RBCC Red Blood Cell Collection

CRYAA (CRYA1, HSPB4) [Confidence: low (only semi-automatic identification from reviews)]
Alpha-crystallin A chain (Heat shock protein beta-4; HspB4; Alpha-crystallin A(1-172); Alpha-crystallin A(1-168); Alpha-crystallin A(1-162))
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P02489
ID CRYAA_HUMAN Reviewed; 173 AA.
AC P02489; Q53X53;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 2.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Alpha-crystallin A chain;
DE AltName: Full=Heat shock protein beta-4;
DE Short=HspB4;
DE Contains:
DE RecName: Full=Alpha-crystallin A(1-172);
DE Contains:
DE RecName: Full=Alpha-crystallin A(1-168);
DE Contains:
DE RecName: Full=Alpha-crystallin A(1-162);
GN Name=CRYAA; Synonyms=CRYA1, HSPB4;
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 PRELIMINARY PROTEIN SEQUENCE.
RX PubMed=817940; DOI=10.1016/0014-5793(75)80286-9;
RA de Jong W.W., Terwindt E.C., Bloemendal H.;
RT "The amino acid sequence of the A chain of human alpha-crystallin.";
RL FEBS Lett. 58:310-313(1975).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lens;
RX PubMed=8587135; DOI=10.1007/BF00173170;
RA Jaworski C.J.;
RT "A reassessment of mammalian alpha A-crystallin sequences using DNA
RT sequencing: implications for anthropoid affinities of tarsier.";
RL J. Mol. Evol. 41:901-908(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lens;
RX PubMed=8943244; DOI=10.1074/jbc.271.50.31973;
RA Andley U.P., Mathur S., Griest T.A., Petrash J.M.;
RT "Cloning, expression, and chaperone-like activity of human alphaA-
RT crystallin.";
RL J. Biol. Chem. 271:31973-31980(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [LARGE SCALE MRNA].
RC TISSUE=Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-104.
RX PubMed=2918909; DOI=10.1038/337752a0;
RA Jaworski C.J., Piatigorsky J.;
RT "A pseudo-exon in the functional human alpha A-crystallin gene.";
RL Nature 337:752-754(1989).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-63 AND 166-173.
RC TISSUE=Spleen;
RX PubMed=3758227; DOI=10.1016/S0014-4835(86)80098-7;
RA McDevitt D.S., Hawkins J.W., Jaworski C.J., Piatigorsky J.;
RT "Isolation and partial characterization of the human alpha A-
RT crystallin gene.";
RL Exp. Eye Res. 43:285-291(1986).
RN [10]
RP PROTEIN SEQUENCE OF 13-21 AND 79-88.
RX PubMed=8999933; DOI=10.1074/jbc.272.4.2268;
RA Lampi K.J., Ma Z., Shih M., Shearer T.R., Smith J.B., Smith D.L.,
RA David L.L.;
RT "Sequence analysis of betaA3, betaB3, and betaA4 crystallins completes
RT the identification of the major proteins in young human lens.";
RL J. Biol. Chem. 272:2268-2275(1997).
RN [11]
RP STRUCTURE OF CARBOHYDRATE.
RX PubMed=1730617;
RA Roquemore E.P., Dell A., Morris H.R., Panico M., Reason A.J.,
RA Savoy L.-A., Wistow G.J., Zigler J.S. Jr., Earles B.J., Hart G.W.;
RT "Vertebrate lens alpha-crystallins are modified by O-linked N-
RT acetylglucosamine.";
RL J. Biol. Chem. 267:555-563(1992).
RN [12]
RP PHOSPHORYLATION AT SER-122, DISULFIDE BOND, PROTEOLYTIC PROCESSING OF
RP C-TERMINAL, DEAMIDATION AT ASN-101, AND MASS SPECTROMETRY.
RX PubMed=8175657;
RA Miesbauer L.R., Zhou X., Yang Z., Yang Z., Sun Y., Smith D.L.,
RA Smith J.B.;
RT "Post-translational modifications of water-soluble human lens
RT crystallins from young adults.";
RL J. Biol. Chem. 269:12494-12502(1994).
RN [13]
RP PHOSPHORYLATION AT SER-122.
RX PubMed=8759518; DOI=10.1006/exer.1996.0060;
RA Takemoto L.J.;
RT "Differential phosphorylation of alpha-A crystallin in human lens of
RT different age.";
RL Exp. Eye Res. 62:499-504(1996).
RN [14]
RP PROTEOLYTIC PROCESSING; SUSCEPTIBILITY TO OXIDATION; PHOSPHORYLATION
RP AT SER-45 AND SER-122, DISULFIDE BOND, DEAMIDATION AT GLN-6; GLN-50;
RP GLN-90; ASN-101 AND GLN-147, AND MASS SPECTROMETRY.
RX PubMed=9068373; DOI=10.1006/exer.1996.0160;
RA Lund A.L., Smith J.B., Smith D.L.;
RT "Modifications of the water-insoluble human lens alpha-crystallins.";
RL Exp. Eye Res. 63:661-672(1996).
RN [15]
RP DEAMIDATION AT ASN-101.
RX PubMed=9543632; DOI=10.1076/ceyr.17.3.247.5218;
RA Takemoto L.J.;
RT "Quantitation of asparagine-101 deamidation from alpha-A crystallin
RT during aging of the human lens.";
RL Curr. Eye Res. 17:247-250(1998).
RN [16]
RP PROTEOLYTIC PROCESSING OF C-TERMINAL, ACETYLATION AT LYS-70,
RP PHOSPHORYLATION, DEAMIDATION AT ASN-101, AND MASS SPECTROMETRY.
RX PubMed=9655350;
RA Lin P.P., Barry R.C., Smith D.L., Smith J.B.;
RT "In vivo acetylation identified at lysine 70 of human lens alphaA-
RT crystallin.";
RL Protein Sci. 7:1451-1457(1998).
RN [17]
RP PHOSPHORYLATION, SUSCEPTIBILITY TO OXIDATION, PROTEOLYTIC PROCESSING
RP OF C-TERMINAL, AND MASS SPECTROMETRY.
RX PubMed=10930324; DOI=10.1006/exer.2000.0868;
RA Hanson S.R.A., Hasan A., Smith D.L., Smith J.B.;
RT "The major in vivo modifications of the human water-insoluble lens
RT crystallins are disulfide bonds, deamidation, methionine oxidation and
RT backbone cleavage.";
RL Exp. Eye Res. 71:195-207(2000).
RN [18]
RP REVIEW.
RX PubMed=12369933; DOI=10.2174/1389203013381107;
RA Ganea E.;
RT "Chaperone-like activity of alpha-crystallin and other small heat
RT shock proteins.";
RL Curr. Protein Pept. Sci. 2:205-225(2001).
RN [19]
RP PROTEOLYTIC PROCESSING, AND TISSUE SPECIFICITY.
RX PubMed=12356833;
RA Thampi P., Hassan A., Smith J.B., Abraham E.C.;
RT "Enhanced C-terminal truncation of alphaA- and alphaB-crystallins in
RT diabetic lenses.";
RL Invest. Ophthalmol. Vis. Sci. 43:3265-3272(2002).
RN [20]
RP DEAMIDATION AT ASN-123, AND MUTAGENESIS OF ASN-123.
RX PubMed=18754677; DOI=10.1021/bi8001902;
RA Chaves J.M., Srivastava K., Gupta R., Srivastava O.P.;
RT "Structural and functional roles of deamidation and/or truncation of
RT N- or C-termini in human alpha A-crystallin.";
RL Biochemistry 47:10069-10083(2008).
RN [21]
RP SUBUNIT.
RX PubMed=17909943; DOI=10.1007/s11010-007-9615-2;
RA Kallur L.S., Aziz A., Abraham E.C.;
RT "C-Terminal truncation affects subunit exchange of human alphaA-
RT crystallin with alphaB-crystallin.";
RL Mol. Cell. Biochem. 308:85-91(2008).
RN [22]
RP SUBCELLULAR LOCATION.
RX PubMed=19464326; DOI=10.1016/j.bbamcr.2009.05.005;
RA Vos M.J., Kanon B., Kampinga H.H.;
RT "HSPB7 is a SC35 speckle resident small heat shock protein.";
RL Biochim. Biophys. Acta 1793:1343-1353(2009).
RN [23]
RP SUBUNIT.
RX PubMed=20836128; DOI=10.1002/iub.373;
RA Srinivas P., Narahari A., Petrash J.M., Swamy M.J., Reddy G.B.;
RT "Importance of eye lens alpha-crystallin heteropolymer with 3:1 alphaA
RT to alphaB ratio: stability, aggregation, and modifications.";
RL IUBMB Life 62:693-702(2010).
RN [24]
RP FUNCTION, AND ACETYLATION AT LYS-70 AND LYS-99.
RX PubMed=22120592; DOI=10.1016/j.bbadis.2011.11.011;
RA Nagaraj R.H., Nahomi R.B., Shanthakumar S., Linetsky M.,
RA Padmanabha S., Pasupuleti N., Wang B., Santhoshkumar P., Panda A.K.,
RA Biswas A.;
RT "Acetylation of alphaA-crystallin in the human lens: effects on
RT structure and chaperone function.";
RL Biochim. Biophys. Acta 1822:120-129(2012).
RN [25]
RP SUBUNIT, AND ZINC-BINDING SITES.
RX PubMed=22890888; DOI=10.1007/s10930-012-9439-0;
RA Karmakar S., Das K.P.;
RT "Identification of histidine residues involved in Zn(2+) binding to
RT alphaA- and alphaB-Crystallin by chemical modification and MALDI TOF
RT mass spectrometry.";
RL Protein J. 31:623-640(2012).
RN [26]
RP VARIANT CTRCT9 CYS-116.
RX PubMed=9467006; DOI=10.1093/hmg/7.3.471;
RA Litt M., Kramer P., la Morticella D.M., Murphey W., Lovrien E.W.,
RA Weleber R.G.;
RT "Autosomal dominant congenital cataract associated with a missense
RT mutation in the human alpha crystallin gene CRYAA.";
RL Hum. Mol. Genet. 7:471-474(1998).
RN [27]
RP CHARACTERIZATION OF VARIANT CTRCT9 CYS-116.
RX PubMed=11123904; DOI=10.1021/bi001453j;
RA Cobb B.A., Petrash J.M.;
RT "Structural and functional changes in the alpha A-crystallin R116C
RT mutant in hereditary cataracts.";
RL Biochemistry 39:15791-15798(2000).
RN [28]
RP VARIANT CTRCT9 CYS-49.
RX PubMed=14512969; DOI=10.1038/sj.ejhg.5201046;
RA Mackay D.S., Andley U.P., Shiels A.;
RT "Cell death triggered by a novel mutation in the alphaA-crystallin
RT gene underlies autosomal dominant cataract linked to chromosome 21q.";
RL Eur. J. Hum. Genet. 11:784-793(2003).
RN [29]
RP VARIANT CTRCT9 LEU-21.
RX PubMed=16453125; DOI=10.1007/s00417-005-0234-x;
RA Graw J., Klopp N., Illig T., Preising M.N., Lorenz B.;
RT "Congenital cataract and macular hypoplasia in humans associated with
RT a de novo mutation in CRYAA and compound heterozygous mutations in
RT P.";
RL Graefes Arch. Clin. Exp. Ophthalmol. 244:912-919(2006).
RN [30]
RP VARIANT [LARGE SCALE ANALYSIS] HIS-105.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [31]
RP VARIANT CTRCT9 HIS-116.
RX PubMed=18302245; DOI=10.1002/ajmg.a.32236;
RA Richter L., Flodman P., Barria von-Bischhoffshausen F., Burch D.,
RA Brown S., Nguyen L., Turner J., Spence M.A., Bateman J.B.;
RT "Clinical variability of autosomal dominant cataract, microcornea and
RT corneal opacity and novel mutation in the alpha A crystallin gene
RT (CRYAA).";
RL Am. J. Med. Genet. A 146:833-842(2008).
RN [32]
RP VARIANT CTRCT9 HIS-116, AND CHARACTERIZATION OF VARIANT CTRCT9
RP HIS-116.
RX PubMed=18407550; DOI=10.1002/humu.20724;
RA Gu F., Luo W., Li X., Wang Z., Lu S., Zhang M., Zhao B., Zhu S.,
RA Feng S., Yan Y.-B., Huang S., Ma X.;
RT "A novel mutation in AlphaA-crystallin (CRYAA) caused autosomal
RT dominant congenital cataract in a large Chinese family.";
RL Hum. Mutat. 29:769-769(2008).
RN [33]
RP VARIANT CTRCT9 CYS-12.
RX PubMed=23508780; DOI=10.1007/s00439-013-1289-0;
RA Reis L.M., Tyler R.C., Muheisen S., Raggio V., Salviati L., Han D.P.,
RA Costakos D., Yonath H., Hall S., Power P., Semina E.V.;
RT "Whole exome sequencing in dominant cataract identifies a new
RT causative factor, CRYBA2, and a variety of novel alleles in known
RT genes.";
RL Hum. Genet. 132:761-770(2013).
CC -!- FUNCTION: Contributes to the transparency and refractive index of
