RBCC Red Blood Cell Collection

GNAQ (GAQ) [Confidence: high (present in two of the MS resources)]
Guanine nucleotide-binding protein G(q) subunit alpha (Guanine nucleotide-binding protein alpha-q)

hRBCD IPI00288947
IPI00288947 Guanine nucleotide binding protein (G protein), q polypeptide Guanine nucleotide binding protein (G protein), q polypeptide membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a 2 n/a 1 1 2 1 n/a inner surface of plasma membrane n/a found at its expected molecular weight found at molecular weight

UniProt P50148
ID GNAQ_HUMAN Reviewed; 359 AA.
AC P50148; O15108; Q13462; Q6NT27; Q92471; Q9BZB9;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 07-JUL-2009, sequence version 4.
DT 22-JAN-2014, entry version 133.
DE RecName: Full=Guanine nucleotide-binding protein G(q) subunit alpha;
DE AltName: Full=Guanine nucleotide-binding protein alpha-q;
GN Name=GNAQ; Synonyms=GAQ;
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].
RX PubMed=8825633; DOI=10.1006/geno.1995.1267;
RA Dong Q., Shenker A., Way J., Haddad B.R., Lin K., Hughes M.R.,
RA McBride W.O., Spiegel A.M., Battey J.;
RT "Molecular cloning of human G alpha q cDNA and chromosomal
RT localization of the G alpha q gene (GNAQ) and a processed
RT pseudogene.";
RL Genomics 30:470-475(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Prostate;
RX PubMed=8664309; DOI=10.1016/0005-2736(96)00039-9;
RA Chen B., Leverette R.D., Schwinn D.A., Kwatra M.M.;
RT "Human G(alpha q): cDNA and tissue distribution.";
RL Biochim. Biophys. Acta 1281:125-128(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8836152;
RA Johnson G.J., Leis L.A., Dunlop P.C.;
RT "Specificity of G alpha q and G alpha 11 gene expression in platelets
RT and erythrocytes. Expressions of cellular differentiation and species
RT differences.";
RL Biochem. J. 318:1023-1031(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9700850; DOI=10.1016/S0049-3848(98)00071-1;
RA Gabbeta J., Dhanasekaran N., Rao A.K.;
RT "G alpha q cDNA sequence from human platelets.";
RL Thromb. Res. 91:29-32(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bai X.H., Acharya R., Rivera C., Murtagh J.J.;
RT "Nucleotide sequence of human Gq guanine nucleotide binding protein.";
RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 80-235.
RC TISSUE=Brain cortex;
RX PubMed=1333286; DOI=10.1016/0006-3223(92)90070-G;
RA Lesch K.-P., Manji H.K.;
RT "Signal-transducing G proteins and antidepressant drugs: evidence for
RT modulation of alpha subunit gene expression in rat brain.";
RL Biol. Psychiatry 32:549-579(1992).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 244-337.
RC TISSUE=Hematopoietic;
RX PubMed=7492305;
RA Thomas C.P., Dunn M.J., Mattera R.;
RT "Ca2+ signalling in K562 human erythroleukaemia cells: effect of
RT dimethyl sulphoxide and role of G-proteins in thrombin- and
RT thromboxane A2-activated pathways.";
RL Biochem. J. 312:151-158(1995).
RN [12]
RP INTERACTION WITH SLC9A3R1.
RX PubMed=12193606; DOI=10.1074/jbc.M207910200;
RA Rochdi M.D., Watier V., La Madeleine C., Nakata H., Kozasa T.,
RA Parent J.-L.;
RT "Regulation of GTP-binding protein alpha q (Galpha q) signaling by the
RT ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50).";
RL J. Biol. Chem. 277:40751-40759(2002).
RN [13]
RP INTERACTION WITH PECAM1.
RX PubMed=18672896; DOI=10.1021/bi8003846;
RA Yeh J.C., Otte L.A., Frangos J.A.;
RT "Regulation of G protein-coupled receptor activities by the platelet-
RT endothelial cell adhesion molecule, PECAM-1.";
RL Biochemistry 47:9029-9039(2008).
RN [14]
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 [15]
RP TISSUE SPECIFICITY.
RX PubMed=21923740; DOI=10.1111/j.1365-3083.2011.02635.x;
RA Wang Y., Li Y., He Y., Sun Y., Sun W., Xie Q., Yin G., Du Y., Wang L.,
RA Shi G.;
RT "Expression of G protein alphaq subunit is decreased in lymphocytes
RT from rheumatoid arthritis patients and is correlated with disease
RT activity.";
RL Scand. J. Immunol. 0:0-0(2011).
RN [16]
RP INVOLVEMENT IN CMC, VARIANT SWS GLN-183, AND CHARACTERIZATION OF
RP VARIANT SWS GLN-183.
RX PubMed=23656586; DOI=10.1056/NEJMoa1213507;
RA Shirley M.D., Tang H., Gallione C.J., Baugher J.D., Frelin L.P.,
RA Cohen B., North P.E., Marchuk D.A., Comi A.M., Pevsner J.;
RT "Sturge-Weber syndrome and port-wine stains caused by somatic mutation
RT in GNAQ.";
RL N. Engl. J. Med. 368:1971-1979(2013).
RN [17]
RP CHARACTERIZATION OF VARIANT LEU-209.
RX PubMed=19078957; DOI=10.1038/nature07586;
RA Van Raamsdonk C.D., Bezrookove V., Green G., Bauer J., Gaugler L.,
RA O'Brien J.M., Simpson E.M., Barsh G.S., Bastian B.C.;
RT "Frequent somatic mutations of GNAQ in uveal melanoma and blue
RT naevi.";
RL Nature 457:599-602(2009).
RN [18]
RP VARIANT GLN-183.
RX PubMed=22307269; DOI=10.1007/s00401-012-0948-x;
RA Murali R., Wiesner T., Rosenblum M.K., Bastian B.C.;
RT "GNAQ and GNA11 mutations in melanocytomas of the central nervous
RT system.";
RL Acta Neuropathol. 123:457-459(2012).
CC -!- FUNCTION: Guanine nucleotide-binding proteins (G proteins) are
CC involved as modulators or transducers in various transmembrane
CC signaling systems. Regulates B-cell selection and survival and is
CC required to prevent B-cell-dependent autoimmunity. Regulates
CC chemotaxis of BM-derived neutrophils and dendritic cells (in
CC vitro) (By similarity).
CC -!- SUBUNIT: G proteins are composed of 3 units; alpha, beta and
CC gamma. The alpha chain contains the guanine nucleotide binding
CC site. Binds SLC9A3R1. Forms a complex with PECAM1 and BDKRB2.
CC Interacts with PECAM1.
CC -!- INTERACTION:
CC P49407:ARRB1; NbExp=2; IntAct=EBI-3909604, EBI-743313;
CC P10276:RARA; NbExp=4; IntAct=EBI-3909604, EBI-413374;
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). Membrane (By
CC similarity). Nucleus membrane (By similarity). Note=Colocalizes
CC with the adrenergic receptors, ADREN1A and ADREN1B, at the nuclear
CC membrane of cardiac myocytes (By similarity).
CC -!- TISSUE SPECIFICITY: Predominantly expressed in ovary, prostate,
CC testis and colon. Down-regulated in the peripheral blood
CC lymphocytes (PBLs) of rheumatoid arthritis patients (at protein
CC level).
CC -!- DISEASE: Capillary malformations, congenital (CMC) [MIM:163000]: A
CC form of vascular malformations that are present from birth, tend
CC to grow with the individual, do not regress spontaneously, and
CC show normal rates of endothelial cell turnover. Capillary
CC malformations are distinct from capillary hemangiomas, which are
CC highly proliferative lesions that appear shortly after birth and
CC show rapid growth, slow involution, and endothelial
CC hypercellularity. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Sturge-Weber syndrome (SWS) [MIM:185300]: A syndrome
CC characterized by an intracranial vascular anomaly, leptomeningeal
CC angiomatosis, most often involving the occipital and posterior
CC parietal lobes. The most common features are facial cutaneous
CC vascular malformations (port-wine stains), seizures, and glaucoma.
CC Stasis results in ischemia underlying the leptomeningeal
CC angiomatosis, leading to calcification and laminar cortical
