Dominant-Negative GCMB Mutations Cause an Autosomal Dominant Form of Hypoparathyroidism

Context: Hypoparathyroidism (HP) is characterized by low PTH levels, hypocalcemia, and hyperphosphatemia. Heterozygous mutations in pre-pro-PTH or the calcium-sensing receptor (CaSR) cause some forms of autosomal dominant HP (AD-HP). Furthermore, homozygous mutations in glial cells missing B (GCMB) have been implicated in autosomal recessive HP (AR-HP). In most other HP patients, however, the molecular defect remains undefined. Objective: Our objectives were to determine the genetic defect in the affected members of two unrelated families with AD-HP and define the underlying disease mechanism. Subjects: Several family members affected by AD-HP were investigated. The proband in family A had low calcium detected on routine blood testing, whereas the proband in family B had symptomatic hypocalcemia. Methods: Mutational analysis of the genes encoding pre-pro-PTH, CaSR, and GCMB was performed using PCR-amplified genomic DNA of the probands and other available members of each family. The identified GCMB mutants...