CC the lens. Has chaperone-like activity, preventing aggregation of
CC various proteins under a wide range of stress conditions.
CC -!- SUBUNIT: Heteropolymer composed of three CRYAA and one CRYAB
CC subunits. Inter-subunit bridging via zinc ions enhances stability,
CC which is crucial as there is no protein turn over in the lens. Can
CC also form homodimers and higher homooligomers. Age-dependent C-
CC terminal truncation affects oligomerization.
CC -!- INTERACTION:
CC Self; NbExp=4; IntAct=EBI-6875961, EBI-6875961;
CC P02511:CRYAB; NbExp=7; IntAct=EBI-6875961, EBI-739060;
CC P07315:CRYGC; NbExp=3; IntAct=EBI-6875961, EBI-6875941;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocates to the
CC nucleus during heat shock and resides in sub-nuclear structures
CC known as SC35 speckles or nuclear splicing speckles.
CC -!- TISSUE SPECIFICITY: Expressed in eye lens.
CC -!- PTM: O-glycosylated; contains N-acetylglucosamine side chains.
CC -!- PTM: Deamidation of Asn-101 in lens occurs mostly during the first
CC 30 years of age, followed by a small additional amount of
CC deamidation (approximately 5%) during the next approximately 38
CC years, resulting in a maximum of approximately 50% deamidation
CC during the lifetime of the individual.
CC -!- PTM: Phosphorylation on Ser-122 seems to be developmentally
CC regulated. Absent in the first months of life, it appears during
CC the first 12 years of human lifetime. The relative amount of
CC phosphorylated form versus unphosphorylated form does not change
CC over the lifetime of the individual.
CC -!- PTM: Acetylation at Lys-70 seems to increase chaperone activity.
CC -!- PTM: Undergoes age-dependent proteolytical cleavage at the C-
CC terminus. Alpha-crystallin A(1-172) is the most predominant form
CC produced most rapidly during the first 12 years of age and after
CC this age is present in approximatley 50% of the lens molecules.
CC -!- MASS SPECTROMETRY: Mass=19950; Method=Electrospray; Range=1-173;
CC Source=PubMed:8175657;
CC -!- MASS SPECTROMETRY: Mass=19863; Method=Electrospray; Range=1-172;
CC Source=PubMed:8175657;
CC -!- MASS SPECTROMETRY: Mass=20029; Method=Electrospray; Range=1-173;
CC Note=With 1 phosphate group; Source=PubMed:8175657;
CC -!- MASS SPECTROMETRY: Mass=19951; Method=Electrospray; Range=1-173;
CC Source=PubMed:9655350;
CC -!- MASS SPECTROMETRY: Mass=19864; Method=Electrospray; Range=1-172;
CC Source=PubMed:9655350;
CC -!- MASS SPECTROMETRY: Mass=19947; Method=Electrospray; Range=1-173;
CC Source=PubMed:10930324;
CC -!- MASS SPECTROMETRY: Mass=19851; Method=Electrospray; Range=1-172;
CC Source=PubMed:10930324;
CC -!- DISEASE: Note=Alpha-crystallin A 1-172 is found at nearly twofold
CC higher levels in diabetic lenses than in age-matched control
CC lenses (PubMed:12356833).
CC -!- DISEASE: Cataract 9, multiple types (CTRCT9) [MIM:604219]: An
CC opacification of the crystalline lens of the eye that frequently
CC results in visual impairment or blindness. Opacities vary in
CC morphology, are often confined to a portion of the lens, and may
CC be static or progressive. In general, the more posteriorly located
CC and dense an opacity, the greater the impact on visual function.
CC CTRCT9 includes nuclear, zonular central nuclear, anterior polar,
CC cortical, embryonal, anterior subcapsular, fan-shaped, and total
CC cataracts, among others. In some cases cataract is associated with
CC microcornea without any other systemic anomaly or dysmorphism.
CC Microcornea is defined by a corneal diameter inferior to 10 mm in
CC both meridians in an otherwise normal eye. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the small heat shock protein (HSP20)
CC family.
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DR EMBL; U05569; AAA97523.1; -; mRNA.
DR EMBL; U66584; AAC50900.1; -; mRNA.
DR EMBL; X14789; CAA32891.1; -; mRNA.
DR EMBL; CR407691; CAG28619.1; -; mRNA.
DR EMBL; AP001631; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP001748; BAA95535.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09497.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09498.1; -; Genomic_DNA.
DR EMBL; BC069528; AAH69528.1; -; mRNA.
DR EMBL; BC113598; AAI13599.1; -; mRNA.
DR EMBL; M35628; AAA52106.1; -; Genomic_DNA.
DR EMBL; M35629; AAA52105.1; -; Genomic_DNA.
DR PIR; S03344; CYHUAA.
DR RefSeq; NP_000385.1; NM_000394.2.
DR UniGene; Hs.184085; -.
DR DisProt; DP00444; -.
DR ProteinModelPortal; P02489; -.
DR SMR; P02489; 1-171.
DR DIP; DIP-41265N; -.
DR IntAct; P02489; 4.
DR MINT; MINT-220977; -.
DR STRING; 9606.ENSP00000291554; -.
DR PhosphoSite; P02489; -.
DR UniCarbKB; P02489; -.
DR DMDM; 1706112; -.
DR SWISS-2DPAGE; P02489; -.
DR PaxDb; P02489; -.
DR PeptideAtlas; P02489; -.
DR PRIDE; P02489; -.
DR DNASU; 1409; -.
DR Ensembl; ENST00000291554; ENSP00000291554; ENSG00000160202.
DR GeneID; 1409; -.
DR KEGG; hsa:1409; -.
DR UCSC; uc002zdd.1; human.
DR CTD; 1409; -.
DR GeneCards; GC21P044589; -.
DR HGNC; HGNC:2388; CRYAA.
DR MIM; 123580; gene.
DR MIM; 604219; phenotype.
DR neXtProt; NX_P02489; -.
DR Orphanet; 1377; Cataract-microcornea syndrome.
DR Orphanet; 98991; Nuclear cataract.
DR Orphanet; 98995; Zonular cataract.
DR PharmGKB; PA26906; -.
DR eggNOG; NOG278874; -.
DR HOGENOM; HOG000233954; -.
DR HOVERGEN; HBG054766; -.
DR InParanoid; P02489; -.
DR KO; K09541; -.
DR OMA; GPKVQSG; -.
DR OrthoDB; EOG7WHHBK; -.
DR PhylomeDB; P02489; -.
DR GeneWiki; CRYAA; -.
DR GenomeRNAi; 1409; -.
DR NextBio; 5761; -.
DR PRO; PR:P02489; -.
DR ArrayExpress; P02489; -.
DR Bgee; P02489; -.
DR CleanEx; HS_CRYAA; -.
DR Genevestigator; P02489; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005212; F:structural constituent of eye lens; IEA:UniProtKB-KW.
DR GO; GO:0051082; F:unfolded protein binding; IMP:UniProtKB.
DR GO; GO:0007015; P:actin filament organization; IEA:Ensembl.
DR GO; GO:0060561; P:apoptotic process involved in morphogenesis; IEA:Ensembl.
DR GO; GO:0048596; P:embryonic camera-type eye morphogenesis; IEA:Ensembl.
DR GO; GO:0070309; P:lens fiber cell morphogenesis; IEA:Ensembl.
DR GO; GO:0007005; P:mitochondrion organization; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR GO; GO:0032387; P:negative regulation of intracellular transport; IDA:HGNC.
DR GO; GO:0030307; P:positive regulation of cell growth; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl.
DR GO; GO:0006457; P:protein folding; IEA:Ensembl.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0042542; P:response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
DR GO; GO:0070141; P:response to UV-A; IEA:Ensembl.
DR GO; GO:0007021; P:tubulin complex assembly; IEA:Ensembl.
DR GO; GO:0007601; P:visual perception; IMP:UniProtKB.
DR InterPro; IPR002068; a-crystallin/Hsp20_dom.
DR InterPro; IPR001436; Alpha-crystallin/HSP.
DR InterPro; IPR012274; Alpha-crystallin_A.
DR InterPro; IPR003090; Alpha-crystallin_N.
DR InterPro; IPR008978; HSP20-like_chaperone.
DR PANTHER; PTHR11527:SF36; PTHR11527:SF36; 1.
DR Pfam; PF00525; Crystallin; 1.
DR Pfam; PF00011; HSP20; 1.
DR PIRSF; PIRSF036514; Sm_HSP_B1; 1.
DR PRINTS; PR00299; ACRYSTALLIN.
DR SUPFAM; SSF49764; SSF49764; 1.
DR PROSITE; PS01031; HSP20; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cataract; Chaperone; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Eye lens protein; Glycoprotein; Metal-binding; Nucleus; Oxidation;
KW Phosphoprotein; Polymorphism; Reference proteome;
KW Sensory transduction; Vision; Zinc.
FT CHAIN 1 173 Alpha-crystallin A chain.
FT /FTId=PRO_0000125865.
FT CHAIN 1 172 Alpha-crystallin A(1-172).
FT /FTId=PRO_0000226639.
FT CHAIN 1 168 Alpha-crystallin A(1-168).
FT /FTId=PRO_0000423503.
FT CHAIN 1 162 Alpha-crystallin A(1-162).
FT /FTId=PRO_0000423504.
FT METAL 79 79 Zinc 1 (Probable).
FT METAL 100 100 Zinc 2 (By similarity).
FT METAL 102 102 Zinc 2 (By similarity).
FT METAL 107 107 Zinc 1 (Probable).
FT METAL 115 115 Zinc 1 (Probable).
FT SITE 1 1 Susceptible to oxidation.
FT SITE 18 18 Susceptible to oxidation.
FT SITE 34 34 Susceptible to oxidation.
FT SITE 138 138 Susceptible to oxidation.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 6 6 Deamidated glutamine; partial.
FT MOD_RES 45 45 Phosphoserine.
FT MOD_RES 50 50 Deamidated glutamine; partial.
FT MOD_RES 70 70 N6-acetyllysine.
FT MOD_RES 90 90 Deamidated glutamine; partial.
FT MOD_RES 99 99 N6-acetyllysine.
FT MOD_RES 101 101 Deamidated asparagine; partial.
FT MOD_RES 122 122 Phosphoserine.
FT MOD_RES 123 123 Deamidated asparagine; partial.
FT MOD_RES 147 147 Deamidated glutamine; partial.
FT CARBOHYD 162 162 O-linked (GlcNAc) (By similarity).
FT DISULFID 131 142
FT VARIANT 12 12 R -> C (in CTRCT9).
FT /FTId=VAR_070032.
FT VARIANT 21 21 R -> L (in CTRCT9; associated with
FT macular hypoplasia and a generally
FT hypopigmented fundus).
FT /FTId=VAR_046892.
FT VARIANT 49 49 R -> C (in CTRCT9; nuclear cataract).
FT /FTId=VAR_038375.
FT VARIANT 105 105 D -> H (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036564.
FT VARIANT 116 116 R -> C (in CTRCT9; zonular central
FT nuclear cataract; reduced chaperone-like
FT activity and increased membrane-binding
FT capacity).
FT /FTId=VAR_003819.
FT VARIANT 116 116 R -> H (in CTRCT9; reverse phase-high-
FT performance liquid chromatography
FT suggests an increase hydrophobicity of
FT the mutant protein; loss of chaperone
FT activity of the mutant is seen in DL-
FT dithiothreitol-induced insulin
FT aggregation assay; fast protein liquid
FT chromatography purification shows that
FT the mutant protein has increased binding
FT affinity to lysozyme).
FT /FTId=VAR_046893.
FT MUTAGEN 123 123 N->D: Impairs chaperone activity.
FT CONFLICT 45 45 S -> T (in Ref. 9; AAA52105).
FT CONFLICT 153 155 THA -> HT (in Ref. 2).
SQ SEQUENCE 173 AA; 19909 MW; 81804A8439837D50 CRC64;
MDVTIQHPWF KRTLGPFYPS RLFDQFFGEG LFEYDLLPFL SSTISPYYRQ SLFRTVLDSG
ISEVRSDRDK FVIFLDVKHF SPEDLTVKVQ DDFVEIHGKH NERQDDHGYI SREFHRRYRL
PSNVDQSALS CSLSADGMLT FCGPKIQTGL DATHAERAIP VSREEKPTSA PSS
//

