Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia

dc.contributor.authorNesbit, M. Andrew
dc.contributor.authorHannan, Fadil M.
dc.contributor.authorHowles, Sarah A.
dc.contributor.authorBabinsky, Valerie N.
dc.contributor.authorHead, Rosie A.
dc.contributor.authorCranston, Treena
dc.contributor.authorRust, Nigel
dc.contributor.authorHobbs, Maurine R.
dc.contributor.authorHeath, Hunter, III
dc.contributor.authorThakker, Rajesh V.
dc.contributor.departmentMedicine, School of Medicine
dc.date.accessioned2025-05-06T11:23:52Z
dc.date.available2025-05-06T11:23:52Z
dc.date.issued2013
dc.description.abstractBackground: Familial hypocalciuric hypercalcemia is a genetically heterogeneous disorder with three variants: types 1, 2, and 3. Type 1 is due to loss-of-function mutations of the calcium-sensing receptor, a guanine nucleotide-binding protein (G-protein)-coupled receptor that signals through the G-protein subunit α11 (Gα11). Type 3 is associated with adaptor-related protein complex 2, sigma 1 subunit (AP2S1) mutations, which result in altered calcium-sensing receptor endocytosis. We hypothesized that type 2 is due to mutations effecting Gα11 loss of function, since Gα11 is involved in calcium-sensing receptor signaling, and its gene (GNA11) and the type 2 locus are colocalized on chromosome 19p13.3. We also postulated that mutations effecting Gα11 gain of function, like the mutations effecting calcium-sensing receptor gain of function that cause autosomal dominant hypocalcemia type 1, may lead to hypocalcemia. Methods: We performed GNA11 mutational analysis in a kindred with familial hypocalciuric hypercalcemia type 2 and in nine unrelated patients with familial hypocalciuric hypercalcemia who did not have mutations in the gene encoding the calcium-sensing receptor (CASR) or AP2S1. We also performed this analysis in eight unrelated patients with hypocalcemia who did not have CASR mutations. In addition, we studied the effects of GNA11 mutations on Gα11 protein structure and calcium-sensing receptor signaling in human embryonic kidney 293 (HEK293) cells. Results: The kindred with familial hypocalciuric hypercalcemia type 2 had an in-frame deletion of a conserved Gα11 isoleucine (Ile200del), and one of the nine unrelated patients with familial hypocalciuric hypercalcemia had a missense GNA11 mutation (Leu135Gln). Missense GNA11 mutations (Arg181Gln and Phe341Leu) were detected in two unrelated patients with hypocalcemia; they were therefore identified as having autosomal dominant hypocalcemia type 2. All four GNA11 mutations predicted disrupted protein structures, and assessment on the basis of in vitro expression showed that familial hypocalciuric hypercalcemia type 2-associated mutations decreased the sensitivity of cells expressing calcium-sensing receptors to changes in extracellular calcium concentrations, whereas autosomal dominant hypocalcemia type 2-associated mutations increased cell sensitivity. Conclusions: Gα11 mutants with loss of function cause familial hypocalciuric hypercalcemia type 2, and Gα11 mutants with gain of function cause a clinical disorder designated as autosomal dominant hypocalcemia type 2.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationNesbit MA, Hannan FM, Howles SA, et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N Engl J Med. 2013;368(26):2476-2486. doi:10.1056/NEJMoa1300253
dc.identifier.urihttps://hdl.handle.net/1805/47791
dc.language.isoen_US
dc.publisherMassachusetts Medical Society
dc.relation.isversionof10.1056/NEJMoa1300253
dc.relation.journalThe New England Journal of Medicine
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectHypocalcemia
dc.subjectExtracellular fluid
dc.subjectGerm-line mutation
dc.subjectProtein conformation
dc.subjectSignal transduction
dc.titleMutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia
dc.typeArticle
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