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CONTEXT: Autosomal dominant hypocalcemia types 1 and 2 (ADH1 and ADH2) are caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and its signaling partner, the G-protein subunit α11 (Gα11), respectively. Over 70 different gain-of-function CaSR mutations, but only 6 different gain-of-function Gα11 mutations are reported to date. METHODS: We ascertained two additional ADH families and investigated them for CaSR and Gα11 mutations. The effects of identified variants on CaSR signaling were evaluated by transiently transfecting wild-type (WT) and variant expression constructs into HEK293 cells stably expressing CaSR (HEK-CaSR), and measuring intracellular calcium (Ca2+i) and MAPK responses following stimulation with extracellular calcium (Ca2+e). RESULTS: CaSR variants were not found, but two novel heterozygous germline Gα11 variants, p.Gly66Ser and p.Arg149His, were identified. Homology modelling of these revealed that the Gly66 and Arg149 residues are located at the interface between the Gα11 helical and GTPase domains, which is involved in guanine nucleotide binding, and this is the site of three other reported ADH2 mutations. The Ca2+i and MAPK responses of cells expressing the variant Ser66 or His149 Gα11 proteins were similar to WT cells at low Ca2+e, but significantly increased in a dose-dependent manner following Ca2+e stimulation, thereby indicating that the p.Gly66Ser and p.Arg149His variants represent pathogenic gain-of-function Gα11 mutations. Treatment of Ser66- and His149-Gα11 expressing cells with the CaSR negative allosteric modulator NPS 2143 normalized Ca2+i and MAPK responses. CONCLUSION: Two novel ADH2-causing mutations that highlight the Gα11 interdomain interface as a hotspot for gain-of-function Gα11 mutations have been identified.

Original publication

DOI

10.1210/clinem/dgz251

Type

Journal article

Journal

J Clin Endocrinol Metab

Publication Date

10/12/2019

Keywords

G-protein, calcium-sensing receptor, parathyroid hormone