MIM 123580
*RECORD*
*FIELD* NO
123580
*FIELD* TI
*123580 CRYSTALLIN, ALPHA-A; CRYAA
;;CRYSTALLIN, ALPHA-1; CRYA1;;
HEAT-SHOCK PROTEIN BETA-4; HSPB4
read more*FIELD* TX

DESCRIPTION

The transparency and high refractive index of the normal eye lens
necessary for focusing visible light on the retina is achieved by a
regular arrangement of the lens fiber cells during growth of the
lenticular body and by the high concentration and the supramolecular
organization of the alpha-, beta- (see 123610), and gamma- (see 123660)
crystallins, the major protein components of the vertebrate eye lens.
Alpha-crystallin is composed of 2 primary gene products--alpha-A and
alpha-B (123590) (summary by Moormann et al., 1982).

CLONING

Quax-Jeuken et al. (1985) isolated bovine cDNA clones for the alpha-A
and alpha-B subunits of crystallin.

Wistow (1985) stated that the CRYAA gene encodes a deduced 173-amino
acid protein that is highly stable and evolutionarily conserved.

GENE STRUCTURE

The CRYAA gene contains 3 exons (Wistow, 1985).

Jaworski and Piatigorsky (1989) discovered what they termed a
pseudo-exon within the active single-copy human gene CRYA1. The
pseudo-exon appeared to be in the early stages of extinction, perhaps
the result of a failed experiment in the evolution of this specialized,
lens-specific protein.

MAPPING

Using a cDNA clone for Southern analysis of DNA from human-rodent
hybrids, Quax-Jeuken et al. (1985) assigned the gene for alpha-A
crystallin (CRYA1) to chromosome 21. The authors suggested that juvenile
cataract of Down syndrome may be related to trisomy of the CRYA1 gene.
Hawkins et al. (1987) confirmed the assignment to chromosome 21 by
probing of somatic cell hybrids and regionalized the gene to 21q22.3 by
in situ hybridization and use of parent cells containing various parts
of chromosome 21 in creation of the hybrid cells. By linkage studies
with RFLPs, Petersen et al. (1991) confirmed the assignment to 21q22.3
and indicated the position of the CRYA1 gene in relation to 15 other
genes and DNA markers in that band.

In the mouse, Skow and Donner (1985) found that alpha-A-crystallin
(symbolized Acry-1) is linked to H2 on mouse chromosome 17 and is
located between glyoxalase and H-2K, very close to the latter. Skow et
al. (1985) demonstrated that the corresponding locus in the rat is
linked to the major histocompatibility locus. Kaye et al. (1990) mapped
the Crya-1 gene to mouse chromosome 17 by means of Southern analysis of
mouse/Chinese hamster somatic cell hybrids and regionalized the
assignment by in situ hybridization. They found that the gene is located
in an area that shows conservation with human chromosome 6 rather than
human chromosome 21. Thus, this may be an example of failure of homology
of synteny.