CC necrosis. The clinical course is highly variable and some children
CC experience intractable seizures, mental retardation, and recurrent
CC stroke-like episodes. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the G-alpha family. G(q) subfamily.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/GNAQID43280ch9q21.html";
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DR EMBL; U40038; AAC50363.1; -; mRNA.
DR EMBL; U43083; AAB06875.1; -; mRNA.
DR EMBL; L76256; AAB39498.1; -; mRNA.
DR EMBL; AF329284; AAG61117.1; -; mRNA.
DR EMBL; AF011496; AAB64301.1; -; mRNA.
DR EMBL; AF493896; AAM12610.1; -; mRNA.
DR EMBL; AL160268; CAI12198.1; -; Genomic_DNA.
DR EMBL; AL160278; CAI12198.1; JOINED; Genomic_DNA.
DR EMBL; AL355535; CAI12198.1; JOINED; Genomic_DNA.
DR EMBL; AL355535; CAI14669.1; -; Genomic_DNA.
DR EMBL; AL160268; CAI14669.1; JOINED; Genomic_DNA.
DR EMBL; AL160278; CAI14669.1; JOINED; Genomic_DNA.
DR EMBL; AL160278; CAI15999.1; -; Genomic_DNA.
DR EMBL; AL160268; CAI15999.1; JOINED; Genomic_DNA.
DR EMBL; AL355535; CAI15999.1; JOINED; Genomic_DNA.
DR EMBL; CH471089; EAW62607.1; -; Genomic_DNA.
DR EMBL; BC057777; AAH57777.1; -; mRNA.
DR EMBL; BC067850; AAH67850.1; -; mRNA.
DR EMBL; BC069520; AAH69520.1; -; mRNA.
DR EMBL; BC075096; AAH75096.1; -; mRNA.
DR EMBL; BC075097; AAH75097.1; -; mRNA.
DR EMBL; L40629; AAA99950.1; -; mRNA.
DR PIR; S59635; S59635.
DR PIR; S71963; S71963.
DR RefSeq; NP_002063.2; NM_002072.4.
DR UniGene; Hs.269782; -.
DR ProteinModelPortal; P50148; -.
DR SMR; P50148; 18-354.
DR IntAct; P50148; 9.
DR MINT; MINT-262439; -.
DR STRING; 9606.ENSP00000286548; -.
DR PhosphoSite; P50148; -.
DR DMDM; 251757492; -.
DR PaxDb; P50148; -.
DR PRIDE; P50148; -.
DR DNASU; 2776; -.
DR Ensembl; ENST00000286548; ENSP00000286548; ENSG00000156052.
DR GeneID; 2776; -.
DR KEGG; hsa:2776; -.
DR UCSC; uc004akw.3; human.
DR CTD; 2776; -.
DR GeneCards; GC09M080331; -.
DR HGNC; HGNC:4390; GNAQ.
DR HPA; CAB010036; -.
DR HPA; HPA048886; -.
DR MIM; 163000; phenotype.
DR MIM; 185300; phenotype.
DR MIM; 600998; gene.
DR neXtProt; NX_P50148; -.
DR Orphanet; 624; Nevi flammei.
DR Orphanet; 3205; Sturge-Weber syndrome.
DR PharmGKB; PA174; -.
DR eggNOG; NOG322962; -.
DR HOGENOM; HOG000038729; -.
DR HOVERGEN; HBG063184; -.
DR InParanoid; P50148; -.
DR KO; K04634; -.
DR OMA; LKISYGV; -.
DR OrthoDB; EOG7ZWD1W; -.
DR PhylomeDB; P50148; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; P50148; -.
DR ChiTaRS; GNAQ; human.
DR GeneWiki; GNAQ; -.
DR GenomeRNAi; 2776; -.
DR NextBio; 10922; -.
DR PRO; PR:P50148; -.
DR ArrayExpress; P50148; -.
DR Bgee; P50148; -.
DR CleanEx; HS_GNAQ; -.
DR Genevestigator; P50148; -.
DR GO; GO:0005834; C:heterotrimeric G-protein complex; IBA:RefGenome.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031683; F:G-protein beta/gamma-subunit complex binding; IBA:RefGenome.
DR GO; GO:0001664; F:G-protein coupled receptor binding; IBA:RefGenome.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0005096; F:GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0003924; F:GTPase activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004871; F:signal transducer activity; IBA:RefGenome.
DR GO; GO:0007202; P:activation of phospholipase C activity; TAS:ProtInc.
DR GO; GO:0007189; P:adenylate cyclase-activating G-protein coupled receptor signaling pathway; IBA:RefGenome.
DR GO; GO:0007610; P:behavior; IEA:Ensembl.
DR GO; GO:0048066; P:developmental pigmentation; IEA:Ensembl.
DR GO; GO:0042733; P:embryonic digit morphogenesis; IEA:Ensembl.
DR GO; GO:0021884; P:forebrain neuron development; IEA:Ensembl.
DR GO; GO:0007215; P:glutamate receptor signaling pathway; IBA:RefGenome.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; IMP:BHF-UCL.
DR GO; GO:0016322; P:neuron remodeling; IEA:Ensembl.
DR GO; GO:0060158; P:phospholipase C-activating dopamine receptor signaling pathway; IBA:RefGenome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0050821; P:protein stabilization; IMP:BHF-UCL.
DR GO; GO:0001508; P:regulation of action potential; IBA:RefGenome.
DR GO; GO:0035412; P:regulation of catenin import into nucleus; IMP:BHF-UCL.
DR GO; GO:0045634; P:regulation of melanocyte differentiation; IEA:Ensembl.
DR GO; GO:0001501; P:skeletal system development; IEA:Ensembl.
DR Gene3D; 1.10.400.10; -; 1.
DR InterPro; IPR000654; Gprotein_alpha_Q.
DR InterPro; IPR001019; Gprotein_alpha_su.
DR InterPro; IPR011025; GproteinA_insert.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR10218; PTHR10218; 1.
DR Pfam; PF00503; G-alpha; 1.
DR PRINTS; PR00318; GPROTEINA.
DR PRINTS; PR00442; GPROTEINAQ.
DR SMART; SM00275; G_alpha; 1.
DR SUPFAM; SSF47895; SSF47895; 1.
DR SUPFAM; SSF52540; SSF52540; 2.
PE 1: Evidence at protein level;
KW ADP-ribosylation; Complete proteome; Disease mutation; GTP-binding;
KW Lipoprotein; Magnesium; Membrane; Metal-binding; Nucleotide-binding;
KW Nucleus; Palmitate; Polymorphism; Reference proteome; Transducer.
FT CHAIN 1 359 Guanine nucleotide-binding protein G(q)
FT subunit alpha.
FT /FTId=PRO_0000203760.
FT NP_BIND 46 53 GTP (By similarity).
FT NP_BIND 180 186 GTP (By similarity).
FT NP_BIND 205 209 GTP (By similarity).
FT NP_BIND 274 277 GTP (By similarity).
FT METAL 53 53 Magnesium (By similarity).
FT METAL 186 186 Magnesium (By similarity).
FT BINDING 331 331 GTP; via amide nitrogen (By similarity).
FT MOD_RES 183 183 ADP-ribosylarginine; by cholera toxin (By
FT similarity).
FT LIPID 9 9 S-palmitoyl cysteine (By similarity).
FT LIPID 10 10 S-palmitoyl cysteine (By similarity).
FT VARIANT 183 183 R -> Q (in SWS; found as somatic mosaic
FT mutation in CMC; also found in
FT melanocytomas sample; somatic mutation;
FT shows significant activation of EPHB2
FT compared to control).
FT /FTId=VAR_067270.
FT VARIANT 209 209 Q -> L (found in blue naevi and uveal
FT melanoma samples; somatic mutation;
FT constitutive activation).
FT /FTId=VAR_067271.
FT VARIANT 355 355 E -> D (in dbSNP:rs1059531).
FT /FTId=VAR_059319.
FT CONFLICT 4 4 E -> D (in Ref. 5; AAB64301).
FT CONFLICT 28 29 QL -> HV (in Ref. 1; AAC50363).
FT CONFLICT 92 92 R -> T (in Ref. 5; AAB64301).
FT CONFLICT 103 103 Y -> C (in Ref. 5; AAB64301).
FT CONFLICT 324 324 I -> N (in Ref. 2; AAB06875).
FT CONFLICT 337 337 I -> V (in Ref. 5; AAB64301).
FT CONFLICT 358 358 L -> A (in Ref. 3; AAB39498).
SQ SEQUENCE 359 AA; 42142 MW; 6F69C4F617DFA7C7 CRC64;
MTLESIMACC LSEEAKEARR INDEIERQLR RDKRDARREL KLLLLGTGES GKSTFIKQMR
IIHGSGYSDE DKRGFTKLVY QNIFTAMQAM IRAMDTLKIP YKYEHNKAHA QLVREVDVEK
VSAFENPYVD AIKSLWNDPG IQECYDRRRE YQLSDSTKYY LNDLDRVADP AYLPTQQDVL
RVRVPTTGII EYPFDLQSVI FRMVDVGGQR SERRKWIHCF ENVTSIMFLV ALSEYDQVLV
ESDNENRMEE SKALFRTIIT YPWFQNSSVI LFLNKKDLLE EKIMYSHLVD YFPEYDGPQR
DAQAAREFIL KMFVDLNPDS DKIIYSHFTC ATDTENIRFV FAAVKDTILQ LNLKEYNLV
//

MIM 163000
*RECORD*
*FIELD* NO
163000
*FIELD* TI
#163000 CAPILLARY MALFORMATIONS, CONGENITAL; CMC
;;NEVI FLAMMEI, FAMILIAL MULTIPLE;;
read morePORT-WINE STAIN;;
CAPILLARY MALFORMATIONS; CMAL
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
congenital capillary malformations can be caused by somatic mosaic
mutation in the GNAQ gene (600998) on chromosome 9q21.

