Context: Hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and absent or markedly reduced serum levels of intact PTH. The transcription factor GCM2 is critical for the development of parathyroid glands in mice and humans.

Objective: We sought to determine the prevalence of GCM2 gene mutations in patients with familial or sporadic forms of isolated hypoparathyroidism (IH).

Design and Setting: We used PCR to analyze the promoter, the exons, and flanking intronic sequences in 10 IH families with 17 affected members and in 10 patients with sporadic IH. Wild-type and mutant GCM2 proteins were expressed in HEK293 cells and characterized.

Results: We identified nine single nucleotide changes, three in the 5′ untranslated region and six in exon 5, that led to nonsynonymous changes in the GCM2 protein (G203S, I227V, Y282D, N315D, Q330L, and M354V). Variant GCM2 proteins had normal size, nuclear localization, and transactivational function when expressed in HEK293 cells. Similar analyses of two previously described GCM2 missense mutations, R47L and G63S, revealed decreased nuclear expression and markedly reduced (5–20% of normal) transactivational activity. The variant alleles did not segregate with inheritance of IH, and many of the single nucleotide substitutions were present in DNA from unrelated normal subjects, suggesting that these base changes were polymorphisms.

Conclusion: Our study describes nine single nucleotide changes in the GCM2 gene that represent polymorphisms. Although GCM2 mutations appear to be an uncommon cause of IH, the wide variety of GCM2 polymorphisms suggests that variant alleles may have a role in determining parathyroid function.