Gene Mapping And Identification For Osteoporosis And Benign Familial Adult Myoclonus Epilepsy

The present study aims to map and identify genes of two kinds of diseases, i.e. osteoporosis and benign familial adult myoclonus epilepey, the former with complex hetitable mode and the latter with autosomal dominant heritance mode.Regarding Osteoporosis, we utilized genetic epidemiology strategy and proteomics study strategy to map and identify the genes, on two levels i. e. DNA and protein levels, for osteoporosis in Chinese Han female populations.1) Firstly, we used a RFLP marker MspI and a microsatllite marker (GT) n in COL1A2 genes, and utilized QTDT programs to test association and linkage of this gene with bone mineral density and bone size in Chinese nuclear families. The two markers were in close linkage disequilibrium. We detected the following significant within-family association: MspI and BMD at spine (p = 0. 013), total hip(p = 0. 053), and intertrochanter(p = 0. 004), (GT) 17 and BMD at spine (p = 0. 012) , femoral neck (p = 0. 032) , and trochanter (p = 0. 023); (GT) 12 and BMD at spine (p = 0. 009); M(GT) 12and BMD at spine (p = 0. 009) , total hip (p = 0. 017) , and trochanter (p = 0. 001); (GT) 18 and BMD at total hip (p = 0. 053) , femoral neck (p = 0.024); m(GT)18 and BMD at femoral neck (p = 0. 013). MspI and bone size at intertrochanter (p = 0.024) and total hip (p = 0. 043) . Except MspI and total hip bone size, the above associations were all confirmed by permutation test. These indicated that C0L1A2 is in linkage disequilibrium with QTL underlying BMD and bone size in Chinese Han females.2) Secondly, we utilized two-way analysis of variation to test the relationship of 14 pairs of interaction among 7 genes with Chinese females' peak bone mass. We found significant interaction effect of ERP X IL6 on PBM at total hip(P = 0. 019), intertrochanter (P = 0. 016), and femoral neck(P = 0. 019), AHSG×IL6 on femeral neck PBM(P = 0. 046) . Carriers of GGPp have an average of 18. 0%,. 19. 5% and 14. 8% higher BMD at total hip, intertrochanter, and femoral neck than carriers of GGpp. GGSS carriers have an average of 18. 8% higher femoral neck BMD than GGSs carriers.3) Most importantly, we utilized the proteomics strategy into the study of complex, disease osteoporosis. Through two dimension electrophorosis combined mass spectrometry, we compared the protein expression profiles of circulating monocytes from Chinese Han females with high vs. low PBM. A total of 96 irredundant proteins were identified. Six of them were confirmed by western blotting for their differential expression in the two samples: WDR1, gelsolin, K-alpha-1 tubulin, RSU1, PSMA5, P4HB. They might be involved in monocytes' attachment, transendothelial movement, and differentiation into osteoclast, thus affect the osteoclastogenesis, and finally lead to BMD variationRegarding BFAME, we diagnosed and recruited a large pedigree affected with BFAME, for the first time in Chinese. Firstly, we excluded the two chromosomal.regions previously reported linked to BFAME in Japanese and Italy. Through whole geneome scan and genehunter analysis, we mapped the causative gene in a new chromosomal region 10pl5 and narrowed it within a region spanning 6.0 Mb. Combined the specific clinical features, our results indicated that the pedigree may belong to a new subtype of BFAME.The present study represents the first attempt to identify genes for osteoporosis using proteomics strategy, and we successfully identified six interesting proteins which might relative to osteoclastgeneiss, including two new factors, i.e. PSMA5 and P4HB. This study is also the first effort of exploring the specific genetic locus of BFAME in Chinese pedigree. The new genomic region identified in the Chinese pedigree indicates the existences of a third subtype of BFAME.