Context: Hypoparathyroidism (HP) is characterized by low parathyroid hormone (PTH) levels, hypocalcemia and hyperphosphatemia. Heterozygous mutations in preproPTH or the calcium-sensing receptor (CaSR) cause some forms of autosomal dominant HP (AD-HP). Furthermore, homozygous mutations in glial-cell missing B (GCMB) have been implicated in autosomal recessive HP (AR-HP). In most other HP patients, however, the molecular defect remains undefined.

Objective: Determine the genetic defect in the affected members of two unrelated families with AD-HP and define the underlying disease mechanism.

Subjects: Several members affected by AD-HP were investigated. The proband in family A had low calcium detected on routine blood testing, while the proband in family B had symptomatic hypocalcemia.

Methods: Mutational analysis of preproPTH, CaSR, and GCMB was performed using PCR-amplified genomic DNA of the probands and other available members of each family. The identified GCMB mutants were characterized by Western blot analysis and luciferase reporter assay using DF-1 fibroblasts.

Results: Two novel heterozygous mutations located in the last GCMB exon (c.1389delT and c.1399delC in families A and B, respectively) were identified that both lead to frame-shifts and replacement of the putative transactivation domain within carboxyl-terminal regions by unrelated amino acid sequence. The mutant GCMB proteins were well expressed and both showed dose-dependent inhibition of the transactivation capacity of wild-type protein in luciferase reporter assays.

Conclusions: The dominant negative effect observed in vitro for both GCMB mutations provides a plausible explanation for the impaired PTH secretion observed in the two unrelated families with AD-HP.