Sturge-Weber syndrome (185300), which includes port-wine stains, is also
caused by somatic mosaic mutation in the GNAQ gene.

DESCRIPTION

Capillary malformations are a form of vascular malformation that are
present from birth, tend to grow with the individual, do not regress
spontaneously, and show normal rates of endothelial cell turnover.
Capillary malformations are distinct from capillary hemangiomas
(602089), which are highly proliferative lesions that appear shortly
after birth and show rapid growth, slow involution, and endothelial
hypercellularity (Spring and Bentz, 2005; Legiehn and Heran, 2006).

CLINICAL FEATURES

Referred to as birthmarks, nevi flammei consist of dark red,
nonelevated, sharply circumscribed patches which blanch on pressure with
a glass, leaving a residual brown hyperpigmentation. Nevus flammeus is a
frequent birthmark in the newborn infant, especially located in the
central forehead; it fades spontaneously over a few months or years, as
a rule. Shuper et al. (1984) referred to this lesion in the newborn as
salmon patch and stated that it is incorrect to call it nevus flammeus.

The proposita of the family described by Shuper et al. (1984) had 5 nevi
flammei, 2 on her neck, 2 on her arms, and a very large purple one on
her right groin and upper leg. Selmanowitz (1968) described a family
with nevus flammeus of the forehead. Association with Unna nevus
(163100) in several members of a family was reported by Merlob and
Reisner (1985).

In the family reported by Breugem et al. (2002), 12 members were
affected and 11 were examined. The proband was a 6-year-old girl with a
capillary malformation on the upper part of the left leg measuring 31 x
27 cm. She had several smaller capillary malformations on both feet and
the left arm. The mother had several capillary malformations on her
right arm, inside her left lower arm, and on her right lower leg. The
sister of the proband had a large capillary malformations (30 x 30 cm)
on her right upper leg. Several smaller capillary malformations were
seen all over her body. The deceased grandmother was reported to have
multiple small capillary malformations on her thorax. An uncle of the
proband had a large capillary malformation on the anterolateral side of
his left upper leg (30 x 30 cm) and a smaller capillary malformation on
the anterior side of his left lower leg (10 x 5 cm). When he was 9 years
old, he had an overgrowth of this leg with a 9-cm difference in leg
length, which was subsequently treated with an epiphysodesis. As a
result, that leg was 0.5 cm shorter when he was an adult, but the
difference in leg circumference remained unchanged. He had no symptoms
indicative of Klippel-Trenaunay syndrome (149000).

Of 60 subjects with inherited capillary malformation from 13 families
studied by Eerola et al. (2002), 19 had a lesion on the face, 15 in the
nuchal region, and 26 in other parts of the body.

INHERITANCE

Shelley and Livingood (1949) described 12 cases in 7 sibships in 4
generations of a family, with 5 instances of male-to-male transmission.
Two generations were skipped in one branch of the family.

In a family reported by Shuper et al. (1984), affected persons occurred
in 3 generations and by inference someone in a fourth (earliest)
generation may have been affected or at least had the gene.

Among 280 consecutive new patients with port-wine stains applying for
laser treatment, van der Horst et al. (1999) stated that 55 (19.6%)
mentioned relatives with the same anomaly. They constructed pedigrees of
32 families with 2 or more affected members, including probands. They
presented 9 representative pedigrees with 3 or more affected members.
They concluded that no clear mode of inheritance could be discerned,
although the family displayed in their Figure 1 was consistent with
autosomal dominant inheritance, including male-to-male transmission.

MAPPING

Breugem et al. (2002) described a family with capillary malformations
occurring in members of 3 generations. By linkage they mapped the trait
to 5q13-q22, in a region spanning 48 cM between markers D5S647 and
D5S659. They cited the position of Mulliken and Young (1988), who
suggested that vascular tumors (hemangiomas) and vascular malformations
represent 2 separate categories. However, the fact that infantile
capillary hemangioma also maps to 5q, although in a slightly different
area, raises the question of whether they may not be fundamentally the
same.

Eerola et al. (2002) studied 13 families with inherited capillary
malformation. A genome scan was performed in the 6 most informative
families. Capillary malformation segregated as a dominant trait with
evidence for incomplete penetrance and phenotypic variation. A
non-parametric multipoint linkage analysis gave strong evidence of
linkage to chromosome 5q. By adding 7 additional small families, a 69-cM
region of linkage was obtained between markers D5S407 and D5S2098 with a
maximum Z score of 6.72. Parametric linkage analysis gave a maximum hlod
of 4.84 at marker D5S2044 on 5q15. When the 4 unlinked families were
excluded from linkage analysis, a maximum multipoint lod score of 7.22
was obtained at D5S2044, and the most likely linked region covered 23 cM
between markers D5S1962 and D5S652 corresponding to 5q13-q15. This locus
was designated CMC1.

HETEROGENEITY

Eerola et al. (2003) screened 17 families with cutaneous capillary
malformations for mutations in the RASA1 gene (139150). In 6 of these
families, manifesting an association of atypical capillary malformations
with either arteriovenous malformation, arteriovenous fistula, or Parkes
Weber syndrome (608355), they found RASA1 mutations; they named this
association CM-AVM for 'capillary malformation-arteriovenous
malformation'; see 608354. In 11 of these families no mutation in the
RASA1 gene was found, indicating genetic heterogeneity.

MOLECULAR GENETICS

In affected skin from 12 (92%) of 13 patients with nonsyndromic
port-wine stains, Shirley et al. (2013) detected the presence of a
somatic gain-of-function missense mutation in the GNAQ gene (R183Q;
600998.0001). The R183Q mutation was also found in either
port-wine-stained skin or brain tissue from 23 (88%) of 26 patients with
Sturge-Weber syndrome (185300). Shirley et al. (2013) suggested that
nonsyndromic port-wine stains may represent a late origin of the somatic
GNAQ mutation in vascular endothelial cells, whereas in Sturge-Weber
syndrome, the mutation may occur earlier in development, in progenitor
cells that are precursors to a larger variety of cell types and tissues,
leading to the syndromic phenotype. Five (0.7%) of 669 samples from the
1000 Genomes database were positive for R183Q; noting that the reported
prevalence of port-wine stains is 0.3% to 0.5%, Shirley et al. (2013)
hypothesized that the 0.7% prevalence in that database represented the
occurrence of port-wine stains in the population.

*FIELD* RF
1. Breugem, C. C.; Alders, M.; Salieb-Beugelaar, G. B.; Mannens, M.
M. A. M.; Van Der Horst, C. M.; Hennekam, R. C. M.: A locus for hereditary
capillary malformations mapped on chromosome 5q. Hum. Genet. 110:
343-347, 2002.

2. Eerola, I.; Boon, L. M.; Mulliken, J. B.; Burrows, P. E.; Dompmartin,
A.; Watanabe, S.; Vanwijck, R.; Vikkula, M.: Capillary malformation-arteriovenous
malformation, a new clinical and genetic disorder caused by RASA1
mutations. Am. J. Hum. Genet. 73: 1240-1249, 2003.

3. Eerola, I.; Boon, L. M.; Watanabe, S.; Grynberg, H.; Mulliken,
J. B.; Vikkula, M.: Locus for susceptibility for familial capillary
malformation ('port-wine stain') maps to 5q. Europ. J. Hum. Genet. 10:
375-380, 2002.

