Lee Kwang-Soo, Song Hae-Ryong, Cho Tae-Joon, Kim Hyon J, Lee Tae-Mi, Jin Hyun-Seok, Park Hyun-Young, Kang Seongman, Jung Sung-Chul, Koo Soo Kyung
Division of Genetic Disease, Department of Biomedical Sciences, National Institute of Health, Seoul, Korea.
Hum Mutat. 2006 Jun;27(6):599. doi: 10.1002/humu.9423.
Mutations in the type I collagen genes COL1A1 and COL1A2 are responsible for the dominantly inherited connective tissue disorder osteogenesis imperfecta (OI). The severity of OI is diverse, ranging from perinatal lethality to a very mild phenotype that is characterized by normal stature and the absence of deformities. Although there have been several studies on the mutational spectra of COL1A1 and/or COL1A2 in Western populations, very few cases have been reported from Asia. In this study, we investigated 67 unrelated Korean probands with OI and used nucleotide sequence analysis to detect COL1A1 and COL1A2 mutations. Thirty-five different mutations were identified in the two genes, including 24 novel mutations. Among the 35 kinds of detected mutations, 15 were glycine substitutions (seven in COL1A1 and eight in COL1A2), one was a nonsense mutation, four were frameshift mutations in COL1A1, three were in-frame duplications in COL1A2, and 12 were splice site mutations (seven in COL1A1 and five in COL1A2). Until now, mutations in the COL1A1 and COL1A2 genes known to cause OI were unique and rarely repeated in other families. Interestingly, the c.982G>A (p.Gly328Ser) mutation in COL1A2 was found recurrently and was the causative mutation in five independent OI probands. Haplotype analysis of the COL1A2 gene revealed that four probands from five independent OI probands with c.982G>A (p.Gly328Ser) had a common haplotype. Our clinical data showed the heterogeneity even within a specific genotype, which suggested the complex expression of this disease.
I型胶原蛋白基因COL1A1和COL1A2的突变是导致显性遗传结缔组织疾病成骨不全症（OI）的原因。OI的严重程度各不相同，从围产期致死到非常轻微的表型，其特征是身材正常且无畸形。尽管西方人群中已经对COL1A1和/或COL1A2的突变谱进行了多项研究，但亚洲报道的病例很少。在本研究中，我们调查了67名无关的韩国OI先证者，并使用核苷酸序列分析来检测COL1A1和COL1A2突变。在这两个基因中鉴定出35种不同的突变，包括24种新突变。在检测到的35种突变中，15种是甘氨酸替代（COL1A1中有7种，COL1A2中有8种），1种是无义突变，4种是COL1A1中的移码突变，3种是COL1A2中的框内重复，12种是剪接位点突变（COL1A1中有7种，COL1A2中有5种）。到目前为止，已知导致OI的COL1A1和COL1A2基因中的突变是独特的，在其他家族中很少重复。有趣的是，COL1A2中的c.982G>A（p.Gly328Ser）突变被反复发现，并且是5个独立的OI先证者中的致病突变。COL1A2基因的单倍型分析显示，来自5个独立的具有c.982G>A（p.Gly328Ser）的OI先证者中的4个先证者具有共同的单倍型。我们的临床数据显示即使在特定基因型内也存在异质性，这表明该疾病的表达复杂。
