Isolated hypoparathyroidism (HP) is a rare endocrine disorder in which hypocalcemia and hyperphosphatemia are the result of a deficiency of PTH.The symptoms associated with HP are due to hypocalcemia and include muscle cramps, tetany, and seizures.Most cases of HP appear to be sporadic.However, familial forms of the disease have been described, which show either an autosomal recessive (AR) or autosomal dominant (AD) mode of inheritauce.Causes of HP include activating mutations in the gene encoding the CaSR, mutations in pre-pro-PTH and GCMB.Our objective was to analyze gene mutations in a large cohort of Korean patients with sporadic or familial forms of isolated hypoparathyroidism (IH).Two IH families and 17 patients with sporadic IH were identified and included in the analysis.All coding exons and exon-intron borders of prepro-PTH, CaSR and GCMB were sequenced using PCR-amplified DNA.One heterozygous GCMB mutation (C 106R mutant) was further analyzed with functional studies, including electrophoretic mobility shift assays (EMSA) and luciférase-reporter assays to assess DNA-binding and transactivation ability.In one family, we identified a novel heterozygous mutation in exon 2 of GCMB in an affected female and her son, but not in healthy members of this family and not in DNA from >50 healthy controls.The nucleotide changes amino acid residue 106 (C 106R) that is located in the putative DNA-binding domain of GCMB and is conserved in numerous mammalian species.Functional studies revealed reduced binding of the mutant protein as determined by EMSA using a GCM binding motif.The mutant GCMB furthermore revealed significantly reduced activity in luciferase assays using DF1 cells and 6xgbs Luc reporter.In two other patients with sporadic IH, we furthermore identified heterozygous CaSR mutations (D410E and P221L).In addition, one single nucleotide polymorphisms (SNP) was found in the preproPTH gene (c.247C>A), two SNPs in the CaSR gene (c.2956G>T, c2968A>G), and four SNPs in the GCMB gene (c.1-44T>C, c.91-242A>G, c.343+163G>A, c.583-72A>T).The R990G missense mutation in CaSR, previously identified in patients with hypercalciuria, was identified in three IH patients.These SNPs are listed in the public databases.We have identified a novel GCMB mutation that may explain AD-HP.Also, we have identified two heterozygous CaSR mutations (one novel and one known mutation), and several SNPs in the three candidate genes.Future functional studies of the CaSR mutations will help elucidate the molecular mechanism leading to idiopathic hypoparathyroidism.