Loss-of-function Thr347Ala Variant in the G Protein Subunit-Α11 Causes Familial Hypocalciuric Hypercalcemia 2

Abstract

Abstract Context and Objectives To date, only 4 loss-of-function variants in the GNA11 gene encoding the G protein subunit α11 (Gα11) leading to familial hypocalciuric hypercalcemia (FHH) 2 have been characterized. Gα11 is involved in calcium-sensing receptor (CaSR) signaling, and loss-of-function variants in GNA11 lead to reduced agonist potency at CaSR and an FHH phenotype. Design and participants We have identified a family with a heterozygous GNA11 Thr347Ala variant and characterized its impact on calcium homeostasis in FHH2 patients and the signaling properties of CaSR through the Gα11-Thr347Ala variant in vitro. Main Outcome Measures The index patient and her family had clinical, biochemical, and genetic analyses performed. The expression levels of Gα11 and the cell-surface expression levels of CaSR in human embryonic kidney 293A Gq/11 knockout cells (ΔGq/11-HEK293A) cotransfected with CaSR and Gα11 [wild type (WT) or Thr347Ala] were determined, and the functional properties exhibited by calcium at CaSR were characterized in an inositol monophosphate (IP1) accumulation assay. Results Heterozygous carriers of the GNA11 Thr347Ala variant had mild asymptomatic hypercalcemia, hypocalciuria, and inappropriately high normal PTH levels considering their elevated serum calcium levels. Whereas the variant did not impact Gα11 expression or CaSR cell surface expression levels, calcium displayed a moderately but significantly lower agonist potency at CaSR/Gα11-Thr347Ala-transfected cells compared with CaSR/Gα11-WT-transfected cells in the IP1 accumulation assay (EC50 values of 5.67 mM and 4.38 mM, respectively). Conclusion This identification of a novel GNA11 variant causing FHH2 substantiates the important role of Gα11 for CaSR signaling and Ca2+ homeostasis.