title: Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.
abstract: Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR.
authors.affiliation: MRC Molecular Endocrinology Group, Royal Postgraduate Medical School, London, United Kingdom.
authors.forename: S H
authors.initials: SH
authors.lastname: Pearce
authors.forename: D
authors.initials: D
authors.lastname: Trump
authors.forename: C
authors.initials: C
authors.lastname: Wooding
authors.forename: G M
authors.initials: GM
authors.lastname: Besser
authors.forename: S L
authors.initials: SL
authors.lastname: Chew
authors.forename: D B
authors.initials: DB
authors.lastname: Grant
authors.forename: D A
authors.initials: DA
authors.lastname: Heath
authors.forename: I A
authors.initials: IA
authors.lastname: Hughes
authors.forename: C R
authors.initials: CR
authors.lastname: Paterson
authors.forename: M P
authors.initials: MP
authors.lastname: Whyte
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002118:Calcium / Q000097:blood; D002648:Child; D017931:DNA Primers; D005260:Female; D016147:Genes, Tumor Suppressor; D006580:Genetic Carrier Screening; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics* / Q000378:metabolism*; D006961:Hyperparathyroidism / Q000235:genetics* / Q000378:metabolism*; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010280:Parathyroid Glands / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics*; D012016:Reference Values; D015183:Restriction Mapping
chemical_list: D017931:DNA Primers; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium