Full text data of GNA11
GNA11
(GA11)
[Confidence: high (present in two of the MS resources)]
Guanine nucleotide-binding protein subunit alpha-11; G alpha-11; G-protein subunit alpha-11 (Guanine nucleotide-binding protein G(y) subunit alpha)
Guanine nucleotide-binding protein subunit alpha-11; G alpha-11; G-protein subunit alpha-11 (Guanine nucleotide-binding protein G(y) subunit alpha)
UniProt
P29992
ID GNA11_HUMAN Reviewed; 359 AA.
AC P29992; O15109; Q14350; Q6IB00;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 15-JUL-1998, sequence version 2.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=Guanine nucleotide-binding protein subunit alpha-11;
DE Short=G alpha-11;
DE Short=G-protein subunit alpha-11;
DE AltName: Full=Guanine nucleotide-binding protein G(y) subunit alpha;
GN Name=GNA11; Synonyms=GA11;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Retina;
RX PubMed=1902575; DOI=10.1073/pnas.88.9.3907;
RA Jiang M., Pandey S., Tran V.T., Fong H.K.W.;
RT "Guanine nucleotide-binding regulatory proteins in retinal pigment
RT epithelial cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:3907-3911(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bai X.H., Acharya R., Bai Y.H., Murtagh J.J.;
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
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 [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 (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
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 [7]
RP PROTEIN SEQUENCE OF 42-52 AND 159-166, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RA Bienvenut W.V., Calvo F., Kolch W.;
RL Submitted (MAR-2008) to UniProtKB.
RN [8]
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 [9]
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 [10]
RP PALMITOYLATION AT CYS-9 AND CYS-10.
RX PubMed=21044946; DOI=10.1194/jlr.D011106;
RA Forrester M.T., Hess D.T., Thompson J.W., Hultman R., Moseley M.A.,
RA Stamler J.S., Casey P.J.;
RT "Site-specific analysis of protein S-acylation by resin-assisted
RT capture.";
RL J. Lipid Res. 52:393-398(2011).
RN [11]
RP VARIANTS HYPOC2 CYS-60 AND TRP-211.
RX PubMed=23782177; DOI=10.1056/NEJMp1302941;
RA Memtsoudis S.G., Besculides M.C., Mazumdar M.;
RT "A rude awakening--the perioperative sleep apnea epidemic.";
RL N. Engl. J. Med. 368:2352-2353(2013).
RN [12]
RP VARIANTS HHC2 GLN-135 AND ILE-200 DEL, VARIANTS HYPOC2 GLN-181 AND
RP LEU-341, CHARACTERIZATION OF VARIANTS HHC2 GLN-135 AND ILE-200 DEL,
RP AND CHARACTERIZATION OF VARIANTS HYPOC2 GLN-181 AND LEU-341.
RX PubMed=23802516; DOI=10.1056/NEJMoa1300253;
RA Nesbit M.A., Hannan F.M., Howles S.A., Babinsky V.N., Head R.A.,
RA Cranston T., Rust N., Hobbs M.R., Heath H. III, Thakker R.V.;
RT "Mutations affecting G-protein subunit alpha11 in hypercalcemia and
RT hypocalcemia.";
RL N. Engl. J. Med. 368:2476-2486(2013).
CC -!- FUNCTION: Guanine nucleotide-binding proteins (G proteins) are
CC involved as modulators or transducers in various transmembrane
CC signaling systems. Acts as an activator of phospholipase C.
CC -!- SUBUNIT: G proteins are composed of 3 units; alpha, beta and
CC gamma. The alpha chain contains the guanine nucleotide binding
CC site.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor (Probable).
CC -!- DISEASE: Hypocalciuric hypercalcemia, familial 2 (HHC2)
CC [MIM:145981]: A form of hypocalciuric hypercalcemia, a disorder of
CC mineral homeostasis that is transmitted as an autosomal dominant
CC trait with a high degree of penetrance. It is characterized
CC biochemically by lifelong elevation of serum calcium
CC concentrations and is associated with inappropriately low urinary
CC calcium excretion and a normal or mildly elevated circulating
CC parathyroid hormone level. Hypermagnesemia is typically present.
CC Affected individuals are usually asymptomatic and the disorder is
CC considered benign. However, chondrocalcinosis and pancreatitis
CC occur in some adults. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hypocalcemia, autosomal dominant 2 (HYPOC2) [MIM:615361]:
CC A form of hypocalcemia, a disorder of mineral homeostasis
CC characterized by blood calcium levels below normal, and low or
CC normal serum parathyroid hormone concentrations. Disease
CC manifestations include hypocalcemia, paresthesias, carpopedal
CC spasm, seizures, hypercalciuria with nephrocalcinosis or kidney
CC stones, and ectopic and basal ganglia calcifications. Note=The
CC disease is caused by mutations affecting the gene represented in
CC 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/GNA11ID43272ch19p13.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M69013; AAA58624.1; -; mRNA.
DR EMBL; AF011497; AAB64303.1; -; mRNA.
DR EMBL; AF493900; AAM12614.1; -; mRNA.
DR EMBL; CR457004; CAG33285.1; -; mRNA.
DR EMBL; AC005262; AAC25615.1; -; Genomic_DNA.
DR EMBL; BC089041; AAH89041.1; -; mRNA.
DR EMBL; BC096225; AAH96225.1; -; mRNA.
DR EMBL; BC096226; AAH96226.1; -; mRNA.
DR EMBL; BC096227; AAH96227.1; -; mRNA.
DR EMBL; L40630; AAA99949.1; -; mRNA.
DR PIR; A39394; RGHUGY.
DR RefSeq; NP_002058.2; NM_002067.3.
DR UniGene; Hs.650575; -.
DR UniGene; Hs.654784; -.
DR ProteinModelPortal; P29992; -.
DR SMR; P29992; 37-354.
DR IntAct; P29992; 2.
DR MINT; MINT-4999662; -.
DR STRING; 9606.ENSP00000078429; -.
DR PhosphoSite; P29992; -.
DR DMDM; 3041682; -.
DR PaxDb; P29992; -.
DR PRIDE; P29992; -.
DR Ensembl; ENST00000078429; ENSP00000078429; ENSG00000088256.
DR GeneID; 2767; -.
DR KEGG; hsa:2767; -.
DR UCSC; uc002lxd.3; human.
DR CTD; 2767; -.
DR GeneCards; GC19P003094; -.
DR HGNC; HGNC:4379; GNA11.
DR HPA; HPA048886; -.
DR MIM; 139313; gene.
DR MIM; 145981; phenotype.
DR MIM; 615361; phenotype.
DR neXtProt; NX_P29992; -.
DR Orphanet; 428; Autosomal dominant hypocalcemia.
DR Orphanet; 101049; Familial hypocalciuric hypercalcemia type 2.
DR PharmGKB; PA28764; -.
DR eggNOG; NOG322962; -.
DR HOGENOM; HOG000038729; -.
DR HOVERGEN; HBG063184; -.
DR InParanoid; P29992; -.
DR KO; K04635; -.
DR OMA; EHRYVNA; -.
DR OrthoDB; EOG7ZWD1W; -.
DR PhylomeDB; P29992; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; GNA11; human.
DR GeneWiki; GNA11; -.
DR GenomeRNAi; 2767; -.
DR NextBio; 10884; -.
DR PRO; PR:P29992; -.
DR ArrayExpress; P29992; -.
DR Bgee; P29992; -.
DR CleanEx; HS_GNA11; -.
DR Genevestigator; P29992; -.
DR GO; GO:0005834; C:heterotrimeric G-protein complex; IBA:RefGenome.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
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: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:0007188; P:adenylate cyclase-modulating G-protein coupled receptor signaling pathway; IBA:RefGenome.
