HGNC Approved Gene Symbol: GNA11
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:3,094,362-3,123,999 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Hypocalcemia, autosomal dominant 2 | 615361 | Autosomal dominant | 3 |
| Hypocalciuric hypercalcemia, type II | 145981 | Autosomal dominant | 3 |
Strathmann and Simon (1991) described the Gna11 gene in the mouse. The human 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.
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.
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).
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.
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.
In affected members of a large 4-generation family segregating autosomal dominant hypocalcemia, Li et al. (2014) identified a heterozygous missense mutation in the GNA11 gene (R60L; 139313.0007) that segregated with disease in the family and was not found in 1,200 in-house whole-exome sequencing samples.
In a 65-year-old woman of Indian origin with hypocalciuric hypercalcemia, who was negative for mutation in the CASR and AP2S1 genes, Gorvin et al. (2016) sequenced exons and adjacent splice sites of the GNA11 gene and identified heterozygosity for a missense mutation (T54M; 139313.0008). Family members were unavailable for segregation analysis. Functional studies demonstrated impairment of Ca(2+)-channel signaling with the mutant protein.
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.
Using RNA-seq followed by filtering, Ayturk et al. (2016) analyzed congenital hemangioma samples from 8 individuals and identified GNAQ as the only gene with variants in 3 or more samples that were not found in controls. Reanalysis of the samples showed that 6 of the 8 had a somatic GNAQ mutation, all involving the glutamine at amino acid 209: Q209L in 4, Q309P in 1, and Q209H in 1; the remaining 2 samples had a GNA11 mutation at the same residue, Q209L. The mutations were confirmed in 6 samples by digital droplet PCR (ddPCR) and/or molecular inversion probe sequencing (MIP-seq), and the somatic nature of the variants was verified by ddPCR testing of saliva or blood from 4 participants. Using a combination of ddPCR and MIP-seq, the authors also tested 8 archival formalin-fixed, paraffin-embedded congenital hemangioma samples and 4 chorangioma samples, and found a likely GNAQ (Q209L and Q209P) or GNA11 (Q209L) mutation in 4 of the congenital hemangioma samples. Ayturk et al. (2016) noted that the same GNAQ or GNA11 mutation (Q209L) occurred in both rapidly involuting congenital hemangioma (RICH) samples and in noninvoluting congenital hemangioma (NICH) samples, suggesting that other genetic, epigenetic, and/or environmental factors likely account for the these tumors' different postnatal behaviors.
In experiments in transfected HEK293-CASR cells, Li et al. (2014) observed significant functional differences between protooncogenic mutations in GNA11 and those associated with hypocalcemia. The protooncogenic Q209L mutation produced far greater activation of ERK1/2 (MAPK3; 601795/MAPK1; 176948) than the hypocalcemia-associated R60L mutation, and Q209L also showed greater activation of p38 (MAPK14; 600289) and JNK (MAPK8; 601158). In addition, Q209L demonstrated constitutive activation of an SRE promoter-luciferase reporter, indicating enhanced downstream signaling through the MAPK pathway, whereas R60L produced only moderately increased ligand-dependent activation compared to wildtype. Li et al. (2014) proposed that the reduced activity of R60L compared to Q209L might provide an explanation for survival of individuals carrying the R60L mutation in their germline.
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.
Wettschureck et al. (2006) found that mice with forebrain-specific deletion of G-alpha-q and G-alpha-11 had spontaneous epileptic seizures starting at age 3 months, with increased frequency as they aged. Histologic and immunohistochemical analyses revealed neuronal degeneration and reactive gliosis in the hippocampal CA1 region of knockout mice. Pharmacologic and electrophysiologic analyses indicated that endocannabinoid-mediated protective mechanisms were intact in knockout mice, but endogenous cannabinoid synthesis was impaired, resulting in increased seizure susceptibility and impaired neuroprotection.
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.
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.
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.
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.
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.
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.
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.
In 6 affected members of a large 4-generation family segregating autosomal dominant hypocalcemia (HYPOC2; 615361), originally reported by Hunter et al. (1981), Li et al. (2014) identified heterozygosity for a c.179G-T transversion in the GNA11 gene, resulting in an arg60-to-leu (R60L) substitution at a critical residue within the alpha-1 helix that forms a salt bridge with asp71 from the helical domain that stabilizes linker 1. The mutation segregated with disease in the family and was not found in 1,200 in-house whole-exome sequencing samples. Transfected HEK293 cells expressing the R60L mutant showed a leftward shift of the concentration-response curve, indicating enhanced sensitivity to changes in extracellular calcium concentrations consistent with a gain-of-function mutation. Li et al. (2014) noted that all affected members of this family developed mild postnatal growth failure and were significantly shorter than their unaffected relatives.
In a 65-year-old woman of Indian origin with hypocalciuric hypercalcemia (HHC2; 145981), Gorvin et al. (2016) identified heterozygosity for a c.161C-T transition (c.161C-T, NM_002067) in exon 2 of the GNA11 gene, resulting in a thr54-to-met (T54M) substitution at a highly conserved residue within the alpha-1 helix. Family members were unavailable for segregation analysis. The variant was not found in the NHLBI-ESP or ExAC databases. Functional studies in transiently transfected HEK293-CaSR cells demonstrated a rightward shift in the Ca(2+) concentration-response curve with significantly elevated mean EC(50) values for the T54M mutant compared to wildtype GNA11, consistent with impairment of CaSR signal transduction. In addition, cells expressing the T54M mutant had significantly reduced maximal signaling responses compared to cells expressing the wildtype protein or the previously reported L135Q mutant (139313.0002).
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