BES2003 Poster Presentations Endocrine Tumours and Neoplasia (47 abstracts)
Hyperparathyroidism-jaw tumour syndrome (HPT-JT) in Romany families from Portugal is due to a founder mutation of parafibromin
BM Cavaco 1 , L Guerra 2 , D Carvalho 3 , KJ Bradley 4 , B Harding 4 , AM Kennedy 4 , MA Santos 1 , LG Sobrinho 1 , RV Thakker 4 & V Leite 1
1Centro de Investigacao de Patobiologia Molecular, Instituto Portugues de Oncologia de Francisco Gentil, Lisboa, Portugal; 2Servico de Endocrinologia, Hospital Curry Cabral, Lisboa, Portugal; 3Servico de Endocrinologia, Hospital de S. Joao, Porto, Portugal; 4Molecular Endocrinology Group, University of Oxford, Nuffield Department of Clinical Medicine, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK.
The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disease characterised by the occurrence of parathyroid tumours, which are often carcinomas, and fibro-osseous tumours of the jaw bones. The HPT-JT gene is on chromosome 1q25 and consists of 17 exons that encode a 531 amino-acid protein, designated PARAFIBROMIN (Nature Genetics, in press). Thirteen heterozygous germline mutations that result in truncated or inactivated forms of PARAFIBROMIN have been identified in HPT-JT families. We recently identified 6 families with 43 members (11 affected, 32 unaffected), of Romany origin in Portugal, who had features of the HPT-JT syndrome. Thus, 9 members had developed primary hyperparathyroidism at young ages [mean (plus/minus SD) = 35 plus/minus 16 years], and 2 had parathyroid carcinomas, 2 had cystic adenomas, and 3 had adenomas, and 2 had ossifying fibromas of the jaw. We postulated that they may have a common ancestor and PARAFIBROMIN mutation, and investigated this by haplotype analysis utilising 13 microsatellite polymorphisms from the 1q25-q31 region, and by DNA sequence analysis of the gene encoding PARAFIBROMIN. The 11 affected individuals were found to share a common haplotype over an approximately 12.5cM region on chromosome 1q25-q31, encompassed centromerically by D1S222 and telomerically by D1S2622. Furthermore, a TG deletion in exon 8, involving codons 255 and 256 was identified in the 11 affected individuals. This 2 bp deletion is predicted to result in a frameshift that encodes 9 missense amino-acids followed by a premature Stop at codon 264. In addition, this mutation was also identified in 13 individuals (age range 12 to 57 years) who are asymptomatic and biochemically normal, and this is consistent with an age-related penetrance for HPT-JT. Thus, our studies have demonstrated that the HPT-JT syndrome in these 6 Romany families from Portugal is due to a founder mutation of the gene encoding PARAFIBROMIN.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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