4. Legiehn, G. M.; Heran, M. K. S.: Classification, diagnosis, and
interventional radiologic management of vascular malformations. Orthop.
Clin. N. Am. 37: 435-474, 2006.

5. Merlob, P.; Reisner, S. H.: Familial nevus flammeus of the forehead
and Unna's nevus. Clin. Genet. 27: 165-166, 1985.

6. Mulliken, J. B.; Young, A. E. (eds.): Vascular Birthmarks: Hemangiomas
and Vascular Malformations. Philadelphia: W. B. Saunders Co. , 1988.

7. Selmanowitz, V. J.: Nevus flammeus of the forehead. J. Pediat. 73:
755-757, 1968.

8. Shelley, W. B.; Livingood, C. S.: Familial multiple nevi flammei. Arch.
Derm. Syph. 59: 343-345, 1949.

9. Shirley, M. D.; Tang, H.; Gallione, C. J.; Baugher, J. D.; Frelin,
L. P.; Cohen, B.; North, P. E.; Marchuk, D. A.; Comi, A. M.; Pevsner,
J.: Sturge-Weber syndrome and port-wine stains caused by somatic
mutation in GNAQ. New Eng. J. Med. 368: 1971-1979, 2013.

10. Shuper, A.; Merlob, P.; Garty, B.; Varsano, I.: Familial multiple
naevi flammei. J. Med. Genet. 21: 112-113, 1984.

11. Spring, M. A.; Bentz, M. L.: Cutaneous vascular lesions. Clin.
Plast. Surg. 32: 171-186, 2005.

12. van der Horst, C. M. A. M.; van Eijk, T. G. J.; de Borgie, C.
A. J. M.; Koster, P. H. L.; Struycken, P. M.; Strackee, S. D.: Hereditary
port-wine stains, do they exist? Lasers Med. Sci. 14: 238-243, 1999.

*FIELD* CS

Skin:
Multiple nevi flammei;
Port-wine stain

Inheritance:
Autosomal dominant

*FIELD* CN
Marla J. F. O'Neill - updated: 6/5/2013
Cassandra L. Kniffin - updated: 12/5/2008
Anne M. Stumpf - updated: 12/19/2003
Victor A. McKusick - updated: 12/18/2003
Michael B. Petersen - updated: 1/13/2003
Victor A. McKusick - updated: 5/10/2002
Victor A. McKusick - updated: 1/24/2000

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 10/16/2013
carol: 6/5/2013
wwang: 12/8/2008
ckniffin: 12/5/2008
joanna: 3/18/2004
alopez: 12/19/2003
terry: 12/18/2003
cwells: 1/13/2003
joanna: 6/3/2002
cwells: 5/29/2002
cwells: 5/20/2002
terry: 5/10/2002
carol: 1/30/2000
terry: 1/24/2000
mimadm: 12/2/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
marie: 12/15/1986

MIM 185300
*RECORD*
*FIELD* NO
185300
*FIELD* TI
#185300 STURGE-WEBER SYNDROME; SWS
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreSturge-Weber syndrome can be caused by somatic mosaic mutation in the
GNAQ gene (600998) on chromosome 9q21.

Nonsyndromic port-wine stains (CMC; 163000) are also caused by somatic
mosaic mutation in the GNAQ gene.

DESCRIPTION

Sturge-Weber syndrome is characterized by an intracranial vascular
anomaly, leptomeningeal angiomatosis, most often involving the occipital
and posterior parietal lobes. The most common symptoms and signs are
facial cutaneous vascular malformations (port-wine stains), seizures,
and glaucoma. Stasis results in ischemia underlying the leptomeningeal
angiomatosis, leading to calcification and laminar cortical necrosis.
The clinical course is highly variable and some children experience
intractable seizures, mental retardation, and recurrent stroke-like
episodes (review by Thomas-Sohl et al., 2004).

CLINICAL FEATURES

The Klippel-Trenaunay-Weber syndrome (149000) is sometimes associated
with SWS (see Bonse, 1951 and Nonnenmacher, 1955).

Debicka and Adamczak (1979) described Sturge-Weber syndrome in father
and son, both of whom had, in addition to trigeminal angiomatous nevi,
evidence of central nervous system involvement. The son had congenital
glaucoma and the father had simple glaucoma. All manifestations were
more pronounced in the son.

Sujansky and Conradi (1995) reviewed the outcome in 52 adults, aged 18
to 63 years, ascertained through the Sturge-Weber Foundation, and
surveyed by written questionnaires, telephone interviews, and review of
medical records. The distribution of port-wine stains (cranial 98%,
extracranial 52%) and the prevalence of glaucoma (60%), seizures (83%),
neurologic deficit (65%), and other complications were established. The
age of onset of glaucoma varied from birth to 41 years and the age of
onset of seizures from birth to 23 years. In those with and those
without seizures, the prevalence of developmental delay (43% vs 0%),
emotional and behavioral problems (85% vs 58%), special education
requirements (71% vs 0%), and employability (46% vs 48%) was determined.
Overall, 39% were financially self sufficient. Ten participants produced
20 liveborn offspring; 17 were healthy, and tuberous sclerosis, a
cafe-au-lait spot, and a 'birthmark' were found in 1 child each.

Griffiths et al. (1996) found enlargement of the choroid plexus in the
hemisphere affected with SWS in an MRI study of 15 children.

Another ocular manifestation of SWS is circumscribed choroidal
hemangioma (CCH). Porrini et al. (2003) found that photodynamic therapy
in 10 SWS patients with symptomatic CCH of the posterior pole resulted
in improved visual acuity in all.

Quigg et al. (2006) presented photographs and brain images of an infant
with SWS. The patient had a bilateral ophthalmologic port-wine stain in
the trigeminal distribution and an extracranial nevus on the chest.
Bilateral or more lower facial involvement occurs in 15% of patients
with SWS. Head radiograph showed gyral calcifications of a subarachnoid
angioma across most of the right hemisphere. Quigg et al. (2006) noted
that leptomeningeal involvement often leads to hemiparesis, mental
retardation, and epilepsy.

Among 21 children aged 18 months to 10 years with SWS and unilateral
cerebral hemispheric involvement, Juhasz et al. (2007) found a
significant correlation between decreased white matter volume in the
affected hemisphere and cognitive decline. There was no correlation with
gray matter volume. The authors hypothesized that white matter
abnormalities in SWS may be due to hypoxic injury secondary to impaired
venous drainage. Cognitive impairment was not related to seizures.

Hall et al. (2007) reported 6 patients with phakomatosis
pigmentovascularis type II, consisting of nevus flammeus and mongolian
spots; 2 patients were diagnosed with Klippel-Trenaunay syndrome, and 3
had features consistent with both Klippel-Trenaunay and Sturge-Weber
syndromes. There were 4 patients with macrocephaly and 1 with
microcephaly; 4 patients had CNS abnormalities, including 3 with
hydrocephalus, 1 with Arnold-Chiari malformation, and 1 with
polymicrogyria; 3 patients had mental retardation; and 1 patient had
seizures. Hall et al. (2007) suggested that in the presence of
persistent, extensive, and aberrant mongolian spots, the vascular
abnormalities of Klippel-Trenaunay and Sturge-Weber syndromes carry a
worse prognosis.

BIOCHEMICAL FEATURES

Using PET scans to correlate cortical glucose hypometabolism with
clinical features in 13 children with unilateral cerebral SWS, Lee et
al. (2001) found that the extent and degree of glucose asymmetry were
sensitive markers of seizure severity and cognitive decline. Both
seizure frequency and lifetime number of seizures showed a positive
correlation with area of mildly asymmetric cortical hypometabolism,
suggesting a nociferous effect on the remainder of the brain. Patients
with a higher IQ had a larger area of severely asymmetric cortical
metabolism, suggesting early functional reorganization.

PATHOGENESIS

Tyzio et al. (2009) reported the histopathologic findings of brain
tissue derived from 4 pediatric SWS patients who underwent surgical
hemispherectomy for refractory epilepsy at a mean age of 10.5 months.
There were changes in cortical layering, with neuronal degeneration and
loss, with many neurons containing perinuclear chromatin aggregates and
nuclear condensation. Gray matter contained irregular vascular
dilatations and calcifications. Neurons had small soma and dendrites
that were tiny and poorly branched, reflecting a reduced degree of
neuronal maturation. These findings were consistent with an
ischemic/hypoxic process. Electrophysiologic studies showed that neurons
had spontaneous activity and a more depolarized resting membrane
potential, indicative of increased excitability. Studies of GABA
channels indicated that they had an inhibitory and anticonvulsive effect
on SWS neurons.

