Analysis of disease genes for skeletal dysplasias

为了建立骨骼发育不良、骨和软骨遗传性疾病的DNA诊断系统，并深入了解其发病机制，我对骨骼发育不良进行了遗传分析，并获得了以下结果：1.直接测序并不总是可靠的。2.我们在X连锁显性点状软骨发育不良中发现了3个新的EBP突变，发现X染色体失活导致家族内表型变异。(1)We在假性软骨发育不全和MED（多发性骨骺发育不良）中发现了9种新的COMP突变以及基因型-表型相关性。(2)We首次鉴定出Torrance型扁平脊椎骨发育不良是由COL 2A 1突变引起的。(3)We在以下疾病中发现了新的突变：（4）在软骨发育不良、先天性脊椎骨骺发育不良、先天性脊椎骨骺发育不良、Stickler综合征和迟发性脊椎骨骺发育不良中发现了COL 2A 1。（5）MED中的MAIN 3和COL 9A 3。（6）软骨-毛发中的RMRP。（7）TGF β 1在Camurati-Engelmann病中的表达。（8）Shwachman-Diamond综合征的SBDS。3.我们发现在假性软骨发育不全和多发性骨骺发育不良患者中，携带COMP突变的患者循环COMP降低。

To establish a system for DNA diagnosis of skeletal dysplasias, genetic disorders of bone and cartilage, and gain insight for their pathogenesis, I performed genetic analysis of skeletal dysplasias and obtained the following results.1.Direct sequencing is not always reliable. Allele specific PCR amplification could occur due to sequence identity between a PCR primer and an amplicon.2.We identified 3 novel EBP mutations in X-linked dominant chondrodysplasia punctata and found skewed X-chromosome inactivation causes intra-familial phenotypic variation.(1)We identified 9 novel COMP mutations in pseudoachondroplasia and MED (multiple epiphyseal dysplasia) and genotype-phenotype association.(2)We identified for the first time that platyspondylic skeletal dysplasia, Torrance type is caused by COL2A1 mutation.(3)We found novel mutations in the following disease:(4)COL2A 1 in hypochondrogenesis、 spondyloepiphyseal dysplasia congenita、 Kniest dysplasia、Stickler syndrome and spondyloepiphyseal dysplasia tarda.(5)MAIN3 and COL9A3 in MED.(6)RMRP in Cartilage-Hair ].(7)TGFB1 in Camurati-Engelmann disease.(8)SBDS in Shwachman-Diamond syndrome.3.We found circulating COMP is decreased in pseudoachondroplasia and multiple epiphyseal dysplasia patients carrying COMP mutations.