IFNGRI and TNFAIP3 in a Maltese family with a highly penetrant form of osteoporosis

Abstract

Osteoporosis is a metabolic bone disease with a strong genetic component. It is characterised by decreased bone mineral density (BMD), deterioration of the micro architecture of bone and an increased susceptibility to fractures. In the last decade, much research using different approaches such as linkage and association, has been devoted to understand the genetic mechanism behind this complex trait. In this study, a linkage approach was taken. Suggestive linkage to chromosome 6q23-4 was reported from a genome-wide scan performed in a Maltese family with a history of osteoporosis. In this study, fine-mapping was carried by the use of additional microsatellite markers. Multipoint linkage analysis assuming dominant and recessive modes of inheritance with variable penetrance was performed. This revealed suggestive evidence linkage to a marker at 6q23-24, where a peak multipoint parametric LOD score of 1.91 and a non-parametric LOD score (NPL) of 7.06 were obtained under a dominant mode of inheritance with 90% penetrance and a phenocopy rate of 1 % by Easylinkage v5.05 using GENEHUNTER v2.1. Following fine-mapping, the putative susceptibility region was reduced from 20cM to that of 7cM. Based on the knowledge of bone physiology, interferon gamma receptor 1 (IFNGRl) and tumour necrosis factor alpha-induced protein factor 3 (TNFAIP3) were the two candidate genes sequenced. Both genes are located approximately I cM away from the indicated marker. A number of sequence variants were identified in IFNGRl, amongst which a novel non-synonymous sequence variant in exon 7, resulting in the amino acid change from valine to leucine at codon 289 (V289L). Sequencing of TNF AIP3 exons did not result in the identification of any sequence variants.