GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are linked to GNA11 gene mutations affecting the Gα11 protein and calcium-sensing receptor (CaSR) signaling.
• Previous reports documented a limited number of FHH2 and ADH2-associated GNA11 mutations.

Purpose of the Study:

• To identify and characterize germline GNA11 variants in a large cohort of patients with unexplained hypercalcemia or hypocalcemia.
• To determine the clinical significance of identified GNA11 variants, distinguishing between disease-causing mutations and benign polymorphisms.

Main Methods:

• Screened over 1200 probands for germline GNA11 variants over a 10-year period.
• Classified variants into synonymous, noncoding, and nonsynonymous categories.
• Utilized in silico analysis, 3D homology modeling, and in vitro functional assays (luciferase reporter assays, CaSR-expressing HEK293 cell studies) to assess variant pathogenicity.

Main Results:

• Identified 37 different germline GNA11 variants, including 14 synonymous, 12 noncoding, and 11 nonsynonymous.
• Confirmed 9 previously reported disease-causing nonsynonymous variants in 13 probands.
• Characterized remaining variants: Ala65Thr predicted benign; Met87Val (hypercalcemic) predicted benign via modeling and functional assays; two noncoding variants (5'UTR and intronic deletions) confirmed as benign polymorphisms through in vitro assays.

Conclusions:

• Likely disease-causing GNA11 variants were identified in less than 1% of probands with hypercalcemia or hypocalcemia.
• The study highlights the importance of distinguishing rare benign GNA11 polymorphisms from pathogenic mutations in the genetic diagnosis of calcium disorders.
• This comprehensive analysis expands the understanding of GNA11 variants in the context of calcium homeostasis disorders.