GCM2 – Familial Isolated Hyperparathyroidism

Familial isolated hyperparathyroidism (FIHP) is a rare autosomal dominant endocrine disorder characterized by parathyroid hormone excess and hypercalcemia. Germline-activating variants in the parathyroid-specific transcription factor GCM2 (Gene Symbol) have been implicated in FIHP (Disease Name). FIHP accounts for about 1% of primary hyperparathyroidism cases and shows genetic heterogeneity involving MEN1, CDC73, CASR, and GCM2.

In an exome sequencing study of eight unrelated FIHP kindreds, three rare missense variants in the C-terminal conserved inhibitory domain (CCID) of GCM2 were identified, with two recurrent variants (c.1144G>A and c.1181A>C) present in seven of 40 (18%) kindreds. The c.1181A>C (p.Tyr394Ser) variant co-segregated with disease in multiple affected family members and was absent in unaffected relatives (PMID:27745835).

Functional assays demonstrated that CCID variants increased GCM2 transcriptional activity in luciferase reporter systems by 1.5- to 2-fold over wild type, confirming a gain-of-function mechanism. Deletion analyses delineated the CCID as an autoinhibitory region, and variant-driven dysregulation of parathyroid hormone promoter activity provided mechanistic concordance with the hypersecretion phenotype (PMID:27745835).

An ethnicity-focused study in Ashkenazi Jewish FIHP kindreds found the p.Tyr394Ser variant in 41% of families and in 27% of sporadic primary hyperparathyroidism cases, whereas p.Leu379Gln (c.1136T>A) was enriched in European kindreds. These data support a founder effect and variable penetrance across populations (PMID:29264504).

Conflicting in vivo evidence arises from a knock-in mouse model harboring the orthologous p.Y392S variant, which exhibited normal parathyroid development and calcium homeostasis, suggesting species-specific effects or compensatory regulation (PMID:37885910).

Collectively, germline gain-of-function GCM2 variants meet criteria for a Strong gene–disease association: co-segregation in multiple families, recurrence in diverse cohorts, and consistent in vitro functional activation. Inclusion of GCM2 in FIHP genetic testing panels enhances molecular diagnosis, informs surgical management, and guides family counseling.

References

• American Journal of Human Genetics • 2016 • GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism PMID:27745835
• Journal of the Endocrine Society • 2017 • Ethnicity of Patients With Germline GCM2-Activating Variants and Primary Hyperparathyroidism PMID:29264504
• Journal of the Endocrine Society • 2023 • A Knock-In Mouse Model of the Gcm2 Variant p.Y392S Develops Normal Parathyroid Glands PMID:37885910

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