DR GO; GO:0048066; P:developmental pigmentation; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; 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:0001508; P:regulation of action potential; IBA:RefGenome.
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; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disease mutation; GTP-binding; Lipoprotein;
KW Magnesium; Membrane; Metal-binding; Nucleotide-binding; Palmitate;
KW Reference proteome; Transducer.
FT CHAIN 1 359 Guanine nucleotide-binding protein
FT subunit alpha-11.
FT /FTId=PRO_0000203746.
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.
FT LIPID 10 10 S-palmitoyl cysteine.
FT VARIANT 60 60 R -> C (in HYPOC2).
FT /FTId=VAR_070165.
FT VARIANT 135 135 L -> Q (in HHC2; induces a decrease in
FT sensitivity to changes in extracellular
FT calcium concentrations).
FT /FTId=VAR_070166.
FT VARIANT 181 181 R -> Q (in HYPOC2; induces an increase in
FT sensitivity to changes in extracellular
FT calcium concentrations).
FT /FTId=VAR_070167.
FT VARIANT 200 200 Missing (in HHC2; induces a decrease in
FT sensitivity to changes in extracellular
FT calcium concentrations).
FT /FTId=VAR_070168.
FT VARIANT 211 211 S -> W (in HYPOC2).
FT /FTId=VAR_070169.
FT VARIANT 341 341 F -> L (in HYPOC2; induces an increase in
FT sensitivity to changes in extracellular
FT calcium concentrations).
FT /FTId=VAR_070170.
FT CONFLICT 6 6 M -> I (in Ref. 2; AAB64303).
FT CONFLICT 266 266 N -> H (in Ref. 8; AAA99949).
FT CONFLICT 285 285 Y -> H (in Ref. 8; AAA99949).
FT CONFLICT 301 302 DA -> EP (in Ref. 1; AAA58624).
FT CONFLICT 310 310 L -> P (in Ref. 2; AAB64303).
SQ SEQUENCE 359 AA; 42123 MW; DD37176589E66046 CRC64;
MTLESMMACC LSDEVKESKR INAEIEKQLR RDKRDARREL KLLLLGTGES GKSTFIKQMR
IIHGAGYSEE DKRGFTKLVY QNIFTAMQAM IRAMETLKIL YKYEQNKANA LLIREVDVEK
VTTFEHQYVS AIKTLWEDPG IQECYDRRRE YQLSDSAKYY LTDVDRIATL GYLPTQQDVL
RVRVPTTGII EYPFDLENII FRMVDVGGQR SERRKWIHCF ENVTSIMFLV ALSEYDQVLV
ESDNENRMEE SKALFRTIIT YPWFQNSSVI LFLNKKDLLE DKILYSHLVD YFPEFDGPQR
DAQAAREFIL KMFVDLNPDS DKIIYSHFTC ATDTENIRFV FAAVKDTILQ LNLKEYNLV
//
ID GNA11_HUMAN Reviewed; 359 AA.
AC P29992; O15109; Q14350; Q6IB00;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 15-JUL-1998, sequence version 2.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=Guanine nucleotide-binding protein subunit alpha-11;
DE Short=G alpha-11;
DE Short=G-protein subunit alpha-11;
DE AltName: Full=Guanine nucleotide-binding protein G(y) subunit alpha;
GN Name=GNA11; Synonyms=GA11;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Retina;
RX PubMed=1902575; DOI=10.1073/pnas.88.9.3907;
RA Jiang M., Pandey S., Tran V.T., Fong H.K.W.;
RT "Guanine nucleotide-binding regulatory proteins in retinal pigment
RT epithelial cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:3907-3911(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bai X.H., Acharya R., Bai Y.H., Murtagh J.J.;
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
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 [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 (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
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 [7]
RP PROTEIN SEQUENCE OF 42-52 AND 159-166, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RA Bienvenut W.V., Calvo F., Kolch W.;
RL Submitted (MAR-2008) to UniProtKB.
RN [8]
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 [9]
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 [10]
RP PALMITOYLATION AT CYS-9 AND CYS-10.
RX PubMed=21044946; DOI=10.1194/jlr.D011106;
RA Forrester M.T., Hess D.T., Thompson J.W., Hultman R., Moseley M.A.,
RA Stamler J.S., Casey P.J.;
RT "Site-specific analysis of protein S-acylation by resin-assisted
RT capture.";
RL J. Lipid Res. 52:393-398(2011).
RN [11]
RP VARIANTS HYPOC2 CYS-60 AND TRP-211.
RX PubMed=23782177; DOI=10.1056/NEJMp1302941;
RA Memtsoudis S.G., Besculides M.C., Mazumdar M.;
RT "A rude awakening--the perioperative sleep apnea epidemic.";
RL N. Engl. J. Med. 368:2352-2353(2013).
RN [12]
RP VARIANTS HHC2 GLN-135 AND ILE-200 DEL, VARIANTS HYPOC2 GLN-181 AND
RP LEU-341, CHARACTERIZATION OF VARIANTS HHC2 GLN-135 AND ILE-200 DEL,
RP AND CHARACTERIZATION OF VARIANTS HYPOC2 GLN-181 AND LEU-341.
RX PubMed=23802516; DOI=10.1056/NEJMoa1300253;
RA Nesbit M.A., Hannan F.M., Howles S.A., Babinsky V.N., Head R.A.,
RA Cranston T., Rust N., Hobbs M.R., Heath H. III, Thakker R.V.;
RT "Mutations affecting G-protein subunit alpha11 in hypercalcemia and
RT hypocalcemia.";
RL N. Engl. J. Med. 368:2476-2486(2013).
CC -!- FUNCTION: Guanine nucleotide-binding proteins (G proteins) are
CC involved as modulators or transducers in various transmembrane
CC signaling systems. Acts as an activator of phospholipase C.
CC -!- SUBUNIT: G proteins are composed of 3 units; alpha, beta and
CC gamma. The alpha chain contains the guanine nucleotide binding
CC site.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor (Probable).
CC -!- DISEASE: Hypocalciuric hypercalcemia, familial 2 (HHC2)
CC [MIM:145981]: A form of hypocalciuric hypercalcemia, a disorder of
CC mineral homeostasis that is transmitted as an autosomal dominant
CC trait with a high degree of penetrance. It is characterized
CC biochemically by lifelong elevation of serum calcium
CC concentrations and is associated with inappropriately low urinary
CC calcium excretion and a normal or mildly elevated circulating
CC parathyroid hormone level. Hypermagnesemia is typically present.
CC Affected individuals are usually asymptomatic and the disorder is
CC considered benign. However, chondrocalcinosis and pancreatitis
CC occur in some adults. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hypocalcemia, autosomal dominant 2 (HYPOC2) [MIM:615361]:
CC A form of hypocalcemia, a disorder of mineral homeostasis
CC characterized by blood calcium levels below normal, and low or
CC normal serum parathyroid hormone concentrations. Disease
CC manifestations include hypocalcemia, paresthesias, carpopedal
CC spasm, seizures, hypercalciuria with nephrocalcinosis or kidney
CC stones, and ectopic and basal ganglia calcifications. Note=The
CC disease is caused by mutations affecting the gene represented in
CC 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/GNA11ID43272ch19p13.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M69013; AAA58624.1; -; mRNA.
DR EMBL; AF011497; AAB64303.1; -; mRNA.
DR EMBL; AF493900; AAM12614.1; -; mRNA.
DR EMBL; CR457004; CAG33285.1; -; mRNA.
DR EMBL; AC005262; AAC25615.1; -; Genomic_DNA.
DR EMBL; BC089041; AAH89041.1; -; mRNA.
DR EMBL; BC096225; AAH96225.1; -; mRNA.
