Endocrine Abstracts

Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder characterised by hypercalcaemia and inappropriately low renal calcium excretion. FHH can be classified into three types: FHH1, caused by calcium-sensing receptor (CaSR) loss-of-function mutations, accounting for >65% of cases; FHH2, due to loss-of-function mutations of the G-protein α₁₁ subunit (Gα₁₁); and FHH3, resulting from loss-of-function mutations in the adaptor protein-2 sigma subunit (AP2σ), encoded by AP2S1, identified in 25% cases. The genetic cause in the remaining FHH patients is unknown. Activated CaSR signals predominantly via the Gα_q/11 family of G-proteins leading to activation of mitogen-activated protein kinase, and intracellular calcium release. Gα_q and Gα₁₁ are highly related, have identical tissue expression, and considerable functional overlap. Somatic mutations have been identified in both genes in uveal melanoma, and a parathyroid-specific mouse double knockout of Gnaq/Gna11 phenocopies mice deleted for one allele of CaSR, indicating that the protein family is important in CaSR signalling. We therefore hypothesised that GNAQ mutations may be a cause of FHH. We examined for mutations within the seven exons, exon-intron boundaries and untranslated regions of GNAQ by sequence analysis of leukocyte DNA, isolated from twenty FHH patients who did not have CaSR, GNA11 and AP2S1 mutations. No mutations were identified in the coding or non-coding regions of GNAQ. Binomial probability analysis, using the assumption that mutations in GNAQ would occur at a prevalence of 20% in FHH patients negative for mutations in CaSR, GNA11 and AP2S1, indicated that the likelihood of detecting at least one GNAQ mutation was >99% in this sample size of twenty patients. Therefore, we conclude that it is unlikely that loss-of-function mutations in GNAQ contribute to FHH pathogenesis, and that Gα₁₁ may have a more critical role in calcaemic tissues than the closely related Gα_q.