Carp-like' mouth;
Open mouth;
Macrostomia;
Short, thin upper lip;
Inverted V-shaped upper lip;
Prominent lower lip;
High-arched palate;
Protruding tongue;
Drooling;
[Teeth];
Widely-spaced upper incisors;
[Neck];
Short neck (less common)

ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux;
Vomiting;
Constipation;
Gut dysmotility

GENITOURINARY:
[External genitalia, male];
Hypogonadism;
Small testes;
Hypoplastic scrotum;
Micropenis;
Hypospadias;
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Renal hypoplasia (less common);
[Bladder];
Vesicoureteral reflux (less common)

SKELETAL:
Delayed bone age;
[Spine];
Kyphoscoliosis (approximately 30%);
[Limbs];
Genua valga;
[Hands];
Slender, tapering fingers;
Brachydactyly;
Clinodactyly of isolated digits;
[Feet];
Talipes equinovarus;
Talipes calcaneovalgus;
Pes planus

NEUROLOGIC:
[Central nervous system];
Mental retardation, severe, profound;
Hypotonia, early;
Hypertonia of lower limbs, later;
Hyperreflexia;
Seizures (in 35%);
[Behavioral/psychiatric manifestations];
Paroxysmal bursts of laughter;
Repetitive, self-stimulatory behavior using upper limbs;
Fingers in mouth;
Hyperactivity;
Self-absorbed

HEMATOLOGY:
Absence of Hb H inclusions in red blood cells

MISCELLANEOUS:
Variable phenotype;
Alpha-thalassemia/mental retardation syndrome (301040) is an allelic
disorder

MOLECULAR BASIS:
Caused by mutations in the helicase-2 gene (XH2, 300032.0011)

*FIELD* CN
Cassandra L. Kniffin - revised: 6/23/2005

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

*FIELD* ED
joanna: 03/24/2011
joanna: 5/22/2007
joanna: 12/30/2005
ckniffin: 6/23/2005

*FIELD* CN
Marla J. F. O'Neill - updated: 11/17/2005
Cassandra L. Kniffin - reorganized: 7/14/2005
Cassandra L. Kniffin - updated: 6/23/2005
Victor A. McKusick - updated: 3/15/2000
Victor A. McKusick - updated: 12/21/1998

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

*FIELD* ED
wwang: 11/13/2008
alopez: 11/29/2007
alopez: 2/19/2007
carol: 2/15/2007
wwang: 11/23/2005
terry: 11/17/2005
carol: 7/15/2005
carol: 7/14/2005
ckniffin: 6/23/2005
carol: 3/30/2000
mcapotos: 3/28/2000
terry: 3/15/2000
terry: 12/21/1998
warfield: 4/20/1994
mimadm: 2/28/1994
carol: 6/4/1993
carol: 6/3/1993
carol: 10/7/1992
supermim: 3/17/1992

RBCC Red Blood Cell Collection

Full text data of ATRX