GNA11 – Autosomal Dominant Hypocalcemia Type 2 (ADH2)

GNA11 encodes the G protein α‐subunit Gα11, a critical transducer of calcium‐sensing receptor (CaSR) signals that regulate extracellular calcium homeostasis. Heterozygous gain‐of‐function (GOF) mutations in GNA11 cause autosomal dominant hypocalcemia type 2 (ADH2), whereas loss‐of‐function (LOF) alleles lead to familial hypocalciuric hypercalcemia type 2 (FHH2) (PMID:36970776).

To date, eight unrelated ADH2 probands and four FHH2 probands have been reported with distinct GNA11 missense variants in a cohort of >1200 individuals referred for hypo- or hypercalcemia (PMID:36970776). Nine nonsynonymous variants (including p.Thr54Met, p.Arg60His, p.Arg60Leu, p.Gly66Ser, p.Arg149His, p.Arg181Gln, p.Phe220Ser, p.Val340Met and p.Phe341Leu) in 13 probands were classified as pathogenic based on segregation with calcium phenotypes and in silico predictions. An example ADH2 variant, c.542G>A (p.Arg181Gln), has been observed in an individual with hypocalcemia and inappropriately low PTH.

The inheritance of ADH2 is autosomal dominant, with no additional segregation beyond sporadic probands reported in the primary cohort. Functional characterization of Gα11 GOF alleles has demonstrated leftward shifts in CaSR‐mediated intracellular calcium dose–response curves, consistent with increased receptor sensitivity, whereas LOF variants show rightward shifts and impaired GDP binding at the interdomain interface (PMID:36970776; PMID:27647839).

Synonymous and noncoding GNA11 variants (14 and 12, respectively) were shown to be benign polymorphisms by luciferase reporter assays, mRNA/protein analyses, and homology modeling, underscoring the importance of rigorous functional follow‐up to distinguish pathogenic ADH2 alleles from neutral variation.

Collectively, the identification of eight ADH2 probands with GOF GNA11 variants, supported by concordant signaling assays and modeling, establishes a strong gene–disease relationship. Ongoing discovery of novel alleles and deeper phenotyping will refine diagnostic criteria and inform targeted therapeutic strategies for calcium‐sensing disorders.

Key take-home: GNA11 gain-of-function mutations cause ADH2 via enhanced CaSR signaling, enabling molecular diagnosis and guiding precision therapy.

References

• Journal of bone and mineral research • 2023 • GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia. PMID:36970776
• Journal of molecular endocrinology • 2016 • Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis. PMID:27647839

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