title: Calcium-sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis.
abstract: OBJECTIVE
  Pancreatitis is an unusual complication of the benign disorder familial hypocalciuric hypercalcaemia (FHH) such that it could represent a distinct subgroup of FHH. In order to study this, we investigated three FHH kindreds with recurrent pancreatitis for mutations of the extracellular calcium-sensing receptor (CaR) to identify a possible common genetic aetiology for typical FHH and that associated with pancreatitis.
  
  
  METHODS
  Three FHH kindreds (18 affected, 14 unaffected members) in which the proband had presented with recurrent pancreatitis were identified. The entire 3234bp coding region of the CaR gene was examined by direct DNA sequencing using fluorochrome labelled dideoxy-terminators. Mutations were confirmed and demonstrated to co-segregate with FHH by restriction enzyme analysis.
  
  
  RESULTS
  Three novel heterozygous missense mutations (Asn178Asp, Arg220Gln and Pro221Ser) in the extracellular domain of the CaR were identified in each of the probands. These mutations, which co-segregated with the hypercalcaemia, were not detected as common polymorphisms in 55 unrelated normocalcaemic controls.
  
  
  CONCLUSIONS
  Familial hypocalciuric hypercalcaemia with recurrent pancreatitis is associated with calcium-sensing receptor mutations, and thus this variant has the same genetic aetiology as typical familial hypocalciuric hypercalcaemia.
authors.affiliation: MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, UK.
authors.forename: S H
authors.initials: SH
authors.lastname: Pearce
authors.forename: C
authors.initials: C
authors.lastname: Wooding
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.forename: S E
authors.initials: SE
authors.lastname: Tollefsen
authors.forename: M P
authors.initials: MP
authors.lastname: Whyte
authors.forename: R V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000328:Adult; D002118:Calcium / Q000652:urine; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000150:complications / Q000235:genetics*; D008297:Male; D009154:Mutation; D010195:Pancreatitis / Q000150:complications / Q000235:genetics*; D010375:Pedigree; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics*; D012008:Recurrence; D015183:Restriction Mapping; D017422:Sequence Analysis, DNA
chemical_list: D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium