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Hyperparathyroidism-Jaw Tumor Syndrome in Roma Families from Portugal Is Due to a Founder Mutation of the HRPT2 Gene

Centro de Investigação de Patobiologia Molecular, Instituto Português de Oncologia de Francisco Gentil, Centro Regional de Oncologia de Lisboa, Sociedade Anónima (B.M.C., M.-A.S., L.G.S., V.L.), 1099-023 Lisboa, Portugal; Molecular Endocrinology Group, Nuffield Department of Clinical Medicine, Botnar Research Center, Nuffield Orthopedic Center, University of Oxford (B.M.C., K.J.B., B.H., R.V.T.), Oxford, United Kingdom OX3 7LD; Serviço de Endocrinologia, Hospital Curry Cabral (L.G.), 1069-166 Lisboa, Portugal; Serviço de Endocrinologia, Hospital de S. João (D.C.), 4200 Porto, Portugal; and Centro de Saúde de Elvas (A.O.), 7350 Elvas, Portugal

Address all correspondence to: Dr. Valeriano Leite, Centro de Investigação de Patobiologia Molecular, Instituto Português de Oncologia de Francisco Gentil, Centro Regional de Oncologia de Lisboa, Sociedade Anómina, Rua Professor Lima Basto, 1099-023 Lisboa, Portugal. E-mail: vleite{at}ipolisboa.min-saude.pt.

The hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors and ossifying jaw fibromas. The gene causing HPT-JT, HRPT2, is located on chromosome 1q31.2 and consists of 17 exons that encode a 531-amino acid protein, designated parafibromin. We recently identified six Roma families in Portugal with 56 members (11 affected and 45 asymptomatic), who had the HPT-JT syndrome. We postulated that they may have a common ancestor and that the HPT-JT syndrome may be due to a mutation of the HRPT2 gene. Haplotype analysis using 14 chromosome 1q24-q32 polymorphic markers showed that the 11 affected individuals shared a common haplotype defined by seven markers that spanned an approximately 12.5-cM region, flanked centromerically by D1S202 and telomerically by D1S306. DNA sequence analysis identified a 2-bp (TG or GT) frameshift deletion in exon 8, which predicts a truncated parafibromin protein, in all 11 affected individuals. This mutation was also found in 19 unaffected individuals (age range, 12–74 yr) who shared the affected haplotype, suggesting a low age-related penetrance for HPT-JT in these families. Thus, the HPT-JT syndrome in six Roma families from Portugal is due to a novel founder mutation in the HRPT2 gene.

This work was supported by Fundação Calouste Gulbenkian, Lisboa, Portugal (to V.L. and B.M.C.); Liga Portuguesa Contra o Cancro, Núcleo Regional Sul, Instituto Português de Oncologia de Francisco Gentil-C.R.O.L, S.A. (to B.M.C.); and the Medical Research Council, United Kingdom (to K.J.B., B.H., and R.V.T.).

K.J.B is a Medical Research Council Clinical Training Fellow.

Abbreviations: ASO, Allele-specific oligonucleotide; HPT-JT, hyperparathyroidism-jaw tumor; MEN, multiple endocrine neoplasia.

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