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

Endocrine (M.Ma., S.R.P., H.J.) and Pediatric Nephrology (H.J.) Units, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Assistance Publique-Hôpitaux de Paris (G.B., B.G., C.S.), Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Université Paris 7, UFR Médicale, 75018 Paris, France; Service d’Endocrinologie et Service de Médecine Infantile III et Génétique Clinique (M.Mu., G.W., B.L.), Centre Hospitalier Universitaire de Nancy et Faculté de Médecine, Nancy-Université/Université Henri Poincaré, 54003 Nancy, France; and Institut National de la Santé et de la Recherche Médicale Unit 561 (C.S.), Hôpital Saint Vincent de Paul, Université Paris 5, UFR Médicale, 75014 Paris, France

Address all correspondence and requests for reprints to: Harald Jüppner, M.D., Massachusetts General Hospital, Endocrine Unit, Thier 1051, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: hjueppner{at}partners.org.

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 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 second transactivation domain within carboxyl-terminal region 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.