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This version published online on February 22, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2450
A more recent version of this article appeared on May 1, 2005
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Submitted on December 13, 2004
Accepted on February 15, 2005

GCMB MUTATION IN FAMILIAL ISOLATED HYPOPARATHYROIDISM WITH RESIDUAL SECRETION OF PARATHYROID HORMONE

CAROLINE THOMÉE, STEFFEN W. SCHUBERT, JASMINE PARMA, PHU QUOC LÊ, SAID HASHEMOLHOSSEINI, MICHAEL WEGNER, and MARC J. ABRAMOWICZ*

Department of Internal Medicine - Children Unit - CHEI, Brussels; Institut für Biochemie, Universität Erlangen-Nürnberg, Germany; Department of Medical Genetics, Hôpital Erasme and Laboratory of Medical Genetics, ULB, Brussels, Belgium

* To whom correspondence should be addressed. E-mail: marcabra{at}ulb.ac.be.

Isolated hypoparathyroidism is an uncommon metabolic disorder characterized by hypocalcemia and hyperphosphatemia, with absent or low levels of parathyroid hormone. It may present as an apparently sporadic disorder, or be transmitted in families as a genetic trait. Mutations of the calcium-sensing receptor gene and of the preproPTH gene have been reported in occasional cases, and a mutation of the parathyroid-specific transcription factor GCMB gene has been reported in one familial case. We here report a second family with isolated hypoparathyroidism and a GCMB mutation. The patients were two siblings from asymptomatic, first-cousin parents, indicating autosomal recessive inheritance. The mutation consisted of the substitution of a glycine residue with a serine at postion 63 (G63S) in the DNA-binding GCM domain of GCMB. Functional studies in transfected cells showed that the mutation caused loss of GCMB function as it abolished transactivation capacity, in spite of normal subcellular localization, protein stability, and DNA-binding specificity. Contrary to the previously reported family, our patients displayed low but clearly detectable levels of parathyroid hormone in plasma. This residual hormone secretion probably results from a very small residual activity of the G63S mutant GCMB.
Key words: embyogenesis • cell proliferation • calcium homeostasis • autosomal recessive heredity • transcription factor • GCMB • hypoparathyroidism




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