DR EMBL; BC096226; AAH96226.1; -; mRNA.
DR EMBL; BC096227; AAH96227.1; -; mRNA.
DR EMBL; L40630; AAA99949.1; -; mRNA.
DR PIR; A39394; RGHUGY.
DR RefSeq; NP_002058.2; NM_002067.3.
DR UniGene; Hs.650575; -.
DR UniGene; Hs.654784; -.
DR ProteinModelPortal; P29992; -.
DR SMR; P29992; 37-354.
DR IntAct; P29992; 2.
DR MINT; MINT-4999662; -.
DR STRING; 9606.ENSP00000078429; -.
DR PhosphoSite; P29992; -.
DR DMDM; 3041682; -.
DR PaxDb; P29992; -.
DR PRIDE; P29992; -.
DR Ensembl; ENST00000078429; ENSP00000078429; ENSG00000088256.
DR GeneID; 2767; -.
DR KEGG; hsa:2767; -.
DR UCSC; uc002lxd.3; human.
DR CTD; 2767; -.
DR GeneCards; GC19P003094; -.
DR HGNC; HGNC:4379; GNA11.
DR HPA; HPA048886; -.
DR MIM; 139313; gene.
DR MIM; 145981; phenotype.
DR MIM; 615361; phenotype.
DR neXtProt; NX_P29992; -.
DR Orphanet; 428; Autosomal dominant hypocalcemia.
DR Orphanet; 101049; Familial hypocalciuric hypercalcemia type 2.
DR PharmGKB; PA28764; -.
DR eggNOG; NOG322962; -.
DR HOGENOM; HOG000038729; -.
DR HOVERGEN; HBG063184; -.
DR InParanoid; P29992; -.
DR KO; K04635; -.
DR OMA; EHRYVNA; -.
DR OrthoDB; EOG7ZWD1W; -.
DR PhylomeDB; P29992; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; GNA11; human.
DR GeneWiki; GNA11; -.
DR GenomeRNAi; 2767; -.
DR NextBio; 10884; -.
DR PRO; PR:P29992; -.
DR ArrayExpress; P29992; -.
DR Bgee; P29992; -.
DR CleanEx; HS_GNA11; -.
DR Genevestigator; P29992; -.
DR GO; GO:0005834; C:heterotrimeric G-protein complex; IBA:RefGenome.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
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: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:0007188; P:adenylate cyclase-modulating G-protein coupled receptor signaling pathway; IBA:RefGenome.
DR GO; GO:0048066; P:developmental pigmentation; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; 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:0001508; P:regulation of action potential; IBA:RefGenome.
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; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disease mutation; GTP-binding; Lipoprotein;
KW Magnesium; Membrane; Metal-binding; Nucleotide-binding; Palmitate;
KW Reference proteome; Transducer.
FT CHAIN 1 359 Guanine nucleotide-binding protein
FT subunit alpha-11.
FT /FTId=PRO_0000203746.
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.
FT LIPID 10 10 S-palmitoyl cysteine.
FT VARIANT 60 60 R -> C (in HYPOC2).
FT /FTId=VAR_070165.
FT VARIANT 135 135 L -> Q (in HHC2; induces a decrease in
FT sensitivity to changes in extracellular
FT calcium concentrations).
FT /FTId=VAR_070166.
FT VARIANT 181 181 R -> Q (in HYPOC2; induces an increase in
FT sensitivity to changes in extracellular
FT calcium concentrations).
FT /FTId=VAR_070167.
FT VARIANT 200 200 Missing (in HHC2; induces a decrease in
FT sensitivity to changes in extracellular
FT calcium concentrations).
FT /FTId=VAR_070168.
FT VARIANT 211 211 S -> W (in HYPOC2).
FT /FTId=VAR_070169.
FT VARIANT 341 341 F -> L (in HYPOC2; induces an increase in
FT sensitivity to changes in extracellular
FT calcium concentrations).
FT /FTId=VAR_070170.
FT CONFLICT 6 6 M -> I (in Ref. 2; AAB64303).
FT CONFLICT 266 266 N -> H (in Ref. 8; AAA99949).
FT CONFLICT 285 285 Y -> H (in Ref. 8; AAA99949).
FT CONFLICT 301 302 DA -> EP (in Ref. 1; AAA58624).
FT CONFLICT 310 310 L -> P (in Ref. 2; AAB64303).
SQ SEQUENCE 359 AA; 42123 MW; DD37176589E66046 CRC64;
MTLESMMACC LSDEVKESKR INAEIEKQLR RDKRDARREL KLLLLGTGES GKSTFIKQMR
IIHGAGYSEE DKRGFTKLVY QNIFTAMQAM IRAMETLKIL YKYEQNKANA LLIREVDVEK
VTTFEHQYVS AIKTLWEDPG IQECYDRRRE YQLSDSAKYY LTDVDRIATL GYLPTQQDVL
RVRVPTTGII EYPFDLENII FRMVDVGGQR SERRKWIHCF ENVTSIMFLV ALSEYDQVLV
ESDNENRMEE SKALFRTIIT YPWFQNSSVI LFLNKKDLLE DKILYSHLVD YFPEFDGPQR
DAQAAREFIL KMFVDLNPDS DKIIYSHFTC ATDTENIRFV FAAVKDTILQ LNLKEYNLV
//
MIM
139313
*RECORD*
*FIELD* NO
139313
*FIELD* TI
*139313 GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-11; GNA11
*FIELD* TX
CLONING
Strathmann and Simon (1991) described the Gna11 gene in the mouse. The
read morehuman gene was cloned by Jiang et al. (1991) and found to be 359 amino
acids long. Mouse Gna11 and Gna15 (139314) are tandemly duplicated in a
head-to-tail array. Davignon et al. (1996) showed that the upstream
gene, Gna11, is ubiquitously expressed, whereas expression of the
downstream gene, Gna15, is restricted to hematopoietic cells. There was
no evidence for alternative splicing within the coding sequence of
either gene.
GENE FUNCTION
Using mice lacking G-alpha subunits specifically in smooth muscle cells,
Wirth et al. (2008) found that G-alpha-q (GNAQ; 600998) and G-alpha-11
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.
GENE STRUCTURE
Strathmann and Simon (1991) found that mouse Gna11 and Gna15 (139314)
are tandemly duplicated in a head-to-tail array, spanning approximately
43 kb. Davignon et al., 1996 further studied the genomic structure of
mouse Gna11 and Gna15. Gna11 and Gna15 each contain 7 exons interposed
by 6 introns. Gna11 is upstream of Gna15, and the region separating the
2 genes is 6 kb long. Phylogenetic trees revealed an approximately
6-fold higher rate of change in Gna15 than in Gna11.
MAPPING
Wilkie et al. (1992) demonstrated that the GNA11 gene is located on
mouse chromosome 10 (by the study of RFLVs in an interspecific
backcross) and on human 19p13 (by in situ hybridization).
MOLECULAR GENETICS
In the proband from a 4-generation kindred with hypocalciuric
hypercalcemia mapping to chromosome 19p13 (HHC2; 145981) and an
unrelated proband with HHC, Nesbit et al. (2013) identified
heterozygosity for a 3-bp in-frame deletion and a missense mutation,
respectively (139313.0001-139313.0002). In addition, 2 unrelated
patients with hypocalcemia (HYPOC2; 615361) were found to be
heterozygous for missense mutations in GNA11 (139313.0003 and
139313.0004). All 4 GNA11 mutations predicted disrupted protein
structures, and functional analysis in HEK293 cells showed that family
hypocalciuric hypercalcemia type II-associated mutations decrease the
sensitivity of cells expressing calcium-sensing receptors to changes in
extracellular calcium concentrations, whereas autosomal dominant
hypocalcemia 2-associated mutations increase cell sensitivity.
