title: Neonatal severe hyperparathyroidism associated with a novel de novo heterozygous R551K inactivating mutation and a heterozygous A986S polymorphism of the calcium-sensing receptor gene.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 2nd Department of Medicine and Department of Physiology, Semmelweis University, Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Tõke
authors.forename: Gábor
authors.initials: G
authors.lastname: Czirják
authors.forename: Attila
authors.initials: A
authors.lastname: Patócs
authors.forename: Balázs
authors.initials: B
authors.lastname: Enyedi
authors.forename: Péter
authors.initials: P
authors.lastname: Gergics
authors.forename: Violetta
authors.initials: V
authors.lastname: Csákváry
authors.forename: Péter
authors.initials: P
authors.lastname: Enyedi
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
mesh_terms: D015519:Bone Density; D002118:Calcium / Q000378:metabolism; D002648:Child; D005192:Family Health; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D006961:Hyperparathyroidism / Q000000981:diagnostic imaging / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D011859:Radiography; D044169:Receptors, Calcium-Sensing / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: C095550:CASR protein, human; D044169:Receptors, Calcium-Sensing; D002118:Calcium