Neonatal severe hyperparathyroidism associated with a novel de novo heterozygous R551K inactivating mutation and a heterozygous A986S polymorphism of the calcium-sensing receptor gene

Judit Tõke, G. Czirják, A. Patócs, Balázs Enyedi, Péter Gergics, Violetta Csákváry, P. Enyedi, Miklós Tóth

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Abstract

Introduction: Neonatal severe hyperparathyroidism (NSHPT) is induced by inactivating mutations of human calcium-sensing receptor (CaSR). Only three heterozygous de novo inactivating mutations of CaSR causing NSHPT have been described. We report the case of a now 11-year-old boy with NSHPT and we characterize a novel inactivating mutation along with the results of some functional analyses. Patient and methods: As a neonate the patient presented the clinical syndrome of NSHPT. At 6 years of age persisting hypercalcaemia without clinical symptoms was documented, and the patient remained completely symptom free without parathyroid surgery until his present age of 11 years. The entire coding region of the CaSR gene of the patient and his family members was sequenced. Functional investigation was performed in HEK-293 cells, transiently transfected with wild type and mutant CaSR plasmid constructs. Results: Sequence analysis revealed a novel de novo heterozygous mutation at codon 551 (AGG→AAG), predicting a change of arginine to lysine (R551K) and a known heterozygous polymorphism (A986S) on the same allele, which was inherited from the father. We demonstrated that the novel R551K mutation significantly reduced the calcium sensitivity of CaSR (EC50: from 3.38 ± 0.62-6.10 ± 0.83 mmol/l), which was not alleviated by the simultaneous presence of A986S polymorphism. Conclusions: We present the fourth NSHPT case induced by a novel de novo heterozygous inactivating mutation (R551K) of the CaSR gene. The disease gradually reverted to a symptomless, benign condition resembling familial hypocalciuric hypercalcaemia without any surgical intervention.

Original languageEnglish
Pages (from-to)385-392
Number of pages8
JournalClinical Endocrinology
Volume67
Issue number3
DOIs
Publication statusPublished - Sep 2007

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Calcium-Sensing Receptors
Hyperparathyroidism
Mutation
Genes
HEK293 Cells
Hypercalcemia
Codon
Fathers
Lysine
Sequence Analysis
Arginine
Plasmids
Alleles
Newborn Infant
Calcium

ASJC Scopus subject areas

  • Endocrinology

Cite this

Neonatal severe hyperparathyroidism associated with a novel de novo heterozygous R551K inactivating mutation and a heterozygous A986S polymorphism of the calcium-sensing receptor gene. / Tõke, Judit; Czirják, G.; Patócs, A.; Enyedi, Balázs; Gergics, Péter; Csákváry, Violetta; Enyedi, P.; Tóth, Miklós.

In: Clinical Endocrinology, Vol. 67, No. 3, 09.2007, p. 385-392.

Research output: Contribution to journalArticle

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AU - Enyedi, Balázs

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