In affected members of 2 unrelated 4-generation families segregating
autosomal dominant hypocalcemia, Mannstadt et al. (2013) identified
heterozygous missense mutations (139313.0005 and 139313.0006) that
segregated with disease in each family.
- Somatic Mutations
By gene sequencing of exon 5 of the GNA11 gene, Van Raamsdonk et al.
(2010) identified somatic mutations affecting residue Q209 in 7% of blue
nevi (603670), 32% of primary uveal melanomas (155720), and 57% of uveal
melanoma metastases. Mutations in the same codon (Q209) of the paralogue
gene GNAQ (600998) were found in 55% of blue nevi, 45% of primary uveal
melanomas, and 22% 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. Mice injected with cells transduced with the GNA11
Q209L mutation developed rapidly growing tumors and metastases, whereas
injection with GNA11 R183C-transduced cells showed lesser potency.
Western blot analysis of melanocytes transduced with Q209L showed
constitutive activation of the MAPK pathway. 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.
ANIMAL MODEL
Using gene targeting, Offermanns et al. (1998) generated Gna11-deficient
mice that were viable and fertile with no apparent behavioral or
morphologic defects. They bred Gnaq-deficient mice with Gna11-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
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE II
GNA11, 3-BP DEL, 598ATC
In affected members of a 4-generation family segregating autosomal
dominant hypocalciuric hypercalcemia (HHC2; 145981), originally studied
by Heath et al. (1992) (kindred 11675), Nesbit et al. (2013) identified
heterozygosity for a 3-bp deletion (c.598_600delATC) in the GNA11 gene,
resulting in an in-frame deletion of the highly conserved ile200 residue
(ile200del). The mutation was not found in 55 controls or in 5,400
exomes from the NHLBI Exome Sequencing Project. Functional analysis in
HEK293 cells stably expressing calcium-sensing receptors demonstrated
that the GNA11 ile200del mutant induces a decrease in sensitivity to
changes in extracellular calcium concentrations.
.0002
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE II
GNA11, LEU135GLN
In a man who presented at 54 years of age with hypocalciuric
hypercalcemia (HHC2; 145981), Nesbit et al. (2013) identified
heterozygosity for a c.404T-A transversion in the GNA11 gene, resulting
in a leu135-to-gln (L135Q) substitution at a highly conserved residue in
the helical domain. The mutation was not found in 55 controls or in
5,400 exomes from the NHLBI Exome Sequencing Project. Functional
analysis in HEK293 cells stably expressing calcium-sensing receptors
demonstrated that the GNA11 L135Q mutant induces a decrease in
sensitivity to changes in extracellular calcium concentrations.
.0003
HYPOCALCEMIA, AUTOSOMAL DOMINANT 2
GNA11, ARG181GLN
In a woman who was diagnosed at 52 years of age with hypocalcemia
(HYPOC2; 615361), Nesbit et al. (2013) identified heterozygosity for a
c.542G-A transition in the GNA11 gene, resulting in an arg181-to-gln
(R181Q) substitution at a highly conserved residue in the alpha-F helix
of the helical domain. The mutation was not found in 55 controls or in
5,400 exomes from the NHLBI Exome Sequencing Project. Functional
analysis in HEK293 cells stably expressing calcium-sensing receptors
demonstrated that the GNA11 R181Q mutant induces an increase in
sensitivity to changes in extracellular calcium concentrations. The
patient was asymptomatic, but was ascertained after another family
member was diagnosed with hypocalcemia.
.0004
HYPOCALCEMIA, AUTOSOMAL DOMINANT 2
GNA11, PHE341LEU
In a woman who presented at 39 years of age with hypocalcemia (HYPOC2;
615361), Nesbit et al. (2013) identified heterozygosity for a c.1023C-G
transversion in the GNA11 gene, resulting in a phe341-to-leu (F341L)
substitution at a highly conserved residue in the GTPase domain. The
mutation was not found in 55 controls or in 5,400 exomes from the NHLBI
Exome Sequencing Project. Functional analysis in HEK293 cells stably
expressing calcium-sensing receptors demonstrated that the GNA11 F341L
mutant induces an increase in sensitivity to changes in extracellular
calcium concentrations. The patient reported a 10-year history of
occasional paresthesias, muscle cramps, and carpopedal spasm.
.0005
HYPOCALCEMIA, AUTOSOMAL DOMINANT 2
GNA11, ARG60CYS
In 6 affected members of a 4-generation family segregating autosomal
dominant hypocalcemia (HYPOC2; 615361), Mannstadt et al. (2013)
identified heterozygosity for a c.178C-T transition in exon 2 of the
GNA11 gene, resulting in an arg60-to-cys (R60C) substitution at a highly
conserved residue. The mutation was not found in unaffected family
members.
.0006
HYPOCALCEMIA, AUTOSOMAL DOMINANT 2
GNA11, SER211TRP
In 9 affected members of a 4-generation family segregating autosomal
dominant hypocalcemia (HYPOC2; 615361), Mannstadt et al. (2013)
identified heterozygosity for a c.632C-G transversion in exon 5 of the
GNA11 gene, resulting in a ser211-to-trp (S211W) substitution at a
highly conserved residue. The mutation was not found in unaffected
family members.
*FIELD* RF
1. Davignon, I.; Barnard, M.; Gavrilova, O.; Sweet, K.; Wilkie, T.
M.: Gene structure of murine Gna11 and Gna15: tandemly duplicated
Gq class G protein alpha subunit genes. Genomics 31: 359-366, 1996.
2. Heath, H., III; Leppert, M. F.; Lifton, R. P.; Penniston, J. T.
: Genetic linkage analysis in familial benign hypercalcemia using
a candidate gene strategy. I: Studies in four families. J. Clin.
Endocr. Metab. 75: 846-851, 1992.
3. Jiang, M.; Pandey, S.; Tran, V. T.; Fong, H. K.: Guanine nucleotide-binding
regulatory proteins in retinal pigment epithelial cells. Proc. Nat.
Acad. Sci. 88: 3907-3911, 1991.
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. Mannstadt, M.; Harris, M.; Bravenboer, B.; Chitturi, S.; Dreijerink,
K. M. A.; Lambright, D. G.; Lim, E. T.; Daly, M. J.; Gabriel, S.;
Juppner, H.: Germline mutations affecting G-alpha-11 in hypoparathyroidism.
(Letter) New Eng. J. Med. 368: 2352-2354, 2013.
6. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Babinsky, V. N.; Head,
R. A.; Cranston, T.; Rust, N.; Hobbs, M. R.; Heath, H., III; Thakker,
R. V.: Mutations affecting G-protein subunit alpha-11 in hypercalcemia
and hypocalcemia. New Eng. J. Med. 368: 2476-2486, 2013.
7. 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,
1998.
8. Strathmann, M. P.; Simon, M. I.: G-alpha-12 and G-alpha-13 subunits
define a fourth class of G protein alpha subunits. Proc. Nat. Acad.
Sci. 88: 5582-5586, 1991.
9. 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.
10. Van Raamsdonk, C. D.; Griewank, K. G.; Crosby, M. B.; Garrido,
M. C.; Vemula, S.; Wiesner, T.; Obenauf, A. C.; Wackernagel, W.; Green,
G.; Bouvier, N.; Sozen, M. M.; Baimukanova, G.; Roy, R.; Heguy, A.;
Dolgalev, I.; Khanin, R.; Busam, K.; Speicher, M. R.; O'Brien, J.;
Bastian, B. C.: Mutations in GNA11 in uveal melanoma. New Eng. J.
Med. 363: 2191-2199, 2010.
