Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2009) 19 P5

SFEBES2009 Poster Presentations Bone (21 abstracts)

Identification of a kindred from Northern Ireland with familial hypocalciuric hypercalcaemia type 3, which maps to chromosome 19q13.3

MA Nesbit 1 , FH Hannan 1 , U Graham 2 , S Hunter 2 , PJ Morrison 3 & RV Thakker 1

1Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast UK; 3Department of Medical Genetics, Belfast City Hospital, Lisburn Road, Belfast, Belfast, UK.

Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder of mineral metabolism that is characterized by lifelong elevation of serum calcium concentrations associated with inappropriately low urinary calcium excretion (calcium clearance:creatinine clearance <0.01). Three separate FHH loci have been identified (FHH1-3). Loss-of-function mutations of the calcium-sensing receptor (CaSR) gene located on 3q21.1, which account for the majority of FHH cases, cause FHH1. The genes causing FHH2 and FHH3, whose chromosomal locations are 19p and 19q13.3, respectively, remain unknown. FHH2 and FHH3 have each been described in only single North American kindreds. We now report the finding of FHH3 in a kindred from Northern Ireland in whom DNA sequence analysis of the coding regions and splice sites of the CaSR gene had not identified any mutations. The family contains three generations and consists of 20 members (14 hypercalcaemic and 6 normocalcaemic). The proband was a 43 year old woman who presented with a corrected serum calcium of 2.80 mmol/l (normal=2.15–2.60 mmol/l), a serum PTH of 52pg/ml (normal =10–65pg/ml), and a urinary calcium clearance:creatinine clearance of 0.006. Venous blood was obtained from the family members, after informed consent, as approved by the local ethical committee, and leukocyte DNA extracted. Single nucleotide polymorphism (SNP) studies of the family members, using 3q21.1 (rs1042636 and rs27625243) and 19q13.3 SNPs (rs889144, rs17294094, and rs11672046), was undertaken by DNA sequence analysis. This excluded the 3q21.1 CaSR locus, but the chromosome 19q13.3 SNPs demonstrated co-segregation with FHH (peak LOD score =2.7 at 0% recombination with SNP rs889144). Thus, our studies have identified a second kindred with FHH3 that maps to chromosome 19q13.3, and these results will facilitate the identification of the responsible gene and give new insights into calcium homeostasis.

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