GENE FUNCTION

The alpha-crystallins show homology with the small heat-shock proteins
of Drosophila and soybean (Schoffl et al., 1984.) Heat-shock proteins
(see 140550) form aggregates, as do alpha-crystallins, and are thought
to protect cellular components under conditions of stress. Perhaps
alpha-crystallin exerts a similar, as yet unknown stabilizing or
protective effect in the lens fiber cells, which have to maintain a
life-long resistance against deleterious influences. On the other hand,
the superfamily of the beta- and gamma-crystallins shows structural
similarities with a bacterial spore coat protein (Wistow, 1985).

The importance of alpha-crystallins in the maintenance of lens
transparency was demonstrated by the work of Brady et al. (1997), who
showed that mice homozygous for a targeted disruption of the
alpha-A-crystallin gene developed cataracts and had cytoplasmic
inclusion bodies containing the small heat-shock protein
alpha-B-crystallin (123590). Litt et al. (1998) speculated that the
cataracts in the family they studied may result from partial loss of the
chaperone function of alpha-A-crystallin and/or from an increased
tendency of the mutant polypeptide to aggregate because of its decreased
positive charge and its gain of a sulfhydryl group. The presence of
congenital microphthalmia in their family indicated that
alpha-A-crystallin, similarly to gamma-E-crystallin in the Elo mutant
mouse (Cartier et al., 1992), plays an important role in the normal
embryologic development of the anterior segment of the eye. In the Elo
mouse, a 1-bp deletion in the gamma-E-crystallin gene causes autosomal
dominant cataract and microphthalmia (Cartier et al., 1992).

The alpha-crystallin subunits alpha-A and alpha-B can each form an
oligomer by itself or with the other. Fu and Liang (2002) used a
2-hybrid system to study heterogeneous interactions among lens
crystallins of different classes. They found interactions between
alpha-A- (or alpha-B-) and beta-B2- or gamma-C- (123680) crystallins,
but the intensity of interaction was one-third that of alpha-A-alpha-B
interactions. HSP27 (602195), a member of the small heat-shock protein
family, showed similar interaction properties with alpha-B-crystallin.
Experiments with N- and C-terminal domain-truncated mutants demonstrated
that both N- and C-terminal domains were important in alpha-A-crystallin
self-interaction, but that only the C-terminal domain was important in
alpha-B-crystallin self-interaction.

Fu and Liang (2003) studied the effect of crystallin gene mutations that
result in congenital cataract on protein-protein interactions.
Interactions between mutated crystallins alpha-A (R116C; 123580.0001),
alpha-B (R120G; 123590.0001), and gamma-C (T5P; 123680.0001) and the
corresponding wildtype proteins, as well as with wildtype
beta-B2-crystallin (123620) and HSP27, were analyzed in a mammalian cell
2-hybrid system. For mutated alpha-A-crystallin, interactions with
wildtype beta-B2- and gamma-C-crystallin decreased and those with
wildtype alpha-B-crystallin and HSP27 increased. For mutated
alpha-B-crystallin, interactions with wildtype alpha-A- and
alpha-B-crystallin decreased, but those with wildtype beta-B2- and
gamma-C-crystallin increased slightly. For mutated gamma-C-crystallin,
most of the interactions were decreased. The results indicated that
crystallin mutations involved in congenital cataracts altered
protein-protein interactions, which might contribute to decreased
protein solubility and formation of cataract.

Kourtis et al. (2012) demonstrated that preconditioning of C. elegans at
a mildly elevated temperature strongly protected from heat-induced
necrosis. The heat-shock transcription factor HSF1 (140580) and the
small heat-shock protein HSP-16.1 mediate cytoprotection by
preconditioning. HSP-16.1 localizes to the Golgi, where it functions
with the calcium- and magnesium-transporting ATPase PMR1 (604384) to
maintain calcium homeostasis under heat stroke. In mouse cortical
neurons and striatal cells, Kourtis et al. (2012) found that
overexpression of crystallin alpha-A, which colocalizes with the Golgi
marker alpha-mannosidase-2 (154582) and the PMR1 ATPase, was sufficient
to protect mammalian neurons from heat stroke-induced death, even in the
absence of preconditioning. Heat stroke caused massive necrotic death
and axonal degeneration in neurons expressing short hairpin RNAs against
Pmr1, even after preconditioning.

MOLECULAR GENETICS

In affected members of a family segregating autosomal dominant
congenital cataracts mapping to chromosome 21q22.3 (CTRCT9; 604219),
Litt et al. (1998) sequenced the coding region of the CRYAA gene and
identified a missense mutation (R116C; 123580.0001) that segregated with
the disorder.

Pras et al. (2000) identified homozygosity for a nonsense mutation in
the CRYAA gene (123580.0002) in 3 sibs from an inbred Jewish Persian
family with autosomal recessive congenital cataract. The patients
underwent cataract extraction in the first 3 months of life, and no
details of the pathologic findings in the lens were available.

Mackay et al. (2003) described a 4-generation Caucasian family
segregating an autosomal dominant form of 'nuclear' cataract presenting
at birth or during infancy and confined to the central zone or fetal
nucleus of the lens. Haplotype analysis indicated that the disease gene
lay in the physical interval between 2 markers flanking the CRYAA gene.
Sequence analysis identified an arg49-to-cys change in the CRYAA gene
(R49C; 123580.0003) in affected individuals.

In a 4-generation family of Indian origin segregating autosomal dominant
fan-shaped cataract and microcornea, Vanita et al. (2006) identified
heterozygosity for the CRYAA R116C missense mutation, previously
detected in a North American family with a zonular type of congenital
cataract by Litt et al. (1998). Based on the tight association of
cataract and microcornea in the Indian family and because expression of
CRYAA has been demonstrated in the anterior eye segment as well the
lens, Vanita et al. (2006) suggested that apart from the lens,
alpha-A-crystallins might play a role in development of the anterior
segment of the eye.

In a sister and brother and their mother with progressive presenile
total cataract, Santhiya et al. (2006) analyzed functional candidate
genes and identified heterozygosity for a missense mutation in the CRYAA
gene (G98R; 123580.0005). The mutation was not found in the unaffected
father or sister, in 30 random DNA samples of Indian origin, or in 96
healthy German controls.

In 12 affected and 4 unaffected members of a 4-generation French family
with autosomal dominant cataract and iris coloboma, Beby et al. (2007)
analyzed microsatellites for 15 known cataract loci and found suggestive
linkage at the CRYAA locus on chromosome 21, as well as a specific
haplotype segregating with the disease. Sequence analysis of the CRYAA
gene revealed that all affected family members were heterozygous for the
R116C mutation; the mutation was not found in unaffected individuals.
Two affected individuals also had congenital microphthalmia; the authors
noted that Cryaa -/- mice have been found to have both microphthalmia
and cataract (Brady et al., 1997).

In 3 affected sibs from a consanguineous Saudi Arabian family with
congenital total white cataract and microcornea mapping to 21q22.3, Khan
et al. (2007) sequenced the candidate gene CRYAA and identified
homozygosity for a missense mutation (R54C; 123580.0006). Their
asymptomatic parents and 1 sib were found to be heterozygous for the
mutation; on slit-lamp examination, all 3 heterozygotes had similar
discernable but clinically insignificant bilateral punctate lenticular
opacities that were not present in the other asymptomatic family
members.

In 3 unrelated Danish families segregating autosomal dominant congenital
cataract and microcornea, Hansen et al. (2007) identified 3 different
heterozygous missense mutations in the CRYAA gene
(123580.0007-123580.0009).

Richter et al. (2008) studied 14 affected and 14 unaffected members of a
large 4-generation Chilean family, previously reported by Shafie et al.
(2006) as 'family ADC54,' segregating autosomal dominant cataract,
microcornea, and/or corneal opacity. Richter et al. (2008) found linkage
to chromosome 21 with a maximum lod score of 4.89 at D21S171, and
identified a heterozygous missense mutation in the CRYAA gene (R116H;
123580.0004) in affected members of the family. There was significant
asymmetry of density, morphology, and color of the cataracts within and
between affected individuals; the variable morphology included anterior
polar, cortical, embryonal, fan-shaped, and anterior subcapsular
cataracts. Richter et al. (2008) stated that, with the exception of iris
coloboma, the clinical features of all 6 previously reported families
with mutations in the CRYAA gene were found in this Chilean family.

In affected members of a 3-generation South Australian family
segregating autosomal dominant lamellar cataract of variable severity,
Laurie et al. (2013) identified heterozygosity for a CRYAA missense
mutation (R21Q; 123580.0010).

ANIMAL MODEL

Hsu et al. (2006) characterized lenses from transgenic mice designed to
express mutant (R116C) and wildtype alpha-A-crystallin subunits.
Expression of R116C alpha-A-crystallin subunits resulted in posterior
cortical cataracts and abnormalities associated with the posterior
suture. The severity of lens abnormalities did not increase between the
ages of 9 and 30 weeks. With respect to opacities and morphologic
abnormalities, lenses from transgenic mice that expressed wildtype human
alpha-A-crystallin subunits were indistinguishable from age-matched
nontransgenic control mice. Similar phenotypes were observed in
different independent lines of R116C transgenic mice that differed by at
least 2 orders of magnitude in the expression level of the mutant
transgenic protein. Low levels of R116C alpha-A-crystallin subunits were
sufficient to induce lens opacities and sutural defects.

*FIELD* AV
.0001
CATARACT 9, MULTIPLE TYPES, WITH OR WITHOUT MICROCORNEA
CRYAA, ARG116CYS

In affected members of a family with autosomal dominant congenital
cataract (CTRCT9; 604219), described as congenital zonular central
nuclear opacities, Litt et al. (1998) identified heterozygosity for a
413G-A transition in exon 3 of the CRYAA gene, resulting in an
arg116-to-cys (R116C) substitution at a highly conserved residue. Five
of the 13 affected individuals also had microphthalmia and microcornea.
The mutation was not found in 14 unaffected family members or 111
unrelated controls.

Cobb and Petrash (2000) examined the quaternary stability of the R116C
CRYA mutant. Homocomplexes of mutant subunits become highly polydisperse
at body temperature. Compared to the wildtype protein, they have reduced
chaperone-like activity and ability to exchange subunits, but increased
membrane-binding capacity.

Fu and Liang (2003) observed that alpha-A-crystallin carrying the R116C
mutation had decreased interaction with wildtype crystallins beta-B2
(123620) and gamma-C (123680) but increased interaction with
alpha-B-crystallin (123590) and HSP27 (602195).

In 12 affected members of a 4-generation French family with autosomal
dominant nuclear cataract and iris coloboma, Beby et al. (2007)
identified heterozygosity for the R116C mutation in the CRYAA gene. The
mutation was not found in unaffected family members.

In a 4-generation family of Indian origin segregating autosomal dominant
fan-shaped cataract and microcornea, Vanita et al. (2006) identified
heterozygosity for the CRYAA R116C missense mutation, which segregated
with disease in the family and was not found in 100 controls. No other
ocular anomalies were detected in affected members of this family.

.0002
CATARACT 9, AUTOSOMAL RECESSIVE
CRYAA, TRP9TER

In 3 affected sibs from an inbred Jewish Persian family with autosomal
recessive congenital cataract, Pras et al. (2000) identified
homozygosity for a G-to-A transition at nucleotide 27 of the CRYAA gene,
resulting in a trp9-to-ter (W9X) substitution. The parents and an
unaffected sib were heterozygous for the mutation.

.0003
CATARACT 9, NUCLEAR
CRYAA, ARG49CYS

In a 4-generation Caucasian family segregating an autosomal dominant
form of 'nuclear' cataract (CTRCT9; 604219), Mackay et al. (2003)
identified heterozygosity for a C-to-T transition in exon 1 of the CRYAA
gene, resulting in an arg49-to-cys (R49C) change. Transfection studies
of lens epithelial cells revealed that, unlike wildtype CRYAA, the
mutant protein was abnormally localized to the nucleus and failed to
protect from staurosporine-induced apoptotic cell death. This was the
first dominant cataract-causing mutation in CRYAA located outside the
phylogenetically conserved 'alpha-crystallin core domain' of the small
heat-shock protein family.

.0004
CATARACT 9, MULTIPLE TYPES, WITH MICROCORNEA
CRYAA, ARG116HIS

In 14 affected members of a large 4-generation Chilean family,
previously reported by Shafie et al. (2006) as 'family ADC54,'
segregating autosomal dominant cataract, microcornea, and/or corneal
opacity (CTRCT9; 604219), Richter et al. (2008) identified a 414G-A
transition in exon 3 of the CRYAA gene, resulting in an arg116-to-his
(R116H) substitution that changes a positively charged residue to a
slightly negatively charged residue in a highly conserved region. The
mutation was not found in 12 controls. There was significant asymmetry
of density, morphology, and color of the cataracts within and between
affected individuals; the variable morphology included anterior polar,
cortical, embryonal, fan-shaped, and anterior subcapsular cataracts.
Microcornea was evident in 3 affected individuals. Richter et al. (2008)
noted that other affected individuals with nystagmus might also have
mild microcornea, which could only be measured under anesthesia.

.0005
CATARACT 9, TOTAL
CRYAA, GLY98ARG

In 3 affected members over 2 generations of an Indian family with total
cataract (CTRCT9; 604219), Santhiya et al. (2006) identified
heterozygosity for a 291G-A transition in exon 2 of the CRYAA gene,
resulting in a gly98-to-arg (G98R) substitution at a highly conserved
residue within the core domain. The mutation was not found in 2
unaffected family members, in 30 random DNA samples of Indian origin, or
in 96 healthy German controls. Cataract in this family began as a
peripheral ring-like cortical opacity in the second decade of life,
progressing to total cataract in the third decade; the affected family
members had no other ocular defects. (The authors stated the nucleotide
change as 292G-A and as 291G-A in the rest of their article.)

.0006
CATARACT 9, TOTAL, WITH MICROCORNEA, AUTOSOMAL RECESSIVE
CRYAA, ARG54CYS

In 3 affected sibs from a consanguineous Saudi Arabian family with
congenital total white cataract with microcornea (CTRCT9; 604219), Khan
et al. (2007) identified homozygosity for a c.160C-T transition in exon
1 of the CRYAA gene, resulting in an arg54-to-cys (R54C) substitution.
Their asymptomatic parents and 1 sib were found to be heterozygous for
the mutation; on slit-lamp examination, all 3 heterozygotes had similar
discernable but clinically insignificant bilateral punctate lenticular
opacities that were not present in the other asymptomatic family
members. The mutation was not found in 60 healthy Saudi individuals.

.0007
CATARACT 9, NUCLEAR, WITH MICROCORNEA
CRYAA, ARG116HIS

In 7 affected members over 3 generations of a Danish family segregating
autosomal dominant congenital nuclear cataract with microcornea (CTRCT9;
604219), Hansen et al. (2007) identified heterozygosity for a c.337G-A
transition in the CRYAA gene, resulting in an arg116-to-his (R116H)
substitution at 1 of the most highly conserved residues in the
alpha-crystallin domain. The mutation was not found in 6 unaffected
family members or 170 ethnically matched controls. Examination of
affected family members revealed nuclear cataracts with polar and/or
equatorial ramification; corneas were 8 to 10 mm in diameter.

.0008
CATARACT 9, MULTIPLE TYPES, WITH MICROCORNEA
CRYAA, ARG12CYS

In a Danish mother and son with posterior polar cataract with
microcornea (CTRCT9; 604219), Hansen et al. (2007) identified
heterozygosity for a c.34C-T transition in exon 1 of the CRYAA gene,
resulting in an arg12-to-cys (R12C) substitution at a highly conserved
residue in the N-terminal region. The mutation was not found in 170
ethnically matched controls. Examination of 1 affected family member
showed posterior polar cataracts, progressing to dense nuclear and
laminar cataracts, with involvement of the anterior and posterior poles;
the cornea was 9.5 mm in diameter. The authors noted that the phenotypes
associated with this mutation and R21W (123580.0009) are similar; both
consist of a central, zonular cataract with varying involvement of the
anterior and posterior poles.

.0009
CATARACT 9, MULTIPLE TYPES, WITH MICROCORNEA
CRYAA, ARG21TRP

In 4 affected members over 3 generations of a Danish family segregating
autosomal dominant central laminar cataract with microcornea (CTRCT9;
604219), Hansen et al. (2007) identified heterozygosity for a c.61C-T
transition in exon 1 of the CRYAA gene, resulting in an arg21-to-trp
(R21W) substitution at a highly conserved residue in the N-terminal
region. The mutation was not found in 170 ethnically matched controls.
Examination of the 4 affected family members showed central and laminar
cataracts, with variable opacification of the anterior and posterior
poles; corneas were 8 to 10 mm in diameter. The authors noted that the
phenotypes associated with this mutation and R12C (123580.0008) are
similar; both consist of a central, zonular cataract with varying
involvement of the anterior and posterior poles.

.0010
CATARACT 9, NUCLEAR LAMELLAR
CRYAA, ARG21GLN

In 5 affected individuals over 3 generations of a South Australian
family with lamellar cataract of variable severity (CTRCT9; 604219),
Laurie et al. (2013) identified heterozygosity for a c.62G-A transition
in the CRYAA gene, resulting in an arg21-to-gln (R21Q) substitution at a
highly conserved residue in the N-terminal region. The proband had
moderate fetal nuclear lamellar cataract diagnosed at age 2 years, and
his brother was diagnosed with dense white nuclear cataract at age 4.5
years. The mutation was not found in 4 unaffected family members or in
95 South Australian controls, but was detected in the asymptomatic
mother, maternal uncle, and maternal grandfather, all of whom displayed
mild lamellar opacity on examination in adulthood following the
children's diagnosis. Western blotting of proteins freshly extracted
from cataractous lens material of the proband demonstrated a marked
reduction in the amount of high molecular weight oligomers compared to
lens material from an unaffected individual.

*FIELD* SA
Brakenhoff et al. (1994); de Jong and Hendriks (1986)
*FIELD* RF
1. Beby, F.; Commeaux, C.; Bozon, M.; Denis, P.; Edery, P.; Morle,
L.: New phenotype associated with an arg116-to-cys mutation in the
CRYAA gene. Arch. Ophthal. 125: 213-216, 2007.

2. Brady, J. P.; Garland, D.; Duglas-Tabor, Y.; Robison, W. G., Jr.;
Groome, A.; Wawrousek, E. F.: Targeted disruption of the mouse alpha
A-crystallin gene induces cataract and cytoplasmic inclusion bodies
containing the small heat shock protein alpha B-crystallin. Proc.
Nat. Acad. Sci. 94: 884-889, 1997.

3. Brakenhoff, R. H.; Henskens, H. A. M.; van Rossum, M. W. P. C.;
Lubsen, N. H.; Schoenmakers, J. G. G.: Activation of the gamma E-crystallin
pseudogene in the human hereditary Coppock-like cataract. Hum. Molec.
Genet. 3: 279-283, 1994.

4. Cartier, M.; Breitman, M. L.; Tsui, L.-C.: A frameshift mutation
in the gamma-E-crystallin gene of the Elo mouse. Nature Genet. 2:
42-45, 1992. Note: Erratum: Nature Genet. 2: 343 only, 1992.

5. Cobb, B. A.; Petrash, J. M.: Structural and functional changes
in the alpha-A-crystallin R116C mutant in hereditary cataracts. Biochemistry 39:
15791-15798, 2000.

6. de Jong, W. W.; Hendriks, W.: The eye lens crystallins: ambiguity
as evolutionary strategy. J. Molec. Evol. 24: 121-129, 1986.

7. Fu, L.; Liang, J. J.-N.: Detection of protein-protein interactions
among lens crystallins in a mammalian two-hybrid system assay. J.
Biol. Chem. 277: 4255-4260, 2002.

8. Fu, L.; Liang, J. J.-N.: Alteration of protein-protein interactions
of congenital cataract crystallin mutants. Invest. Ophthal. Vis.
Sci. 44: 1155-1159, 2003.

9. Hansen, L.; Yao, W.; Eiberg, H.; Kjaer, K. W.; Baggersen, K.; Hejtmancik,
J. F.; Rosenberg, T.: Genetic heterogeneity in microcornea-cataract:
five novel mutations in CRYAA, CRYGD, and GJA8. Invest. Ophthal.
Vis. Sci. 48: 3937-3944, 2007.

10. Hawkins, J. W.; Van Keuren, M. L.; Piatigorsky, J.; Law, M. L.;
Patterson, D.; Kao, F.-T.: Confirmation of assignment of the human
alpha-1-crystallin gene (CRYA1) to chromosome 21 with regional localization
to q22.3. Hum. Genet. 76: 375-380, 1987.

11. Hsu, C.-D.; Kymes, S.; Petrash, J. M.: A transgenic mouse model
for human autosomal dominant cataract. Invest. Ophthal. Vis. Sci. 47:
2036-2044, 2006.

12. Jaworski, C. J.; Piatigorsky, J.: A pseudo-exon in the functional
human alpha-A-crystallin gene. Nature 337: 752-754, 1989.

13. Kaye, N. W.; Lalley, P. A.; Petrash, J. M.; Church, R. L.: Regional
assignment of the mouse alpha-A2-crystallin gene (Crya-1) to chromosome
17A3-B by in situ hybridization. Cytogenet. Cell Genet. 53: 95-96,
1990.

14. Khan, A. O.; Aldahmesh, M. A.; Meyer, B.: Recessive congenital
total cataract with microcornea and heterozygote carrier signs caused
by a novel missense CRYAA mutation (R54C). Am. J. Ophthal. 144:
949-952, 2007.

15. Kourtis, N.; Nikoletopoulou, V.; Tavernarakis, N.: Small heat-shock
proteins protect from heat-stroke-associated neurodegeneration. Nature 490:
213-218, 2012.

16. Laurie, K. J.; Dave, A.; Straga, T.; Souzeau, E.; Chataway, T.;
Sykes, M. J.; Casey, T.; Teo, T.; Pater, J.; Craig, J. E.; Sharma,
S.; Burdon, K. P.: Identification of a novel oligomerization disrupting
mutation in CRYAA associated with congenital cataract in a South Australian
family. Hum. Mutat. 34: 435-438, 2013.

17. Litt, M.; Kramer, P.; LaMorticella, D. M.; Murphey, W.; Lovrien,
E. W.; Weleber, R. G.: Autosomal dominant congenital cataract associated
with a missense mutation in the human alpha crystallin gene CRYAA. Hum.
Molec. Genet. 7: 471-474, 1998.

18. Mackay, D. S.; Andley, U. P.; Shiels, A.: Cell death triggered
by a novel mutation in the alpha-A-crystallin gene underlies autosomal
dominant cataract linked to chromosome 21q. Europ. J. Hum. Genet. 11:
784-793, 2003.

19. Moormann, R. J. M.; den Dunnen, J. T.; Bloemendal, H.; Schoenmakers,
J. G. G.: Extensive intragenic sequence homology in two distinct
rat lens gamma-crystallin cDNAs suggests duplications of a primordial
gene. Proc. Nat. Acad. Sci. 79: 6876-6880, 1982.

20. Petersen, M. B.; Slaugenhaupt, S. A.; Lewis, J. G.; Warren, A.
C.; Chakravarti, A.; Antonarakis, S. E.: A genetic linkage map of
27 markers on human chromosome 21. Genomics 9: 407-419, 1991.

21. Pras, E.; Frydman, M.; Levy-Nissenbaum, E.; Bakhan, T.; Raz, J.;
Assia, E. I.; Goldman, B.; Pras, E.: A nonsense mutation (W9X) in
CRYAA causes autosomal recessive cataract in an inbred Jewish Persian
family. Invest. Ophthal. Vis. Sci. 41: 3511-3515, 2000.

22. Quax-Jeuken, Y.; Quax, W.; van Rens, G.; Meera Khan, P.; Bloemendal,
H.: Complete structure of the alpha-B-crystallin: conservation of
the exon-intron distribution in the two nonlinked alpha-crystallin
genes. Proc. Nat. Acad. Sci. 82: 5819-5823, 1985.

23. Quax-Jeuken, Y.; Quax, W.; van Rens, G.; Meera Khan, P.; Bloemendal,
H.: Assignment of the human alpha-A-crystallin gene (CRYA1) to chromosome
21. (Abstract) Cytogenet. Cell Genet. 40: 727-728, 1985.

24. Richter, L.; Flodman, P.; Barria von-Bischhoffshausen, F.; Burch,
D.; Brown, S.; Nguyen, L.; Turner, J.; Spence, M. A.; Bateman, J.
B.: Clinical variability of autosomal dominant cataract, microcornea
and corneal opacity and novel mutation in the alpha A crystallin gene
(CRYAA). Am. J. Med. Genet. 146A: 833-842, 2008.

25. Santhiya, S. T.; Soker, T.; Klopp, N.; Illig, T.; Prakash, M.
V. S.; Selvaraj, B.; Gopinath, P. M.; Graw, J.: Identification of
a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian
family. Molec. Vis. 12: 768-773, 2006.

26. Schoffl, F.; Rascke, E.; Nagao, R. T.: The DNA sequence analysis
of soybean heat-shock genes and identification of possible regulatory
promoter elements. EMBO J. 3: 2491-2497, 1984.

27. Shafie, S. M.; Barria von-Bischhoffshausen, F. R.; Bateman, J.
B.: Autosomal dominant cataract: intrafamilial phenotypic variability,
interocular asymmetry, and variable progression in four Chilean families. Am.
J. Ophthal. 141: 750-752, 2006.

28. Skow, L. C.; Donner, M. E.: The locus encoding alpha-A-crystallin
is closely linked to H-2K on mouse chromosome 17. Genetics 110:
723-732, 1985.

29. Skow, L. C.; Kunz, H. W.; Gill, T. J., III: Linkage of the locus
encoding the A chain of alpha-crystallin (Acry-1) to the major histocompatibility
complex in the rat. Immunogenetics 22: 291-293, 1985.

30. Vanita, V.; Singh, J. R.; Hejtmancik, J. F.; Nurnberg, P.; Hennies,
H. C.; Singh, D.; Sperling, K.: A novel fan-shaped cataract-microcornea
syndrome caused by a mutation of CRYAA in an Indian family. Molec.
Vis. 12: 518-522, 2006.

31. Wistow, G.: Domain structure and evolution in alpha-crystallins
and small heat shock proteins. FEBS Lett. 181: 1-6, 1985.

*FIELD* CN
Marla J. F. O'Neill - updated: 10/21/2013
Marla J. F. O'Neill - updated: 5/20/2013
Ada Hamosh - updated: 10/25/2012
Marla J. F. O'Neill - updated: 10/27/2008
Marla J. F. O'Neill - updated: 10/17/2008
Jane Kelly - updated: 3/23/2007
Jane Kelly - updated: 3/4/2004
Victor A. McKusick - updated: 11/13/2003
Victor A. McKusick - updated: 3/20/2001
Paul J. Converse - updated: 2/28/2001
Victor A. McKusick - updated: 4/14/1998

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

*FIELD* ED
carol: 10/22/2013
carol: 10/21/2013
carol: 5/20/2013
alopez: 11/1/2012
terry: 10/25/2012
terry: 8/30/2012
carol: 8/28/2012
carol: 5/31/2012
wwang: 10/30/2008
terry: 10/27/2008
carol: 10/17/2008
carol: 3/23/2007
carol: 2/28/2007
carol: 12/15/2006
alopez: 3/29/2006
alopez: 3/28/2006
carol: 3/17/2004
alopez: 3/5/2004
alopez: 3/4/2004
tkritzer: 11/20/2003
tkritzer: 11/19/2003
terry: 11/13/2003
carol: 4/2/2001
mgross: 3/21/2001
terry: 3/20/2001
carol: 2/28/2001
cwells: 2/28/2001
cwells: 2/27/2001
mgross: 11/22/1999
carol: 10/7/1999
dkim: 12/15/1998
carol: 8/27/1998
terry: 8/24/1998
dholmes: 5/11/1998
carol: 4/24/1998
terry: 4/14/1998
carol: 6/23/1997
terry: 12/5/1996
mark: 6/28/1995
supermim: 3/16/1992
carol: 6/10/1991
carol: 3/6/1991
supermim: 9/28/1990
supermim: 3/20/1990

MIM 604219
*RECORD*
*FIELD* NO
604219
*FIELD* TI
#604219 CATARACT 9, MULTIPLE TYPES; CTRCT9
;;CATARACT 9, MULTIPLE TYPES, WITH OR WITHOUT MICROCORNEA;;
read moreCATARACT, AUTOSOMAL DOMINANT;;
CATARACT, AUTOSOMAL RECESSIVE CONGENITAL 1; CATC1
*FIELD* TX
A number sign (#) is used with this entry because multiple types of
cataract (CTRCT9) are caused by heterozygous or homozygous mutation in
the CRYAA gene (123580), which encodes alpha-A-crystallin, on chromosome
21q22.

DESCRIPTION

Mutations in the CRYAA gene have been found to cause multiple types of
cataract, which have been described as nuclear, zonular central nuclear,
laminar, lamellar, anterior polar, posterior polar, cortical, embryonal,
anterior subcapsular, fan-shaped, and total. Cataract associated with
microcornea, sometimes called the cataract-microcornea syndrome, is also
caused by mutation in the CRYAA gene. Both autosomal dominant and
autosomal recessive modes of inheritance have been reported. The symbol
CATC1 was formerly used for the autosomal recessive form of cataract
caused by mutation in the CRYAA gene.

CLINICAL FEATURES

Litt et al. (1998) studied a 4-generation family with autosomal dominant
congenital cataracts that had been described as congenital zonular
central nuclear opacities. In 5 of the 13 affected family members, the
cataracts were also associated with microphthalmia and microcornea. As
adults in their thirties, patients developed cortical and posterior
subcapsular cataracts as well. The time of surgery had varied from
infancy to late childhood. Visual acuity following surgery had been as
good as 20/40 in older adults, but several patients had poor vision in
each eye associated with nystagmus. Other sequelae common in this family
included amblyopia, strabismus, and glaucoma.

Pras et al. (2000) reported 3 sibs from an inbred Jewish Persian family
with autosomal recessive congenital cataract. The patients underwent
cataract extraction in the first 3 months of life, and no details of the
pathologic findings in the lens were available.

Mackay et al. (2003) described a 4-generation Caucasian family
segregating an autosomal dominant form of 'nuclear' cataract presenting
at birth or during infancy and confined to the central zone or fetal
nucleus of the lens. Haplotype analysis indicated that the disease gene
lay in the physical interval between 2 markers flanking the CRYAA gene.

Shafie et al. (2006) examined affected members of 4 Chilean families
segregating autosomal dominant cataract and found significant
intrafamilial variation with respect to morphology, location within the
lens, color, and density. In family 'ADC51,' affected members had
cataracts in variable locations within the lens and of different
densities; the authors documented interocular asymmetry of density and
location and progression. The cataracts included nuclear opacities,
posterior subcapsular cataracts, and combinations, and 1 individual had
a dense white cataract. Two sisters in family 'ADC52' demonstrated
differences in morphology and location of cataract. In family 'ADC53,'
there were differences in cataract location, density of similar and
disparate opacities, morphology, and color among affected members, but
morphology and density were the same in each eye. Cataracts included
embryonal cataract of varying densities, pulverulent cortical opacities,
posterior star-shaped subcapsular cataract with pulverulent opacities in
the cortical or embryonal regions, and dense embryonal cataracts. Some
individuals described progression, although this was not documented by
the authors. Members of family 'ADC54' exhibited significant variability
in the morphology and density of the cataracts; 1 individual had
interocular differences in the color of opacities. Shafie et al. (2006)
concluded that significant intrafamilial variability in cataract
morphology and location within the lens is common in autosomal dominant
cataract.

Vanita et al. (2006) examined 10 affected and 9 unaffected members of a
large 4-generation family of Indian origin segregating autosomal
dominant congenital cataract and microcornea. The bilateral fan-shaped
cataracts were visible at birth and consisted of a round, oval, or
triangular opacity with irregular margins, approximately 3 mm wide,
topped by triangular opacities oriented with the base towards the
periphery. In a 6-year-old patient, the base of 1 of the triangular
opacities coincided with the edge of the fetal nucleus, whereas the 4
other triangular opacities extended beyond the edge of the fetal
nucleus. All affected individuals also had microcornea, with corneas
that were less than 10 mm in diameter. There were no other ocular
abnormalities detected in this family; in particular, no posterior
capsular, polar, or cortical opacities were observed in any of the
affected individuals.

Santhiya et al. (2006) described a 24-year-old Indian woman who had
decreasing vision beginning at age 17 and who was found to have total
opacity on slit-lamp examination, with severe loss of vision. There were
no other associated ocular anomalies of the anterior or posterior
segment. Her mother had undergone cataract surgery at age 35 years. Her
16-year-old brother denied any vision problems, but slit-lamp
examination revealed a peripheral ring-like opacity; he later reported
difficulty with distance vision.

Beby et al. (2007) reported 12 affected members of a 4-generation French
family with autosomal dominant cataract and iris coloboma. All affected
individuals had bilateral early-onset cataract, either present at birth
or developing during the first years of life, consisting of a single
dense axial opacity of 3 mm confined to the embryonic and fetal nuclei
of the lens and associated with bilateral iris coloboma in all patients.
Two affected individuals also had congenital microphthalmia. No
dysmorphic features, mental retardation, or developmental malformations
were observed.

Khan et al. (2007) studied a consanguineous Saudi Arabian family in
which 2 sisters and a brother had congenital total white cataract and
microcornea, with horizontal corneal diameters of approximately 8 mm at
2 years of age. Two of the 3 affected sibs developed bilateral aphakic
glaucoma within a few years of cataract surgery. Their parents and 7
sibs were asymptomatic, but a cousin was reported to have a similar
phenotype. None of the 3 affected sibs had any other significant medical
history, and all other members of the nuclear family had normal vision
and no ocular or systemic disease.

Laurie et al. (2013) described a 3-generation South Australian family
with lamellar cataract of variable severity. The proband was diagnosed
at 2 years of age with moderate fetal nuclear lamellar cataract with no
sutural involvement. His brother was diagnosed at 4.5 years of age with
a more severe phenotype, described as dense white nuclear cataract.
Their asymptomatic mother, maternal uncle, and maternal grandfather all
displayed mild lamellar opacity consisting of fine white dots in a
single lamellar shell; the uncle also had a cortical rider. These
opacities did not affect visual acuity and were only discovered on
examination following the children's diagnosis. The proband's 2 younger
sisters had no sign of cataract.

MAPPING

In a 4-generation family segregating autosomal dominant congenital
cataracts described as congenital zonular central nuclear opacities,
Litt et al. (1998) found linkage of the disorder, which they referred to
as ADCC-2, to chromosome 21q22.3.

In a 4-generation family of Indian origin segregating autosomal dominant
fan-shaped cataract and microcornea, Vanita et al. (2006) performed
genomewide linkage analysis and obtained 2-point lod scores of 2.833
with marker D21S1260 and 1.906 with D21S1259 (theta = 0 for both).
Further analysis gave a maximum lod score of 3.657 with marker D21S1411,
and multipoint analysis also supported linkage in this region of
chromosome 21, with a maximum lod score of 3.546 at D21S1411. Haplotype
analysis revealed recombination events that narrowed the critical region
to an interval on chromosome 21q22.3 that was at least 23.5 cM long.

In a consanguineous Saudi Arabian family with congenital total white
cataract and microcornea, Khan et al. (2007) obtained a lod score of 2.5
at chromosome 21q22.3, a region containing the candidate gene CRYAA.

MOLECULAR GENETICS

In affected members of a family segregating autosomal dominant
congenital cataracts mapping to chromosome 21q22.3, Litt et al. (1998)
sequenced the coding region of the CRYAA gene and identified a
heterozygous missense mutation (R116C; 123580.0001) that segregated with
the disorder.

Pras et al. (2000) identified homozygosity for a nonsense mutation in
the CRYAA gene (W9X; 123580.0002) in 3 sibs from an inbred Jewish
Persian family with autosomal recessive congenital cataract.

In a 4-generation Caucasian family segregating an autosomal dominant
form of 'nuclear' cataract presenting at birth or during infancy and
confined to the central zone or fetal nucleus of the lens, Mackay et al.
(2003) found by haplotype analysis that the disease locus lay in the
physical interval between 2 markers flanking the CRYAA gene. Sequence
analysis identified a missense mutation (R49C; 123580.0003) in the CRYAA
gene in affected individuals.

In a 4-generation family of Indian origin segregating autosomal dominant
fan-shaped cataract and microcornea mapping to chromosome 21q22.3,
Vanita et al. (2006) identified heterozygosity for the CRYAA R116C
missense mutation (123480.0001), previously found in a North American
family with a zonular type of congenital cataract (Litt et al., 1998).
Vanita et al. (2006) noted that despite an identical mutation, the
ocular phenotype was quite different in the 2 families, with the earlier
family exhibiting microphthalmia, amblyopia, strabismus, and glaucoma,
as well as development of cortical and posterior subcapsular cataracts
in the fourth decade of life.