11. Wilkie, T. M.; Gilbert, D. J.; Olsen, A. S.; Chen, X.-N.; Amatruda,
T. T.; Korenberg, J. R.; Trask, B. J.; de Jong, P.; Reed, R. R.; Simon,
M. I.; Jenkins, N. A.; Copeland, N. G.: Evolution of the mammalian
G protein alpha subunit multigene family. Nature Genet. 1: 85-91,
1992.
12. Wirth, A.; Benyo, Z.; Lukasova, M.; Leutgeb, B.; Wettschureck,
N.; Gorbey, S.; Orsy, P.; Horvath, B.; Maser-Gluth, C.; Greiner, E.;
Lemmer, B.; Schutz, G.; Gutkind, J. S.; Offermanns, S.: G-12-G-13-LARG-mediated
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: 08/12/2013
Cassandra L. Kniffin - updated: 12/20/2010
Patricia A. Hartz - updated: 3/6/2008
Marla J. F. O'Neill - updated: 11/6/2007
Victor A. McKusick - updated: 9/30/2004
Dawn Watkins-Chow - updated: 7/11/2002
John A. Phillips, III - updated: 5/12/1998
*FIELD* CD
Victor A. McKusick: 5/19/1992
*FIELD* ED
carol: 08/12/2013
terry: 8/6/2012
wwang: 12/27/2010
ckniffin: 12/20/2010
mgross: 3/6/2008
wwang: 11/12/2007
terry: 11/6/2007
alopez: 9/30/2004
mgross: 7/11/2002
alopez: 7/9/2001
carol: 6/28/1999
alopez: 5/12/1998
jamie: 1/8/1997
jamie: 1/7/1997
mark: 3/20/1996
terry: 3/11/1996
carol: 7/1/1992
carol: 5/19/1992
*RECORD*
*FIELD* NO
139313
*FIELD* TI
*139313 GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-11; GNA11
*FIELD* TX
CLONING
Strathmann and Simon (1991) described the Gna11 gene in the mouse. The
read morehuman gene was cloned by Jiang et al. (1991) and found to be 359 amino
acids long. Mouse Gna11 and Gna15 (139314) are tandemly duplicated in a
head-to-tail array. Davignon et al. (1996) showed that the upstream
gene, Gna11, is ubiquitously expressed, whereas expression of the
downstream gene, Gna15, is restricted to hematopoietic cells. There was
no evidence for alternative splicing within the coding sequence of
either gene.
GENE FUNCTION
Using mice lacking G-alpha subunits specifically in smooth muscle cells,
Wirth et al. (2008) found that G-alpha-q (GNAQ; 600998) and G-alpha-11
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.
GENE STRUCTURE
Strathmann and Simon (1991) found that mouse Gna11 and Gna15 (139314)
are tandemly duplicated in a head-to-tail array, spanning approximately
43 kb. Davignon et al., 1996 further studied the genomic structure of
mouse Gna11 and Gna15. Gna11 and Gna15 each contain 7 exons interposed
by 6 introns. Gna11 is upstream of Gna15, and the region separating the
2 genes is 6 kb long. Phylogenetic trees revealed an approximately
6-fold higher rate of change in Gna15 than in Gna11.
MAPPING
Wilkie et al. (1992) demonstrated that the GNA11 gene is located on
mouse chromosome 10 (by the study of RFLVs in an interspecific
backcross) and on human 19p13 (by in situ hybridization).
MOLECULAR GENETICS
In the proband from a 4-generation kindred with hypocalciuric
hypercalcemia mapping to chromosome 19p13 (HHC2; 145981) and an
unrelated proband with HHC, Nesbit et al. (2013) identified
heterozygosity for a 3-bp in-frame deletion and a missense mutation,
respectively (139313.0001-139313.0002). In addition, 2 unrelated
patients with hypocalcemia (HYPOC2; 615361) were found to be
heterozygous for missense mutations in GNA11 (139313.0003 and
139313.0004). All 4 GNA11 mutations predicted disrupted protein
structures, and functional analysis in HEK293 cells showed that family
hypocalciuric hypercalcemia type II-associated mutations decrease the
sensitivity of cells expressing calcium-sensing receptors to changes in
extracellular calcium concentrations, whereas autosomal dominant
hypocalcemia 2-associated mutations increase cell sensitivity.
In affected members of 2 unrelated 4-generation families segregating
autosomal dominant hypocalcemia, Mannstadt et al. (2013) identified
heterozygous missense mutations (139313.0005 and 139313.0006) that
segregated with disease in each family.
- Somatic Mutations
By gene sequencing of exon 5 of the GNA11 gene, Van Raamsdonk et al.
(2010) identified somatic mutations affecting residue Q209 in 7% of blue
nevi (603670), 32% of primary uveal melanomas (155720), and 57% of uveal
melanoma metastases. Mutations in the same codon (Q209) of the paralogue
gene GNAQ (600998) were found in 55% of blue nevi, 45% of primary uveal
melanomas, and 22% 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. Mice injected with cells transduced with the GNA11
Q209L mutation developed rapidly growing tumors and metastases, whereas
injection with GNA11 R183C-transduced cells showed lesser potency.
Western blot analysis of melanocytes transduced with Q209L showed
constitutive activation of the MAPK pathway. 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.
ANIMAL MODEL
Using gene targeting, Offermanns et al. (1998) generated Gna11-deficient
mice that were viable and fertile with no apparent behavioral or
morphologic defects. They bred Gnaq-deficient mice with Gna11-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
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE II
GNA11, 3-BP DEL, 598ATC
In affected members of a 4-generation family segregating autosomal
dominant hypocalciuric hypercalcemia (HHC2; 145981), originally studied
by Heath et al. (1992) (kindred 11675), Nesbit et al. (2013) identified
heterozygosity for a 3-bp deletion (c.598_600delATC) in the GNA11 gene,
resulting in an in-frame deletion of the highly conserved ile200 residue
(ile200del). The mutation was not found in 55 controls or in 5,400
exomes from the NHLBI Exome Sequencing Project. Functional analysis in
HEK293 cells stably expressing calcium-sensing receptors demonstrated
that the GNA11 ile200del mutant induces a decrease in sensitivity to
changes in extracellular calcium concentrations.
.0002
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE II
GNA11, LEU135GLN
In a man who presented at 54 years of age with hypocalciuric
hypercalcemia (HHC2; 145981), Nesbit et al. (2013) identified
heterozygosity for a c.404T-A transversion in the GNA11 gene, resulting
in a leu135-to-gln (L135Q) substitution at a highly conserved residue in
the helical domain. The mutation was not found in 55 controls or in
5,400 exomes from the NHLBI Exome Sequencing Project. Functional
analysis in HEK293 cells stably expressing calcium-sensing receptors
demonstrated that the GNA11 L135Q mutant induces a decrease in
sensitivity to changes in extracellular calcium concentrations.
.0003
HYPOCALCEMIA, AUTOSOMAL DOMINANT 2
GNA11, ARG181GLN
In a woman who was diagnosed at 52 years of age with hypocalcemia
(HYPOC2; 615361), Nesbit et al. (2013) identified heterozygosity for a
c.542G-A transition in the GNA11 gene, resulting in an arg181-to-gln
(R181Q) substitution at a highly conserved residue in the alpha-F helix
of the helical domain. The mutation was not found in 55 controls or in
5,400 exomes from the NHLBI Exome Sequencing Project. Functional
analysis in HEK293 cells stably expressing calcium-sensing receptors
demonstrated that the GNA11 R181Q mutant induces an increase in
sensitivity to changes in extracellular calcium concentrations. The
patient was asymptomatic, but was ascertained after another family
member was diagnosed with hypocalcemia.