INHERITANCE

Unlike the other phacomatoses, including tuberous sclerosis (see
191100), neurofibromatosis (see 162200), and von Hippel-Lindau disease
(193300), no clear evidence of heredity has been discovered in SWS.

Happle (1987) suggested that somatic mosaicism underlies the
pathogenesis of lesions in SWS and certain other disorders.

In 4 patients with SWS, Huq et al. (2002) compared the chromosomes in
cells from affected areas with those from unaffected areas. In 1
patient, a paracentric inversion of chromosome 4q was present in 40% of
cells cultured from leptomeningeal angiomatosis, but the inversion was
not present in cells cultured from the patient's blood. In a second
patient, approximately 50% of cells from a port-wine stain showed
trisomy 10, whereas this abnormality was not present in the patient's
blood or normal skin.

Comi et al. (2003) compared fibronectin gene and protein expression from
port-wine-derived fibroblasts compared with that from normal
skin-derived fibroblasts of 4 individuals with SWS. The gene expression
of fibronectin was significantly increased in the SWS port-wine-derived
fibroblasts compared with that of fibroblasts from SWS normal skin. Comi
et al. (2003) concluded that the reproducible differences in fibronectin
gene expression between the 2 sets of fibroblasts are consistent with
the presence of a hypothesized somatic mutation underlying SWS.

MOLECULAR GENETICS

Shirley et al. (2013) performed whole-genome sequencing of DNA from
paired samples of visibly affected and normal tissue from 3 SWS patients
and identified 1 nonsynonymous somatic single-nucleotide variant in the
GNAQ gene (R183Q; 600998.0001) that was present in all 3 affected
samples and was not present in the normal-appearing samples. Screening
of additional SWS patients as well as individuals with nonsyndromic
port-wine stains (163000) revealed that all 9 SWS patients were positive
for the R183Q mutation in port-wine-stained skin, 6 (86%) of 7
participants with SWS were negative for the mutation in visibly normal
skin, and 12 (92%) of 13 participants with nonsyndromic port-wine stains
were positive for the mutation. The mutation was also detected in brain
samples from 15 (83%) of 18 SWS patients, whereas all 6 brain samples
from normal controls were negative. Overall, 23 (88%) of 26 SWS patients
were positive for the gain-of-function R183Q mutation in either
port-wine-stained skin or brain tissue. Shirley et al. (2013) suggested
that nonsyndromic port-wine stains may represent a late origin of the
somatic GNAQ mutation in vascular endothelial cells, whereas in
Sturge-Weber syndrome, the mutation may occur earlier in development, in
progenitor cells that are precursors to a larger variety of cell types
and tissues, leading to the syndromic phenotype. Five (0.7%) of 669
samples from the 1000 Genomes database were positive for R183Q; noting
that the reported prevalence of port-wine stains is 0.3% to 0.5%,
Shirley et al. (2013) hypothesized that the 0.7% prevalence in that
database represented the occurrence of port-wine stains in the
population.

*FIELD* SA
Furukawa et al. (1970)
*FIELD* RF
1. Bonse, G.: Roentgenbefunde bei einer Phakomatose (Sturge-Weber
kombiniert mit Klippel-Trenaunay). Fortschr. Roentgenstr. 74: 727,
1951.

2. Comi, A. M.; Hunt, P.; Vawter, M. P.; Pardo, C. A.; Becker, K.
G.; Pevsner, J.: Increased fibronectin expression in Sturge-Weber
syndrome fibroblasts and brain tissue. Pediat. Res. 53: 762-769,
2003.

3. Debicka, A.; Adamczak, P.: Przypadek dziedziczenia zespolu Sturge'a-Webera. Klin.
Oczna 81: 541-542, 1979.

4. Furukawa, T.; Igata, A.; Toyokura, Y.; Ikeda, S.: Sturge-Weber
and Klippel-Trenaunay syndrome with nevus of Ota and Ito. Arch. Derm. 102:
640-645, 1970.

5. Griffiths, P. D.; Blaser, S.; Boodram, M. B.; Armstrong, D.; Harwood-Nash,
D.: Choroid plexus size in young children with Sturge-Weber syndrome. Am.
J. Neuroradiol. 17: 175-180, 1996.

6. Hall, B. D.; Cadle, R. G.; Morrill-Cornelius, S. M.; Bay, C. A.
: Phakomatosis pigmentovascularis: implications for severity with
special reference to mongolian spots associated with Sturge-Weber
and Klippel-Trenaunay syndromes. Am. J. Med. Genet. 143A: 3047-3053,
2007. Note: Erratum: Am. J. Med. Genet. 146A: 945-951, 2008.

7. Happle, R.: Lethal genes surviving by mosaicism: a possible explanation
for sporadic birth defects involving the skin. J. Am. Acad. Derm. 16:
899-906, 1987.

8. Huq, A. H. M. M.; Chugani, D. C.; Hukku, B.; Serajee, F. J.: Evidence
of somatic mosaicism in Sturge-Weber syndrome. Neurology 59: 780-782,
2002.

9. Juhasz, C.; Lai, C.; Behen, M. E.; Muzik, O.; Helder, E. J.; Chugani,
D. C.; Chugani, H. T.: White matter volume as a major predictor of
cognitive function in Sturge-Weber syndrome. Arch. Neurol. 64: 1169-1174,
2007.

10. Lee, J. S.; Asano, E.; Muzik, O.; Chugani, D. C.; Juhasz, C.;
Pfund, Z.; Philip, S.; Behen, M.; Chugani, H. T.: Sturge-Weber syndrome:
correlation between clinical course and FDG PET findings. Neurology 57:
189-195, 2001.

11. Nonnenmacher, H.: Augenaerztliche Betrachtungen zum Symptomenkomplex
morbus Sturge-Weber, Klippel-Trenaunay und Parkes-Weber. Klin. Monatsbl.
Augenheilkd. 126: 154-164, 1955.

12. Porrini, G.; Giovannini, A.; Amato, G.; Ioni, A.; Pantanetti,
M.: Photodynamic therapy of circumscribed choroidal hemangioma. Ophthalmology 110:
674-680, 2003.

13. Quigg, M.; Rust, R. S.; Miller, J. Q.: Clinical findings of the
phakomatoses: Sturge-Weber syndrome. Neurology 66: E17-E18, 2006.

14. Shirley, M. D.; Tang, H.; Gallione, C. J.; Baugher, J. D.; Frelin,
L. P.; Cohen, B.; North, P. E.; Marchuk, D. A.; Comi, A. M.; Pevsner,
J.: Sturge-Weber syndrome and port-wine stains caused by somatic
mutation in GNAQ. New Eng. J. Med. 368: 1971-1979, 2013.

15. Sujansky, E.; Conradi, S.: Outcome of Sturge-Weber syndrome in
52 adults. Am. J. Med. Genet. 57: 35-45, 1995.

16. Thomas-Sohl, K.; Vaslow, D.; Maria, B.: Sturge-Weber syndrome:
a review. Pediat. Neurol. 30: 303-310, 2004.

17. Tyzio, R.; Khalilov, I.; Represa, A.; Crepel, V.; Zilberter, Y.;
Rheims, S.; Aniksztejn, L.; Cossart, R.; Nardou, R.; Mukhtarov, M.;
Minlebaev, M.; Epsztein, J.; and 11 others: Inhibitory actions
of the gamma-aminobutyric acid in pediatric Sturge-Weber syndrome. Ann.
Neurol. 66: 209-218, 2009.

