GNA11 – Familial Hypocalciuric Hypercalcemia Type 2

Familial hypocalciuric hypercalcemia type 2 (FHH2) is an autosomal dominant disorder characterized by lifelong mild-to-moderate hypercalcemia, inappropriately normal or elevated parathyroid hormone levels, and hypocalciuria ([HP:0003127]). FHH2 results from heterozygous loss-of-function variants in GNA11 encoding the Gα11 subunit, a key mediator of calcium-sensing receptor (CaSR) signaling.

Genetic evidence supports the association of GNA11 with FHH2: to date, five unrelated probands have been reported with heterozygous GNA11 missense variants causing FHH2, including c.161C>T (p.Thr54Met) ([PMID:26729423]), c.659T>C (p.Phe220Ser) and c.1023C>G (p.Phe341Leu) in multi-patient screens ([PMID:36970776]), and the novel c.1039A>G (p.Thr347Ala) segregating in a three-generation kindred with concordant hypocalciuria and hypercalcemia ([PMID:38920275]). Each variant was absent or rare in population databases, and familial segregation was demonstrated in the Thr347Ala kindred.

Functional studies confirm that GNA11 loss-of-function variants impair CaSR signaling via haploinsufficiency. The Thr54Met and Thr347Ala mutants each induce a rightward shift in CaSR-mediated inositol monophosphate (IP1) accumulation (EC₅₀ approximately 3.88 mM vs 2.94 mM for Thr54Met; 5.67 mM vs 4.38 mM for Thr347Ala) without affecting Gα11 or CaSR expression ([PMIDs:26729423,38920275]). A Gna11 Asp195Gly mouse model recapitulates the FHH2 phenotype and demonstrates normalization of plasma calcium and PTH with cinacalcet therapy, mirroring human biochemical responses ([PMID:29046478]).

A Danish cohort study found no pathogenic GNA11 mutations in 33 CASR-negative FHH patients, suggesting that GNA11 variants account for a minority (~6%) of FHH cases in that population, but not disputing the gene-disease link ([PMID:27913609]).

Collectively, five independent probands, segregation data, and concordant experimental models establish a strong clinical validity for GNA11 in FHH2. The mechanism is consistent with haploinsufficiency of Gα11 leading to reduced CaSR agonist potency and consequent hypercalcemia with hypocalciuria.

Key Take-home: Heterozygous loss-of-function variants in GNA11 are a validated cause of autosomal dominant FHH2, informing genetic diagnosis and offering a rationale for targeted calcimimetic therapy.

References

• The Journal of clinical endocrinology and metabolism • 2024 • Loss-of-Function Thr347Ala Variant in the G Protein Subunit-α11 Causes Familial Hypocalciuric Hypercalcemia 2 (FHH2) PMID:38920275
• Journal of bone and mineral research • 2016 • A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) PMID:26729423
• Journal of bone and mineral research • 2023 • GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia PMID:36970776
• JCI insight • 2017 • Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation PMID:29046478
• European journal of endocrinology • 2017 • AP2S1 and GNA11 mutations - not a common cause of familial hypocalciuric hypercalcemia PMID:27913609

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