.0004
HYPOCALCEMIA, AUTOSOMAL DOMINANT 2
GNA11, PHE341LEU
In a woman who presented at 39 years of age with hypocalcemia (HYPOC2;
615361), Nesbit et al. (2013) identified heterozygosity for a c.1023C-G
transversion in the GNA11 gene, resulting in a phe341-to-leu (F341L)
substitution at a highly conserved residue in the GTPase domain. The
mutation was not found in 55 controls or in 5,400 exomes from the NHLBI
Exome Sequencing Project. Functional analysis in HEK293 cells stably
expressing calcium-sensing receptors demonstrated that the GNA11 F341L
mutant induces an increase in sensitivity to changes in extracellular
calcium concentrations. The patient reported a 10-year history of
occasional paresthesias, muscle cramps, and carpopedal spasm.
.0005
HYPOCALCEMIA, AUTOSOMAL DOMINANT 2
GNA11, ARG60CYS
In 6 affected members of a 4-generation family segregating autosomal
dominant hypocalcemia (HYPOC2; 615361), Mannstadt et al. (2013)
identified heterozygosity for a c.178C-T transition in exon 2 of the
GNA11 gene, resulting in an arg60-to-cys (R60C) substitution at a highly
conserved residue. The mutation was not found in unaffected family
members.
.0006
HYPOCALCEMIA, AUTOSOMAL DOMINANT 2
GNA11, SER211TRP
In 9 affected members of a 4-generation family segregating autosomal
dominant hypocalcemia (HYPOC2; 615361), Mannstadt et al. (2013)
identified heterozygosity for a c.632C-G transversion in exon 5 of the
GNA11 gene, resulting in a ser211-to-trp (S211W) substitution at a
highly conserved residue. The mutation was not found in unaffected
family members.
*FIELD* RF
1. Davignon, I.; Barnard, M.; Gavrilova, O.; Sweet, K.; Wilkie, T.
M.: Gene structure of murine Gna11 and Gna15: tandemly duplicated
Gq class G protein alpha subunit genes. Genomics 31: 359-366, 1996.
2. Heath, H., III; Leppert, M. F.; Lifton, R. P.; Penniston, J. T.
: Genetic linkage analysis in familial benign hypercalcemia using
a candidate gene strategy. I: Studies in four families. J. Clin.
Endocr. Metab. 75: 846-851, 1992.
3. Jiang, M.; Pandey, S.; Tran, V. T.; Fong, H. K.: Guanine nucleotide-binding
regulatory proteins in retinal pigment epithelial cells. Proc. Nat.
Acad. Sci. 88: 3907-3911, 1991.
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. Mannstadt, M.; Harris, M.; Bravenboer, B.; Chitturi, S.; Dreijerink,
K. M. A.; Lambright, D. G.; Lim, E. T.; Daly, M. J.; Gabriel, S.;
Juppner, H.: Germline mutations affecting G-alpha-11 in hypoparathyroidism.
(Letter) New Eng. J. Med. 368: 2352-2354, 2013.
6. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Babinsky, V. N.; Head,
R. A.; Cranston, T.; Rust, N.; Hobbs, M. R.; Heath, H., III; Thakker,
R. V.: Mutations affecting G-protein subunit alpha-11 in hypercalcemia
and hypocalcemia. New Eng. J. Med. 368: 2476-2486, 2013.
7. 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,
1998.
8. Strathmann, M. P.; Simon, M. I.: G-alpha-12 and G-alpha-13 subunits
define a fourth class of G protein alpha subunits. Proc. Nat. Acad.
Sci. 88: 5582-5586, 1991.
9. 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.
10. Van Raamsdonk, C. D.; Griewank, K. G.; Crosby, M. B.; Garrido,
M. C.; Vemula, S.; Wiesner, T.; Obenauf, A. C.; Wackernagel, W.; Green,
G.; Bouvier, N.; Sozen, M. M.; Baimukanova, G.; Roy, R.; Heguy, A.;
Dolgalev, I.; Khanin, R.; Busam, K.; Speicher, M. R.; O'Brien, J.;
Bastian, B. C.: Mutations in GNA11 in uveal melanoma. New Eng. J.
Med. 363: 2191-2199, 2010.
11. Wilkie, T. M.; Gilbert, D. J.; Olsen, A. S.; Chen, X.-N.; Amatruda,
T. T.; Korenberg, J. R.; Trask, B. J.; de Jong, P.; Reed, R. R.; Simon,
M. I.; Jenkins, N. A.; Copeland, N. G.: Evolution of the mammalian
G protein alpha subunit multigene family. Nature Genet. 1: 85-91,
1992.
12. Wirth, A.; Benyo, Z.; Lukasova, M.; Leutgeb, B.; Wettschureck,
N.; Gorbey, S.; Orsy, P.; Horvath, B.; Maser-Gluth, C.; Greiner, E.;
Lemmer, B.; Schutz, G.; Gutkind, J. S.; Offermanns, S.: G-12-G-13-LARG-mediated
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: 08/12/2013
Cassandra L. Kniffin - updated: 12/20/2010
Patricia A. Hartz - updated: 3/6/2008
Marla J. F. O'Neill - updated: 11/6/2007
Victor A. McKusick - updated: 9/30/2004
Dawn Watkins-Chow - updated: 7/11/2002
John A. Phillips, III - updated: 5/12/1998
*FIELD* CD
Victor A. McKusick: 5/19/1992
*FIELD* ED
carol: 08/12/2013
terry: 8/6/2012
wwang: 12/27/2010
ckniffin: 12/20/2010
mgross: 3/6/2008
wwang: 11/12/2007
terry: 11/6/2007
alopez: 9/30/2004
mgross: 7/11/2002
alopez: 7/9/2001
carol: 6/28/1999
alopez: 5/12/1998
jamie: 1/8/1997
jamie: 1/7/1997
mark: 3/20/1996
terry: 3/11/1996
carol: 7/1/1992
carol: 5/19/1992
MIM
145981
*RECORD*
*FIELD* NO
145981
*FIELD* TI
#145981 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE II; HHC2
;;FAMILIAL BENIGN HYPERCALCEMIA, TYPE II; FBH2;;
read moreHYPERCALCEMIA, FAMILIAL BENIGN, TYPE II
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
familial hypocalciuric hypercalcemia type II (HHC2) is caused by
heterozygous mutation in the GNA11 gene (139313) on chromosome 19p13.
For a general phenotypic description and a discussion of genetic
heterogeneity of hypocalciuric hypercalcemia, see HHC1 (145980).
MAPPING
In a family with hypocalciuric hypercalcemia in which linkage to 3q had
been excluded (kindred 11675), Heath et al. (1992) and Heath et al.
(1993) demonstrated linkage to 19p13.2, obtaining a 2-point lod score of
3.70 (theta = 0.001) at D19S266 and a lod score of 3.44 at D19S20.
MOLECULAR GENETICS
In the proband from a 4-generation kindred with hypocalciuric
hypercalcemia, previously studied by Heath et al. (1992) (kindred
11675), and 9 unrelated patients with familial HHC who were known to be
negative for mutations in the HHC-associated genes CASR (601199) and
AP2S1 (602242), Nesbit et al. (2013) sequenced the candidate gene GNA11.
In the proband from kindred 11675, they identified a heterozygous 3-bp
deletion (139313.0001) that was confirmed to segregate with disease in
the family; in addition, 1 of the 9 unrelated patients with HHC was
found to be heterozygous for a missense mutation (L135Q; 139313.0002).
Functional analysis in HEK293 cells stably expressing calcium-sensing
receptors demonstrated that the mutant GNA11 proteins induce a decrease
in sensitivity to changes in extracellular calcium concentrations.
*FIELD* RF
1. Heath, H., III; Jackson, C. E.; Otterud, B.; Leppert, M. F.: Familial
benign hypercalcemia (FBH) phenotype results from mutations at two
distinct loci on chromosomes 3q and 19p. (Abstract) Clin. Res. 41:
270A only, 1993.
2. Heath, H., III; Leppert, M. F.; Lifton, R. P.; Penniston, J. T.
: Genetic linkage analysis in familial benign hypercalcemia using
a candidate gene strategy. I: Studies in four families. J. Clin.
Endocr. Metab. 75: 846-851, 1992.
3. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Babinsky, V. N.; Head,
R. A.; Cranston, T.; Rust, N.; Hobbs, M. R.; Heath, H., III; Thakker,
R. V.: Mutations affecting G-protein subunit alpha-11 in hypercalcemia
and hypocalcemia. New Eng. J. Med. 368: 2476-2486, 2013.
*FIELD* CS
GU:
Nephrolithiasis uncommon
GI:
Peptic ulcer uncommon;
Pancreatitis
Skin:
Lipomas
Misc:
Neonatal severe primary hyperparathyroidism in homozygotes;
(e.g. Hypocalciuric hypercalcemia, familial .0002)
Radiology:
Chondrocalcinosis
Lab:
Hypocalciuria;
Hypercalcemia;
Hypermagnesemia;
Parathormone-independent renal tubular calcium reabsorption defect;
Ratio of renal calcium clearance to creatinine clearance usually below
0.01;
Ca(2+)-sensing receptor defect (e.g. Hypocalciuric hypercalcemia,
familial .0001);
Defective G protein receptor
Inheritance:
Autosomal dominant with locus heterogeneity (19p13.3)
*FIELD* CN
Marla J. F. O'Neill - updated: 08/12/2013
Marla J. F. O'Neill - updated: 11/30/2011
*FIELD* CD
Victor A. McKusick: 5/7/1993
*FIELD* ED
carol: 08/12/2013
carol: 11/30/2011
carol: 3/18/2004
mimadm: 11/5/1994
carol: 7/19/1993
carol: 5/7/1993
*RECORD*
*FIELD* NO
145981
*FIELD* TI
#145981 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE II; HHC2
;;FAMILIAL BENIGN HYPERCALCEMIA, TYPE II; FBH2;;
read moreHYPERCALCEMIA, FAMILIAL BENIGN, TYPE II
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
familial hypocalciuric hypercalcemia type II (HHC2) is caused by
heterozygous mutation in the GNA11 gene (139313) on chromosome 19p13.
For a general phenotypic description and a discussion of genetic
heterogeneity of hypocalciuric hypercalcemia, see HHC1 (145980).
MAPPING
In a family with hypocalciuric hypercalcemia in which linkage to 3q had
been excluded (kindred 11675), Heath et al. (1992) and Heath et al.
(1993) demonstrated linkage to 19p13.2, obtaining a 2-point lod score of
3.70 (theta = 0.001) at D19S266 and a lod score of 3.44 at D19S20.
MOLECULAR GENETICS
In the proband from a 4-generation kindred with hypocalciuric
hypercalcemia, previously studied by Heath et al. (1992) (kindred
11675), and 9 unrelated patients with familial HHC who were known to be
negative for mutations in the HHC-associated genes CASR (601199) and
AP2S1 (602242), Nesbit et al. (2013) sequenced the candidate gene GNA11.
In the proband from kindred 11675, they identified a heterozygous 3-bp
deletion (139313.0001) that was confirmed to segregate with disease in
the family; in addition, 1 of the 9 unrelated patients with HHC was
found to be heterozygous for a missense mutation (L135Q; 139313.0002).
Functional analysis in HEK293 cells stably expressing calcium-sensing
receptors demonstrated that the mutant GNA11 proteins induce a decrease
in sensitivity to changes in extracellular calcium concentrations.
*FIELD* RF
1. Heath, H., III; Jackson, C. E.; Otterud, B.; Leppert, M. F.: Familial
benign hypercalcemia (FBH) phenotype results from mutations at two
distinct loci on chromosomes 3q and 19p. (Abstract) Clin. Res. 41:
270A only, 1993.
2. Heath, H., III; Leppert, M. F.; Lifton, R. P.; Penniston, J. T.
: Genetic linkage analysis in familial benign hypercalcemia using
a candidate gene strategy. I: Studies in four families. J. Clin.
Endocr. Metab. 75: 846-851, 1992.
3. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Babinsky, V. N.; Head,
R. A.; Cranston, T.; Rust, N.; Hobbs, M. R.; Heath, H., III; Thakker,
R. V.: Mutations affecting G-protein subunit alpha-11 in hypercalcemia
and hypocalcemia. New Eng. J. Med. 368: 2476-2486, 2013.
*FIELD* CS
GU:
Nephrolithiasis uncommon
GI:
Peptic ulcer uncommon;
Pancreatitis
Skin:
Lipomas
Misc:
Neonatal severe primary hyperparathyroidism in homozygotes;
(e.g. Hypocalciuric hypercalcemia, familial .0002)
Radiology:
Chondrocalcinosis
Lab:
Hypocalciuria;
Hypercalcemia;
Hypermagnesemia;
Parathormone-independent renal tubular calcium reabsorption defect;
Ratio of renal calcium clearance to creatinine clearance usually below
0.01;
Ca(2+)-sensing receptor defect (e.g. Hypocalciuric hypercalcemia,
familial .0001);
Defective G protein receptor
Inheritance:
Autosomal dominant with locus heterogeneity (19p13.3)
*FIELD* CN
Marla J. F. O'Neill - updated: 08/12/2013
Marla J. F. O'Neill - updated: 11/30/2011
*FIELD* CD
Victor A. McKusick: 5/7/1993
*FIELD* ED
carol: 08/12/2013
carol: 11/30/2011
carol: 3/18/2004
mimadm: 11/5/1994
carol: 7/19/1993
carol: 5/7/1993
MIM
615361
*RECORD*
*FIELD* NO
615361
*FIELD* TI
#615361 HYPOCALCEMIA, AUTOSOMAL DOMINANT 2; HYPOC2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreautosomal dominant hypocalcemia-2 (HYPOC2) is caused by heterozygous
mutation in the GNA11 gene (139313) on chromosome 19p13.
For a discussion of genetic heterogeneity of autosomal dominant
hypocalcemia, see HYPOC1 (601198).
CLINICAL FEATURES
Mannstadt et al. (2013) studied 2 unrelated 4-generation families
segregating autosomal dominant hypocalcemia. In the first family, the
male proband was diagnosed at 2 years of age with type 1 diabetes
mellitus (see 222100), at which time his total calcium level was normal.
At 5 years of age, he presented with generalized seizures, some of which
were not associated with hypoglycemia; he was treated with carbamazepine
for a year and had no recurrences when treatment was discontinued. At 14
years of age, he complained of tremulousness and muscle cramps and was
found to be hypocalcemic with inappropriately low parathyroid hormone
(PTH) levels. Review of the family history at that time revealed
autosomal dominant transmission of hypocalcemia on the maternal side. In
the second family, the female proband presented with chronic fatigue and
occasional muscle cramps at 20 years of age and was found to have mild
hypocalcemia and mild hyperphosphatemia with a low PTH level. Family
evaluation revealed 9 additional relatives diagnosed with isolated
hypoparathyroidism, all of whom had similarly mild symptoms of
hypocalcemia. None of the affected members of either family had a
history of mucocutaneous candidiasis, hearing loss, or renal
abnormalities, and clinical examination was unremarkable; specifically,
there was no evidence for skin changes.