*FIELD* CS
INHERITANCE:
Isolated cases

HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
Facial hemangiomata;
[Eyes];
Choroidal hemangiomata;
Glaucoma;
Buphthalmos

SKIN, NAILS, HAIR:
[Skin];
Hemangiomata in at least first branch (ophthalmic) of trigeminal nerve
distribution, unilateral, occasionally bilateral

NEUROLOGIC:
[Central nervous system];
Arachnoid hemangiomata;
Cerebral cortical atrophy;
Mental retardation;
Seizures;
'Double contour' convolutional calcification on CT scan

MOLECULAR BASIS:
Caused by somatic mosaic mutation in the guanine nucleotide-binding
protein q gene (GNAQ, 600998.0001)

*FIELD* CN
Marla J. F. O'Neill - updated: 07/31/2013
Kelly A. Przylepa - revised: 12/4/1999

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

*FIELD* ED
joanna: 07/31/2013
joanna: 7/23/2013
joanna: 1/13/2000
joanna: 12/4/1999

*FIELD* CN
Marla J. F. O'Neill - updated: 6/5/2013
Cassandra L. Kniffin - updated: 1/28/2011
Marla J. F. O'Neill - updated: 10/27/2008
Cassandra L. Kniffin - updated: 3/31/2008
Cassandra L. Kniffin - updated: 6/25/2007
Natalie E. Krasikov - updated: 12/19/2003
Jane Kelly - updated: 6/18/2003
Victor A. McKusick - updated: 11/19/2002
Cassandra L. Kniffin - updated: 10/14/2002
Orest Hurko - updated: 4/1/1996

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 10/16/2013
carol: 6/5/2013
wwang: 2/18/2011
ckniffin: 1/28/2011
terry: 11/16/2010
carol: 2/26/2010
carol: 2/18/2010
wwang: 11/3/2008
terry: 10/27/2008
wwang: 4/3/2008
ckniffin: 3/31/2008
wwang: 6/29/2007
ckniffin: 6/25/2007
carol: 2/6/2004
carol: 2/4/2004
alopez: 12/19/2003
carol: 6/18/2003
tkritzer: 11/22/2002
terry: 11/19/2002
tkritzer: 10/31/2002
ckniffin: 10/14/2002
terry: 11/11/1997
terry: 11/10/1997
terry: 11/6/1997
terry: 4/15/1996
mark: 4/1/1996
terry: 4/1/1996
terry: 3/26/1996
mark: 6/20/1995
mimadm: 5/10/1995
carol: 6/25/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989

MIM 600998
*RECORD*
*FIELD* NO
600998
*FIELD* TI
*600998 GUANINE NUCLEOTIDE-BINDING PROTEIN, Q POLYPEPTIDE; GNAQ
;;G PROTEIN, ALPHA SUBUNIT, Gq CLASS;;
read moreG-ALPHA-q
*FIELD* TX

DESCRIPTION

Guanine nucleotide-binding proteins are a family of heterotrimeric
proteins that couple cell surface, 7-transmembrane domain receptors to
intracellular signaling pathways. Receptor activation catalyzes the
exchange of GTP for GDP bound to the inactive G protein alpha subunit
resulting in a conformational change and dissociation of the complex.
The G protein alpha and beta-gamma subunits are capable of regulating
various cellular effectors. Activation is terminated by a GTPase
intrinsic to the G-alpha subunit. G-alpha-q is the alpha subunit of one
of the heterotrimeric GTP-binding proteins that mediates stimulation of
phospholipase C-beta (600230) (summary by Dong et al., 1995).

CLONING

Dong et al. (1995) isolated and characterized cDNA clones from a frontal
cortex cDNA library encoding human G-alpha-q. The encoded protein is 359
amino acids long and is identical in all but 1 amino acid residue to the
mouse protein. Analysis of human genomic DNA revealed an intronless
sequence with strong homology to human GNAQ cDNA. In comparison to GNAQ
cDNA, this genomic DNA sequence included several small deletions and
insertions that altered the reading frame, multiple single based
changes, and a premature termination codon in the open reading frame,
all hallmarks of a processed pseudogene. Probes derived from human GNAQ
cDNA sequence mapped both chromosomes 2 and 9 in higher constringency
genomic blot analyses of DNA from a panel of human/rodent hybrid cell
lines. PCR primers that selectively amplified the pseudogene sequence
generated a product only when DNA containing human chromosome 2 was used
as the template, indicating that the authentic GNAQ gene is located on
chromosome 9.

BIOCHEMICAL FEATURES

- Crystal Structure

G protein-coupled receptor kinase-2 (GRK2; 109635) plays a key role in
the desensitization of G protein-coupled receptor signaling by
phosphorylating activated heptahelical receptors and by sequestering
heterotrimeric G proteins. Tesmer et al. (2005) reported the atomic
structure of GRK2 in complex with G-alpha-q and G-beta-gamma (see
139380, 606981), in which the activated G-alpha subunit of Gq is fully
dissociated from G-beta-gamma and dramatically reoriented from its
position in the inactive G-alpha-beta-gamma heterotrimer. G-alpha-q
forms an effector-like interaction with the GRK2 regulator of G protein
signaling (RGS) homology domain that is distinct from and does not
overlap with that used to bind RGS proteins.

Lutz et al. (2007) determined the crystal structure of the
G-alpha-q-p63RhoGEF (610215)-RhoA (165390) complex, detailing the
interactions of G-alpha-q with the Dbl and pleckstrin homology (DH and
PH) domains of p63RhoGEF. These interactions involved the
effector-binding site and the C-terminal region of G-alpha-q and
appeared to relieve autoinhibition of the catalytic DH domain by the PH
domain. Trio (601893), Duet (604605), and p63RhoGEF were shown to
constitute a family of G-alpha-q effectors that appear to activate RhoA
both in vitro and in intact cells. Lutz et al. (2007) proposed that this
structure represents the crux of an ancient signal transduction pathway
that is expected to be important in an array of physiologic processes.

Waldo et al. (2010) described how heterotrimeric guanine
nucleotide-binding proteins (G proteins) activate PLC-betas and in turn
are deactivated by these downstream effectors. The 2.7-angstrom
structure of PLC-beta-3 (600230) bound to activated G-alpha-q revealed a
conserved module found within PLC-betas and other effectors optimized
for rapid engagement of activated G proteins. The active site of
PLC-beta-3 in the complex is occluded by an intramolecular plug that is
likely removed upon G protein-dependent anchoring and orientation of the
lipase at membrane surfaces. A second domain of PLC-beta-3 subsequently
accelerates guanosine triphosphate hydrolysis by G-alpha-q, causing the
complex to dissociate and terminate signal propagation. Mutations within
this domain dramatically delay signal termination in vitro and in vivo.
Waldo et al. (2010) concluded that their work suggested a dynamic
catch-and-release mechanism used to sharpen spatiotemporal signals
mediated by diverse sensory inputs.

MAPPING

By fluorescence in situ hybridization, Dong et al. (1995) mapped the
GNAQ gene to 9q21 and a pseudogene at 2q14.3-q21.

GENE FUNCTION

G proteins play a major role in signal transduction upon platelet
activation. Rao et al. (1984) reported a patient with diminished
platelet aggregation and secretion in response to multiple agonists
despite presence of normal dense granule stores. The patient was a
46-year-old white female with mild lifelong mucocutaneous bleeding
diathesis associated with prolonged bleeding times and normal platelet
counts. The patient's daughter and father may also have had a history of
easy bruising. Further studies showed that receptor-mediated release of
arachidonic acid from phospholipids and calcium mobilization were
impaired upon platelet activation. They postulated that these abnormal
responses might be due to a defect in signal transduction mechanisms. To
delineate the platelet defect in this patient, Gabbeta et al. (1997)
investigated receptor-stimulated G protein function and reported an
abnormality in G-alpha subunit function associated with a decrease in
immunoreactive G-alpha-q in platelets. To their knowledge, this was the
first description of a human platelet G protein defect.

By study of cultured neonatal rat cardiac myocytes, Adams et al. (1998)
demonstrated that overexpression of wildtype GNAQ resulted in
hypertropic growth. Strikingly, expression of a constitutively activated
mutant of GNAQ, which further increased Gq signaling, produced initial
hypertrophy, which rapidly progressed to apoptotic cardiomyocyte death.
This paradigm was recapitulated during pregnancy in GNAQ overexpressing
mice and in transgenic mice expressing high levels of wildtype GNAQ. The
consequence of cardiomyocyte apoptosis was a transition from compensated
hypertrophy to a rapidly progressive and lethal cardiomyopathy.
Progression from hypertrophy to apoptosis in vitro and in vivo was
coincident with activation of p38 (600289) and JUN (165160) kinases.
These data suggest a mechanism in which moderate levels of Gq signaling
stimulate cardiac hypertrophy, whereas high level Gq activation results
in cardiomyocyte apoptosis. The identification of a single biochemical
stimulus regulating cardiomyocyte growth and death suggested a plausible
mechanism for the progression of compensated hypertrophy to
decompensated heart failure.

