1. ¹Department of Pathology, University of Malta Medical School, G'Mangia, Malta
2. ²Department of Obstetrics and Gynaecology, University of Malta Medical School, G'Mangia, Malta
3. ³Institute of Health Care, University of Malta, G'Mangia, Malta

Correspondence: Professor A Xuereb Anastasi, DNA laboratory, Department of Pathology, University of Malta Medical School, G'Mangia, Malta. Tel: +356 2551882; E-mail: angela.a.xuereb@um.edu.mt

Received 3 April 2006; Revised 17 January 2007; Accepted 14 February 2007; Published online 21 March 2007.

Abstract

Osteoporosis is a metabolic bone disease with a strong genetic component. Family-based linkage studies were performed by a number of investigators to try to identify loci that might contain genes responsible for an increased susceptibility to osteoporosis. A whole-genome linkage scan using 400 microsatellite markers was performed in 27 members from two Maltese families with a highly penetrant form of osteoporosis. The phenotype was defined by lumbar and femoral z-scores calculated after measurement of bone mineral density by DEXA. Both males and females were among the affected individuals. Multipoint parametric and non-parametric linkage analyses were performed by EasyLinkage v4.01 using GENEHUNTER v2.1, assuming dominant and recessive modes of inheritance with variable penetrance. Evidence of linkage was observed to a marker at 11p12 where a non-parametric LOD score of 5.77 (P=0.0006) was obtained. A maximum heterogeneity LOD score of 2.55 for this region was obtained for the dominant mode of inheritance with 90% penetrance and a phenocopy rate of 1%. Following fine mapping, the critical interval was narrowed to a region that is 52.94 cM from 11p-telomere. In this region, the gene for tumour necrosis factor receptor-associated factor 6 (TRAF6) is located approximately 1 cM away from the indicated marker. Sequencing of the promoter region and exons of the TRAF6 gene revealed three sequence variants, one of which was found in three affected members within one family.