MAPPING
In a 4-generation family segregating autosomal dominant hypocalcemia in
which mutation in the CASR (601199), PTH (168450), and GCM2 (603716)
genes had been ruled out, Mannstadt et al. (2013) performed a genomewide
scan that revealed linkage to 19p13.3 (lod score, 3.0).
MOLECULAR GENETICS
In 8 unrelated patients with hypocalcemia and low or normal serum
parathyroid hormone concentrations, who were negative for mutation in
the CASR gene (601199), Nesbit et al. (2013) analyzed the candidate gene
GNA11 (139313) and identified heterozygosity for missense mutations in 2
patients (R181Q, 139313.0003; and F341L, 139313.0004). Functional
analysis in HEK293 cells stably expressing calcium-sensing receptors
demonstrated that the mutant GNA11 proteins induce an enhanced
sensitivity to changes in extracellular calcium concentrations, similar
to the effects of gain-of-function mutations in CASR reported in
autosomal dominant hypocalcemia type 1. One of the mutation-positive
patients was asymptomatic, whereas the other reported a 10-year history
of occasional paresthesias, muscle cramping, and carpopedal spasm. Other
family members were unavailable for study.
In a 4-generation family segregating autosomal dominant hypocalcemia
mapping to chromosome 19q13.3, Mannstadt et al. (2013) sequenced the
candidate gene GNA11 and identified a heterozygous missense mutation
(R60C; 139313.0005) that segregated with disease. In an unrelated
4-generation family with hypocalcemia, exome sequencing revealed
heterozygosity for a different missense mutation in GNA11 (S211W;
139313.0006) in affected individuals.
*FIELD* RF
1. Mannstadt, M.; Harris, M.; Bravenboer, B.; Chitturi, S.; Dreijerink,
K. M. A.; Lambright, D. G.; Lim, E. T.; Daly, M. J.; Gabriel, S.;
Juppner, H.: Germline mutations affecting G-alpha-11 in hypoparathyroidism.
(Letter) New Eng. J. Med. 368: 2352-2354, 2013.
2. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Babinsky, V. N.; Head,
R. A.; Cranston, T.; Rust, N.; Hobbs, M. R.; Heath, H., III; Thakker,
R. V.: Mutations affecting G-protein subunit alpha-11 in hypercalcemia
and hypocalcemia. New Eng. J. Med. 368: 2476-2486, 2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Muscle cramps;
Carpopedal spasm
NEUROLOGIC:
[Central nervous system];
Paresthesias
ENDOCRINE FEATURES:
Hypocalcemia;
Parathyroid hormone levels low to low-normal;
Serum phosphorus normal or mildly elevated
MISCELLANEOUS:
Some patients have asymptomatic hypocalcemia
MOLECULAR BASIS:
Caused by mutation in the alpha-11 guanine nucleotide-binding protein
gene (GNA11, 139313.0003)
*FIELD* CD
Marla J. F. O'Neill: 12/9/2013
*FIELD* ED
joanna: 12/09/2013
*FIELD* CD
Marla J. F. O'Neill: 8/6/2013
*FIELD* ED
carol: 08/12/2013
*RECORD*
*FIELD* NO
615361
*FIELD* TI
#615361 HYPOCALCEMIA, AUTOSOMAL DOMINANT 2; HYPOC2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreautosomal dominant hypocalcemia-2 (HYPOC2) is caused by heterozygous
mutation in the GNA11 gene (139313) on chromosome 19p13.
For a discussion of genetic heterogeneity of autosomal dominant
hypocalcemia, see HYPOC1 (601198).
CLINICAL FEATURES
Mannstadt et al. (2013) studied 2 unrelated 4-generation families
segregating autosomal dominant hypocalcemia. In the first family, the
male proband was diagnosed at 2 years of age with type 1 diabetes
mellitus (see 222100), at which time his total calcium level was normal.
At 5 years of age, he presented with generalized seizures, some of which
were not associated with hypoglycemia; he was treated with carbamazepine
for a year and had no recurrences when treatment was discontinued. At 14
years of age, he complained of tremulousness and muscle cramps and was
found to be hypocalcemic with inappropriately low parathyroid hormone
(PTH) levels. Review of the family history at that time revealed
autosomal dominant transmission of hypocalcemia on the maternal side. In
the second family, the female proband presented with chronic fatigue and
occasional muscle cramps at 20 years of age and was found to have mild
hypocalcemia and mild hyperphosphatemia with a low PTH level. Family
evaluation revealed 9 additional relatives diagnosed with isolated
hypoparathyroidism, all of whom had similarly mild symptoms of
hypocalcemia. None of the affected members of either family had a
history of mucocutaneous candidiasis, hearing loss, or renal
abnormalities, and clinical examination was unremarkable; specifically,
there was no evidence for skin changes.
MAPPING
In a 4-generation family segregating autosomal dominant hypocalcemia in
which mutation in the CASR (601199), PTH (168450), and GCM2 (603716)
genes had been ruled out, Mannstadt et al. (2013) performed a genomewide
scan that revealed linkage to 19p13.3 (lod score, 3.0).
MOLECULAR GENETICS
In 8 unrelated patients with hypocalcemia and low or normal serum
parathyroid hormone concentrations, who were negative for mutation in
the CASR gene (601199), Nesbit et al. (2013) analyzed the candidate gene
GNA11 (139313) and identified heterozygosity for missense mutations in 2
patients (R181Q, 139313.0003; and F341L, 139313.0004). Functional
analysis in HEK293 cells stably expressing calcium-sensing receptors
demonstrated that the mutant GNA11 proteins induce an enhanced
sensitivity to changes in extracellular calcium concentrations, similar
to the effects of gain-of-function mutations in CASR reported in
autosomal dominant hypocalcemia type 1. One of the mutation-positive
patients was asymptomatic, whereas the other reported a 10-year history
of occasional paresthesias, muscle cramping, and carpopedal spasm. Other
family members were unavailable for study.
In a 4-generation family segregating autosomal dominant hypocalcemia
mapping to chromosome 19q13.3, Mannstadt et al. (2013) sequenced the
candidate gene GNA11 and identified a heterozygous missense mutation
(R60C; 139313.0005) that segregated with disease. In an unrelated
4-generation family with hypocalcemia, exome sequencing revealed
heterozygosity for a different missense mutation in GNA11 (S211W;
139313.0006) in affected individuals.
*FIELD* RF
1. Mannstadt, M.; Harris, M.; Bravenboer, B.; Chitturi, S.; Dreijerink,
K. M. A.; Lambright, D. G.; Lim, E. T.; Daly, M. J.; Gabriel, S.;
Juppner, H.: Germline mutations affecting G-alpha-11 in hypoparathyroidism.
(Letter) New Eng. J. Med. 368: 2352-2354, 2013.
2. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Babinsky, V. N.; Head,
R. A.; Cranston, T.; Rust, N.; Hobbs, M. R.; Heath, H., III; Thakker,
R. V.: Mutations affecting G-protein subunit alpha-11 in hypercalcemia
and hypocalcemia. New Eng. J. Med. 368: 2476-2486, 2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Muscle cramps;
Carpopedal spasm
NEUROLOGIC:
[Central nervous system];
Paresthesias
ENDOCRINE FEATURES:
Hypocalcemia;
Parathyroid hormone levels low to low-normal;
Serum phosphorus normal or mildly elevated
MISCELLANEOUS:
Some patients have asymptomatic hypocalcemia
MOLECULAR BASIS:
Caused by mutation in the alpha-11 guanine nucleotide-binding protein
gene (GNA11, 139313.0003)
*FIELD* CD
Marla J. F. O'Neill: 12/9/2013
*FIELD* ED
joanna: 12/09/2013
*FIELD* CD
Marla J. F. O'Neill: 8/6/2013
*FIELD* ED
carol: 08/12/2013