GNA11 variants identified in patients with hypercalcemia or hypocalcemia

Sarah A Howles, Caroline M Gorvin, Treena Cranston, Angela Rogers, Anna K Gluck, Hannah Boon, Kate Gibson, Mushtaqur Rahman, Allen Root, M Andrew Nesbit, Fadil M Hannan, Rajesh V Thakker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gain-of-function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calcium-sensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline GNA11 variants in >1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 non-coding, and 11 non-synonymous variants. The synonymous and non-coding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcaemic and hypocalcaemic individuals. Nine of the non-synonymous variants, (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands, have been reported to be FHH2- or ADH2-causing. Of the remaining non-synonymous variants, Ala65Thr, was predicted to be benign and Met87Val, identified in a hypercalcaemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it to be likely benign; and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two non-coding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in GNA11 mRNA or Gα11 protein levels in cells from the patient, and no abnormality in splicing of the GNA11 mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease causing GNA11 variants in <1% of probands with hypercalcemia or hypocalcemia and highlights occurrence of GNA11 rare variants that are benign polymorphisms.

Original languageEnglish
JournalJournal of Bone and Mineral Research
Early online date27 Mar 2023
DOIs
Publication statusE-pub ahead of print - 27 Mar 2023

Bibliographical note

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Keywords

  • Cell/tissue signaling-endocrine pathways
  • calcium-sensing receptor
  • g protein-coupled receptors
  • familial hypocalciuric hypercalcemia

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