Santagata et al. (2001) demonstrated that tubby (601197) functions in
signal transduction from heterotrimeric G protein-coupled receptors.
Receptor-mediated activation of G-alpha-q releases tubby from the plasma
membrane through the action of phospholipase C-beta (see 607120),
triggering translocation of tubby to the cell nucleus. The localization
of tubby-like protein-3 (TULP3; 604730) is similarly regulated.
Santagata et al. (2001) concluded that tubby proteins function as
membrane-bound transcription regulators that translocate to the nucleus
in response to phosphoinositide hydrolysis, providing a direct link
between G protein signaling and the regulation of gene expression.

Using mice lacking G-alpha subunits specifically in smooth muscle cells,
Wirth et al. (2008) found that G-alpha-q and G-alpha-11 (GNA11; 139313)
were required for maintenance of basal blood pressure and for
development of salt-induced hypertension. In contrast, lack of
G-alpha-12 (GNA12; 604394) and G-alpha-13 (GNA13; 604406) and their
effector, Larg (ARHGEF12; 604763), did not alter normal blood pressure
regulation, but blocked development of salt-induced hypertension.

MOLECULAR GENETICS

- Somatic Mutations

Van Raamsdonk et al. (2009) reported frequent somatic mutations in the
heterotrimeric G protein alpha-subunit in blue nevi (603670) (83%) and
ocular melanoma of the uvea (46%) (see 155720). The mutations occurred
exclusively in codon 209 in the Ras-like domain and resulted in
constitutive activation, turning GNAQ into a dominant-acting oncogene.
Van Raamsdonk et al. (2009) concluded that their results demonstrated an
alternative route to MAP kinase activation in melanocytic neoplasia,
providing new opportunities for therapeutic intervention.

Van Raamsdonk et al. (2010) identified somatic mutations affecting
residue Q209 of the GNAQ gene in 55% of blue nevi, 45% of uveal
melanomas, and 22% of uveal melanoma metastases. Somatic mutations
affecting the same residue in the paralog gene GNA11 (139313) were found
in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal
melanoma metastases. The sample group included a total of 713
melanocytic neoplasms. Sequencing of exon 4 of these genes, affecting
residue R183, in 453 melanocytic neoplasms showed a lower prevalence of
mutations: 2.1% of blue nevi and 4.9% of primary uveal melanomas. The
mutations were mutually exclusive, except for a single tumor that
carried mutations at both Q209 and R183 in GNA11. In total, 83% of all
uveal melanomas examined had oncogenic mutations in either GNAQ or
GNA11. Although GNA11 mutations appeared to have a more potent effect on
melanocytes than did GNAQ mutations, there was no difference in patient
survival among those with GNA11 mutations compared to those with GNAQ
mutations.

Populo et al. (2011) identified the GNAQ Q209 mutation in 36% of 22
enucleated uveal melanomas. No associations were found between the
presence of the GNAQ mutation and prognostic parameters, the expression
of ERK1/2 (MAPK3, 601795/MAPK1, 176948), phosphorylated ERK1/2, and cell
cycle markers. Populo et al. (2011) suggested that GNAQ-mutated uveal
melanomas do not exhibit a higher deregulation of proliferation or
higher activation of the MAP kinase signaling pathway than uveal
melanomas without GNAQ activation.

Shirley et al. (2013) performed whole-genome sequencing of DNA from
paired samples of visibly affected and normal tissue from 3 patients
with Sturge-Weber syndrome (SWS; 185300) and identified 1 nonsynonymous
somatic single-nucleotide variant in the GNAQ gene (R183Q; 600998.0001)
that was present in all 3 affected samples and was not present in the
normal-appearing samples. Screening of additional SWS patients as well
as individuals with nonsyndromic port-wine stains (CMC; 163000) revealed
the presence of the R183Q mutation in either port-wine-stained skin or
brain tissue from 23 (88%) of 26 SWS patients as well as in affected
skin from 12 (92%) of 13 patients with nonsyndromic port-wine stains.
Shirley et al. (2013) noted that the GNAQ somatic substitution R183Q, as
well as a more common Q209L substitution, had previously been found in
patients with uveal melanoma (Van Raamsdonk et al., 2010); functional
analysis demonstrated that R183Q has a gain-of-function effect that
activates downstream pathways, although to a lesser degree than the
Q209L mutation.

- Exclusion Studies

Oyesiku et al. (1997) screened 37 pituitary adenomas (see 102200) for
activating mutations of the G-alpha-q gene. G-alpha-q specific primers
were used to generate cDNA by RT-PCR. Fragments of G-alpha-q
cDNA-encompassing residues (arg183, gln209) were screened by SSCP and
then sequenced in both directions. No mutations were detected, and
Oyesiku et al. (1997) concluded that mutations in these regions of the
G-alpha-q cDNA occur infrequently, if at all, in human pituitary
adenomas.

ANIMAL MODEL

Offermanns et al. (1997) generated Gnaq-deficient mice, which suffered
from ataxia with typical signs of motor discoordination. They observed
that about 40% of adult Purkinje cells in the Gnaq-deficient mice
remained multiply innervated by climbing fibers because of a defect in
regression of supernumerary climbing fibers in the third postnatal week.
Offermanns et al. (1997) hypothesized that GNAQ is part of a signaling
pathway involved in the elimination of multiple climbing fiber
innervation during this period.

Offermanns et al. (1997) observed that platelets from Gnaq-deficient
mice were unresponsive to a variety of physiologic platelet activators.
As a result, Gnaq-deficient mice had increased bleeding times and were
protected from collagen and adrenaline-induced thromboembolism.
Offermanns et al. (1997) concluded that GNAQ is essential for the
signaling processes used by different platelet activators.

Offermanns et al. (1998) bred Gnaq-deficient mice with Gna11
(139313)-deficient mice and observed gene dosage effects between Gnaq
and Gna11. Embryos completely lacking both genes died in utero with
heart malformations. Mice inheriting a single copy of either gene died
within hours of birth with craniofacial and/or cardiac defects.
Offermanns et al. (1998) concluded that at least 2 active alleles of
these genes are required for extrauterine life. Genetic, morphologic,
and pharmacologic analyses of intercross offspring inheriting different
combinations of these 2 mutations indicated that Gnaq and Gna11 have
overlapping functions in embryonic cardiomyocyte proliferation and
craniofacial development.

A new class of dominant 'dark skin' (Dsk) mutations was discovered in a
screen of approximately 30,000 mice in a large-scale mutagenesis study.
These result from increased dermal melanin. Van Raamsdonk et al. (2004)
identified 3 of 4 such mutations as hypermorphic alleles of Gnaq and
Gna11, which encode widely expressed G-alpha-q subunits, act in an
additive and quantitative manner, and require endothelin receptor, type
B (EDNRB; 131244). Interaction between Gq and Kit receptor tyrosine
kinase (164920) signaling can mediate coordinate or independent control
of skin and hair color. The results provided a mechanism that can
explain several aspects of human pigmentary variation and show how
polymorphism of essential proteins and signaling pathways can affect a
single physiologic system.

Kero et al. (2007) generated mice with thyrocyte-specific Gna11/Gnaq
deficiency and observed severely reduced iodine organification and
thyroid hormone secretion in response to TSH, with many of the mice
developing hypothyroidism within months after birth. In addition, these
mice lacked the normal proliferative thyroid response to TSH or
goitrogenic diet. Kero et al. (2007) concluded that the GNA11/GNAQ
pathway has an essential role in the adaptive growth of the thyroid
gland.

*FIELD* AV
.0001
STURGE-WEBER SYNDROME, SOMATIC, MOSAIC
CAPILLARY MALFORMATIONS, CONGENITAL, 1, SOMATIC, MOSAIC, INCLUDED
GNAQ, ARG183GLN

Shirley et al. (2013) performed whole-genome sequencing of DNA from
paired samples of visibly affected and normal tissue from 3 patients
with Sturge-Weber syndrome (SWS; 185300) and identified 1 nonsynonymous
somatic single-nucleotide variant, a c.548G-A transition in the GNAQ
gene, resulting in an arg183-to-gln (R183Q) substitution at a highly
conserved residue, that was present in all 3 affected samples and was
not present in the normal-appearing samples. Screening of additional SWS
patients as well as individuals with nonsyndromic port-wine stains
(163000) revealed that all 9 SWS patients were positive for the R183Q
mutation in port-wine-stained skin, 6 (86%) of 7 participants with SWS
were negative for the mutation in visibly normal skin, and 12 (92%) of
13 participants with nonsyndromic port-wine stains were positive for the
mutation. The mutation was also detected in brain samples from 15 (83%)
of 18 SWS patients, whereas all 6 brain samples from normal controls
were negative. Transfection studies in HEK 293T cells showed significant
activation of ERK (600997) by the R183Q mutant compared to control.
Overall, 23 (88%) of 26 SWS patients were positive for the
gain-of-function R183Q mutation in either port wine-stained skin or
brain tissue. Shirley et al. (2013) suggested that nonsyndromic
port-wine stains may represent a late origin of the somatic GNAQ
mutation in vascular endothelial cells, whereas in Sturge-Weber
syndrome, the mutation may occur earlier in development, in progenitor
cells that are precursors to a larger variety of cell types and tissues,
leading to the syndromic phenotype. Five (0.7%) of 669 samples from the
1000 Genomes database were positive for R183Q; noting that the reported
prevalence of port-wine stains is 0.3% to 0.5%, Shirley et al. (2013)
hypothesized that the 0.7% prevalence in that database represented the
occurrence of port-wine stains in the population.

