Linkage to chromosome 11p12 in two Maltese families with a highly penetrant form of osteoporosis

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 ¼ 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.

Effects of a synonymous variant in exon 9 of the CD44 gene on pre-mRNA splicing in a family with osteoporosis

“…Only 3 A alleles were identified in 3 heterozygous individuals, thus giving a population frequency of 2.38% and a minor allele frequency of 0.012 (1.19%). None of the nine affected members from the other pedigree (Pedigree 1), used in the previous linkage study [5], was found to carry the A allele. Fig.…”

“…In a previous linkage study, performed on two Maltese families with a high incidence of osteoporosis, suggestive linkage to chromosome 11p12 was observed [5]. Fine-mapping reduced the linkage interval to a region between markers D11S1392 (50.64 cM) and D11S935 (52.94 cM), with highest total heterogeneity LOD and NPL (3.07 and 7.0, respectively) to marker D11S935.…”

“…Sequencing of the CD44 gene was performed in an extended family (Pedigree 2) participating in a previous linkage study [5] ( Fig. 1 and Table 1).…”

“…Fine-mapping reduced the linkage interval to a region between markers D11S1392 (50.64 cM) and D11S935 (52.94 cM), with highest total heterogeneity LOD and NPL (3.07 and 7.0, respectively) to marker D11S935. Although both families shared the same linkage interval, highest LOD scores were obtained to two different markers with a spacing of approximately 4 cM between them, showing also different inherited alleles, thus suggesting that different genes might be responsible for the disease in different families [5]. Highest LOD and NPL scores (1.77 and 5.9, respectively) were obtained for marker D11S1392 (50.64 cM) in Pedigree 2, while for Pedigree 1 highest scores were obtained to marker D11S4102 (54 cM).…”

“…Still such studies were useful in understanding better the complex pathophysiology of osteoporosis by identifying genes playing a role in various metabolic pathways and other mechanisms that might lead to disease. Linkage studies of monogenic bone diseases revealed several chromosomal regions putting into light various genes that were never thought to be involved in bone physiology such as the low density lipoprotein receptor-related protein (LRP)-5 and sclerostin (SOST) genes [3,4].In a previous linkage study, performed on two Maltese families with a high incidence of osteoporosis, suggestive linkage to chromosome 11p12 was observed [5]. Fine-mapping reduced the linkage interval to a region between markers D11S1392 (50.64 cM) and D11S935 (52.94 cM), with highest total heterogeneity LOD and NPL (3.07 and 7.0, respectively) to marker D11S935.…”