In a sister and brother and their mother with progressive presenile
total cataract, Santhiya et al. (2006) analyzed functional candidate
genes and identified heterozygosity for a missense mutation in the CRYAA
gene (G98R; 123580.0005). The mutation was not found in their unaffected
father or sister, in 30 random DNA samples of Indian origin, or in 96
healthy German controls.

In 12 affected and 4 unaffected members of a 4-generation French family
with autosomal dominant cataract and iris coloboma, Beby et al. (2007)
analyzed microsatellites for 15 known cataract loci and found suggestive
linkage at the CRYAA locus on chromosome 21, as well as a specific
haplotype segregating with the disease. Sequence analysis of the CRYAA
gene revealed that all affected family members were heterozygous for the
R116C mutation; the mutation was not found in unaffected individuals.
Two affected individuals also had congenital microphthalmia; the authors
noted that Cryaa -/- mice have been found to have both microphthalmia
and cataract (Brady et al., 1997).

In 3 affected sibs from a consanguineous Saudi Arabian family with
congenital total white cataract and microcornea mapping to 21q22.3, Khan
et al. (2007) sequenced the candidate gene CRYAA and identified
homozygosity for a missense mutation (R54C; 123580.0006). Their
asymptomatic parents and 1 sib were found to be heterozygous for the
mutation; on slit-lamp examination, all 3 heterozygotes had similar
discernable but clinically insignificant bilateral punctate lenticular
opacities that were not present in the other asymptomatic family
members.

In 10 Danish families segregating autosomal dominant developmental
cataract and microcornea, Hansen et al. (2007) analyzed 9 candidate
genes and identified 5 families with heterozygous mutations, 3 of which
were in the CRYAA gene (123580.0007-123580.0009), 1 in the GJA8 gene
(600897.0008), and 1 in the CRYGD gene (123690.0008). Corneal diameters
varied between 8 and 10 mm. Nystagmus was present in some families and
absent in others, depending primarily on the degree of visual impairment
during the first months of life. Cataract phenotypes varied, but often
involved the nuclei, with cortical laminar elements and anterior and
posterior polar opacities to a variable extent; most cataracts had a
clear peripheral zone. In some patients, cataract progression during the
first years of life was noted.

Richter et al. (2008) studied 14 affected and 14 unaffected members of a
large 4-generation Chilean family, previously reported by Shafie et al.
(2006) as 'family ADC54,' segregating autosomal dominant cataract,
microcornea, and/or corneal opacity. Richter et al. (2008) found linkage
to chromosome 21 with a maximum lod score of 4.89 at D21S171, and
identified a heterozygous missense mutation in the CRYAA gene (R116H;
123580.0004) in affected members of the family. There was significant
asymmetry of density, morphology, and color of the cataracts within and
between affected individuals; the variable morphology included anterior
polar, cortical, embryonal, fan-shaped, and anterior subcapsular
cataracts. Richter et al. (2008) stated that, with the exception of iris
coloboma, the clinical features of all 6 previously reported families
with mutations in the CRYAA gene were found in this Chilean family.

In 4 unrelated South Australian families segregating autosomal dominant
cataract, Laurie et al. (2013) analyzed 10 known congenital
cataract-associated crystallin genes and identified a heterozygous
missense mutation in the CRYAA gene (R21Q; 123580.0010) in all affected
individuals from 1 of the families.

*FIELD* RF
1. Beby, F.; Commeaux, C.; Bozon, M.; Denis, P.; Edery, P.; Morle,
L.: New phenotype associated with an arg116-to-cys mutation in the
CRYAA gene. Arch. Ophthal. 125: 213-216, 2007.

2. Brady, J. P.; Garland, D.; Duglas-Tabor, Y.; Robison, W. G., Jr.;
Groome, A.; Wawrousek, E. F.: Targeted disruption of the mouse alpha
A-crystallin gene induces cataract and cytoplasmic inclusion bodies
containing the small heat shock protein alpha B-crystallin. Proc.
Nat. Acad. Sci. 94: 884-889, 1997.

3. Hansen, L.; Yao, W.; Eiberg, H.; Kjaer, K. W.; Baggersen, K.; Hejtmancik,
J. F.; Rosenberg, T.: Genetic heterogeneity in microcornea-cataract:
five novel mutations in CRYAA, CRYGD, and GJA8. Invest. Ophthal.
Vis. Sci. 48: 3937-3944, 2007.

4. Khan, A. O.; Aldahmesh, M. A.; Meyer, B.: Recessive congenital
total cataract with microcornea and heterozygote carrier signs caused
by a novel missense CRYAA mutation (R54C). Am. J. Ophthal. 144:
949-952, 2007.

5. Laurie, K. J.; Dave, A.; Straga, T.; Souzeau, E.; Chataway, T.;
Sykes, M. J.; Casey, T.; Teo, T.; Pater, J.; Craig, J. E.; Sharma,
S.; Burdon, K. P.: Identification of a novel oligomerization disrupting
mutation in CRYAA associated with congenital cataract in a South Australian
family. Hum. Mutat. 34: 435-438, 2013.

6. Litt, M.; Kramer, P.; LaMorticella, D. M.; Murphey, W.; Lovrien,
E. W.; Weleber, R. G.: Autosomal dominant congenital cataract associated
with a missense mutation in the human alpha crystallin gene CRYAA. Hum.
Molec. Genet. 7: 471-474, 1998.

7. Mackay, D. S.; Andley, U. P.; Shiels, A.: Cell death triggered
by a novel mutation in the alpha-A-crystallin gene underlies autosomal
dominant cataract linked to chromosome 21q. Europ. J. Hum. Genet. 11:
784-793, 2003.

8. Pras, E.; Frydman, M.; Levy-Nissenbaum, E.; Bakhan, T.; Raz, J.;
Assia, E. I.; Goldman, B.; Pras, E.: A nonsense mutation (W9X) in
CRYAA causes autosomal recessive cataract in an inbred Jewish Persian
family. Invest. Ophthal. Vis. Sci. 41: 3511-3515, 2000.

9. Richter, L.; Flodman, P.; Barria von-Bischhoffshausen, F.; Burch,
D.; Brown, S.; Nguyen, L.; Turner, J.; Spence, M. A.; Bateman, J.
B.: Clinical variability of autosomal dominant cataract, microcornea
and corneal opacity and novel mutation in the alpha A crystallin gene
(CRYAA). Am. J. Med. Genet. 146A: 833-842, 2008.

10. Santhiya, S. T.; Soker, T.; Klopp, N.; Illig, T.; Prakash, M.
V. S.; Selvaraj, B.; Gopinath, P. M.; Graw, J.: Identification of
a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian
family. Molec. Vis. 12: 768-773, 2006.

11. Shafie, S. M.; Barria von-Bischhoffshausen, F. R.; Bateman, J.
B.: Autosomal dominant cataract: intrafamilial phenotypic variability,
interocular asymmetry, and variable progression in four Chilean families. Am.
J. Ophthal. 141: 750-752, 2006.

12. Vanita, V.; Singh, J. R.; Hejtmancik, J. F.; Nurnberg, P.; Hennies,
H. C.; Singh, D.; Sperling, K.: A novel fan-shaped cataract-microcornea
syndrome caused by a mutation of CRYAA in an Indian family. Molec.
Vis. 12: 518-522, 2006.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Cataract, congenital, multiple types;
Cataract, zonular central nuclear;
Cataract, nuclear;
Cataract, lamellar;
Opacities in embryonal nuclei;
Cataract, anterior subcapsular;
Cataract, anterior polar;
Cataract, posterior polar;
Cataract, fan-shaped;
Cataract, posterior subcapsular;
Cataract, cortical;
Cataract, laminar;
Cataract, progressive (in some patients);
Cataract, total;
Cataract, presenile;
Microcornea (in some patients);
Coloboma of the iris (in some patients);
Microphthalmia (in some patients);
Decreased visual acuity;
Nystagmus;
Amblyopia;
Strabismus;
Glaucoma

MOLECULAR BASIS:
Caused by mutation in the alpha-A-crystallin gene (CRYAA, 123580.0001)

*FIELD* CD
Marla J. F. O'Neill: 11/5/2013

*FIELD* ED
joanna: 11/05/2013

*FIELD* CN
Marla J. F. O'Neill - updated: 10/21/2013
Marla J. F. O'Neill - updated: 5/20/2013
George E. Tiller - updated: 10/14/2009
Marla J. F. O'Neill - updated: 10/6/2008
Marla J. F. O'Neill - updated: 12/3/2007
Jane Kelly - updated: 12/3/2007
Marla J. F. O'Neill - updated: 5/4/2006

*FIELD* CD
Victor A. McKusick: 10/7/1999

*FIELD* ED
carol: 10/22/2013
carol: 10/21/2013
carol: 5/20/2013
alopez: 12/8/2010
carol: 10/14/2009
carol: 10/8/2008
carol: 10/6/2008
carol: 12/3/2007
carol: 11/15/2007
carol: 6/1/2006
carol: 5/4/2006
wwang: 12/28/2005
carol: 1/14/2003
carol: 10/16/2002
carol: 11/2/2000
carol: 9/1/2000
mcapotos: 7/24/2000
mcapotos: 7/20/2000
carol: 5/12/2000
alopez: 5/4/2000
alopez: 4/28/2000
terry: 4/27/2000
mgross: 11/22/1999
carol: 10/7/1999