*FIELD* RF
1. Adams, J. W.; Sakata, Y.; Davis, M. G.; Sah, V. P.; Wang, Y.; Liggett,
S. B.; Chien, K. R.; Brown, J. H.; Dorn, G. W., II: Enhanced G-alpha-q
signaling: a common pathway mediates cardiac hypertrophy and apoptotic
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2. Dong, Q.; Shenker, A.; Way, J.; Haddad, B. R.; Lin, K.; Hughes,
M. R.; McBride, O. W.; Spiegel, A. M.; Battey, J.: Molecular cloning
of human G-alpha(q) cDNA and chromosomal localization of the G-alpha(q)
gene (GNAQ) and a processed pseudogene. Genomics 30: 470-475, 1995.

3. Gabbeta, J.; Yang, X.; Kowalska, M. A.; Sun, L.; Dhanasekaran,
N.; Rao, A. K.: Platelet signal transduction defect with G-alpha
subunit dysfunction and diminished G-alpha(q) in a patient with abnormal
platelet responses. Proc. Nat. Acad. Sci. 94: 8750-8755, 1997.

4. Kero, J.; Ahmed, K.; Wettschureck, N.; Tunaru, S.; Wintermantel,
T.; Greiner, E.; Schutz, G.; Offermanns, S.: Thyrocyte-specific Gq/G11
deficiency impairs thyroid function and prevents goiter development. J.
Clin. Invest. 117: 2399-2407, 2007.

5. Lutz, S.; Shankaranarayanan, A.; Coco, C.; Ridilla, M.; Nance,
M. R.; Vettel, C.; Baltus, D.; Evelyn, C. R.; Neubig, R. R.; Wieland,
T.; Tesmer, J. J. G.: Structure of G-alpha(q)-p63RhoGEF-RhoA complex
reveals a pathway for the activation of RhoA by GPCRs. Science 318:
1923-1927, 2007.

6. Offermanns, S.; Hashimoto, K.; Watanabe, M.; Sun, W.; Kurihara,
H.; Thompson, R. F.; Inoue, Y.; Kano, M.; Simon, M. I.: Impaired
motor coordination and persistent multiple climbing fiber innervation
of cerebellar Purkinje cells in mice lacking G-alpha-q. Proc. Nat.
Acad. Sci. 94: 14089-14094, 1997.

7. Offermanns, S.; Toombs, C. F.; Hu, Y.-H.; Simon, M. I.: Defective
platelet activation in G-alpha-q-deficient mice. Nature 389: 183-186,
1997.

8. Offermanns, S.; Zhao, L.-P.; Gohla, A.; Sarosi, I.; Simon, M. I.;
Wilkie, T. M.: Embryonic cardiomyocyte hypoplasia and craniofacial
defects in G-alpha-q/G-alpha-11-mutant mice. EMBO J. 17: 4304-4312,
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9. Oyesiku, N. M.; Evans, C.-O.; Brown, M. R.; Blevins, L. S.; Tindall,
G. T.; Parks, J. S.: Pituitary adenomas: screening for G-alpha-q
mutations. J. Clin. Endocr. Metab. 82: 4184-4188, 1997.

10. Populo, H.; Vinagre, J.; Manuel Lopes, J.; Soares, P.: Analysis
of GNAQ mutations, proliferation and MAPK pathway activation in uveal
melanomas. Brit. J. Ophthal. 95: 715-719, 2011.

11. Rao, A. K.; Koike, K.; Willis, J.; Daniel, J. L.; Beckett, C.;
Hassel, B.; Day, H. J.; Smith, J. B.; Holmsen, H.: Platelet secretion
defect associated with impaired liberation of arachidonic acid and
normal myosin light chain phosphorylation. Blood 64: 914-921, 1984.

12. Santagata, S.; Boggon, T. J.; Baird, C. L.; Gomez, C. A.; Zhao,
J.; Shan, W. S.; Myszka, D. G.; Shapiro, L.: G-protein signaling
through tubby proteins. Science 292: 2041-2050, 2001.

13. Shirley, M. D.; Tang, H.; Gallione, C. J.; Baugher, J. D.; Frelin,
L. P.; Cohen, B.; North, P. E.; Marchuk, D. A.; Comi, A. M.; Pevsner,
J.: Sturge-Weber syndrome and port-wine stains caused by somatic
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14. Tesmer, V. M.; Kawano, T.; Shankaranarayanan, A.; Kozasa, T.;
Tesmer, J. J. G.: Snapshot of activated G proteins at the membrane:
the G-alpha-q-GRK2-G-beta-gamma complex. Science 310: 1686-1690,
2005.

15. Van Raamsdonk, C. D.; Bezrookove, V.; Green, G.; Bauer, J.; Gaugler,
L.; O'Brien, J. M.; Simpson, E. M.; Barsh, G. S.; Bastian, B. C.:
Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457:
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16. Van Raamsdonk, C. D.; Fitch, K. R.; Fuchs, H.; Hrabe de Angelis,
M.; Barsh, G. S.: Effects of G-protein mutations on skin color. Nature
Genet. 36: 961-968, 2004.

17. Van Raamsdonk, C. D.; Griewank, K. G.; Crosby, M. B.; Garrido,
M. C.; Vemula, S.; Wiesner, T.; Obenauf, A. C.; Wackernagel, W.; Green,
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18. Waldo, G. L.; Ricks, T. K.; Hicks, S. N.; Cheever, M. L.; Kawano,
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19. Wirth, A.; Benyo, Z.; Lukasova, M.; Leutgeb, B.; Wettschureck,
N.; Gorbey, S.; Orsy, P.; Horvath, B.; Maser-Gluth, C.; Greiner, E.;
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signaling in vascular smooth muscle is required for salt-induced hypertension. Nature
Med. 14: 64-68, 2008. Note: Erratum: Nature Med. 14: 222 only, 2008.

*FIELD* CN
Marla J. F. O'Neill - updated: 6/5/2013
Jane Kelly - updated: 8/16/2011
Ada Hamosh - updated: 6/23/2011
Cassandra L. Kniffin - updated: 12/20/2010
Ada Hamosh - updated: 2/13/2009
Patricia A. Hartz - updated: 3/6/2008
Ada Hamosh - updated: 2/11/2008
Marla J. F. O'Neill - updated: 11/6/2007
Ada Hamosh - updated: 4/18/2006
Victor A. McKusick - updated: 9/27/2004
Dawn Watkins-Chow - updated: 7/11/2002
Ada Hamosh - updated: 7/9/2001
Victor A. McKusick - updated: 11/5/1998
Victor A. McKusick - updated: 9/10/1997

*FIELD* CD
Victor A. McKusick: 1/19/1996

*FIELD* ED
carol: 10/16/2013
tpirozzi: 9/30/2013
carol: 7/31/2013
carol: 6/5/2013
terry: 11/15/2011
carol: 8/23/2011
terry: 8/16/2011
alopez: 6/23/2011
terry: 6/23/2011
wwang: 12/27/2010
ckniffin: 12/20/2010
alopez: 2/16/2009
terry: 2/13/2009
mgross: 3/6/2008
alopez: 2/14/2008
terry: 2/11/2008
wwang: 11/12/2007
terry: 11/6/2007
alopez: 4/24/2006
terry: 4/18/2006
alopez: 9/30/2004
terry: 9/27/2004
mgross: 7/11/2002
alopez: 7/9/2001
terry: 11/5/1998
carol: 7/2/1998
alopez: 5/12/1998
dholmes: 9/22/1997
terry: 9/12/1997
terry: 9/10/1997
mark: 2/15/1996
mark: 1/21/1996