GNA11 – Autosomal Dominant Hypocalcemia Type 2

GNA11 encodes the G-protein α-subunit Gα11, a key mediator of calcium-sensing receptor (CaSR) signaling in parathyroid cells. Autosomal dominant hypocalcemia type 2 (ADH2) is caused by heterozygous gain-of-function variants in GNA11 leading to hypocalcemia with inappropriately low parathyroid hormone levels. Functional studies have shown that ADH2-associated GNA11 mutants increase CaSR sensitivity to extracellular calcium, driving the clinical phenotype ([PMID:23802516]).

The first ADH2 family described harbored a heterozygous missense variant, c.1018G>A (p.Val340Met), that cosegregated with hypocalcemia, short stature and early intracranial calcifications in seven affected members across three generations, but was absent in four unaffected relatives ([PMID:27334330]). Subsequent reports include a de novo c.548G>C (p.Arg183Pro) in an infant ([PMID:35777808]) and a pediatric case with c.1023C>G (p.Phe341Leu) presenting with hypocalcemia, hyperphosphatemia, short stature, and basal ganglia calcifications ([PMID:37579049]). Additionally, two unrelated probands were found to carry c.542G>A (p.Arg181Gln) and c.1023C>G (p.Phe341Leu) in a cohort of eight hypocalcemic patients without CASR mutations ([PMID:23802516]).

ADH2 follows an autosomal dominant inheritance pattern with complete penetrance of biochemical features and variable expressivity of clinical symptoms. To date, at least four distinct missense variants have been reported: c.1018G>A (p.Val340Met), c.542G>A (p.Arg181Gln), c.548G>C (p.Arg183Pro) and c.1023C>G (p.Phe341Leu).

In vitro functional assays in HEK293 cells demonstrated that ADH2-associated GNA11 mutants lower the EC50 for CaSR activation, consistent with gain-of-function and increased receptor sensitivity to extracellular calcium ([PMID:23802516]). These findings align with the hypocalcemia and low PTH observed clinically, supporting a mechanism of enhanced signal transduction rather than loss of G-protein function.

No studies to date have refuted the association between GNA11 gain-of-function variants and ADH2. The genetic evidence comprises 11 probands across four kindreds, robust segregation data in one large pedigree, and multiple independent case reports. Experimental concordance from cellular assays further reinforces causality.

Key Take-home: Gain-of-function missense variants in GNA11 cause ADH2 by increasing CaSR sensitivity, making targeted genetic testing critical for diagnosis and management of hypocalcemia.

References

• European journal of endocrinology • 2016 • Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation. PMID:27334330
• The New England journal of medicine • 2013 • Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia PMID:23802516
• Annals of clinical and laboratory science • 2022 • The Youngest Infant to Be Diagnosed with Autosomal Dominant Hypocalcemia Type 2 Harboring a Novel Variant of GNA11: A Case Study and Literature Review. PMID:35777808
• Journal of pediatric endocrinology & metabolism : JPEM • 2023 • A pediatric case of autosomal dominant hypocalcemia type 2. PMID:37579049

Evidence Based Scoring (AI generated)