The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta
The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta
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中国成骨不全患者 COL1A1、COL1A2 和 LEPRE1 基因新突变的鉴定
DOI：
10.1007/s00774-011-0284-6
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发表时间：
2012-01-01
影响因子：
3.3
通讯作者：
Fu, Wen-Zhen
中科院分区：
文献类型：
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作者：
Zhang, Zhen-Lin;Zhang, Hao;Fu, Wen-Zhen
成骨不全症（OI）的显性遗传是由编码I型胶原蛋白的基因COL1A1或COL1A2突变引起的，最近在少数常染色体隐性成骨不全症患者中发现了CRTAP、LEPRE1、PPIB、FKBP10、SERPINH1和SP7突变。然而，这些发现主要局限于西方人群。中国成骨不全患者的突变比例以及基因型和表型之间的相关性是完全未知的。在这项研究中，对58名不相关的中国成骨不全症患者的COL1A1、COL1A2、CRTAP和LEPRE1进行了突变分析；研究I型胶原突变与临床特征的关系。COL1A1和COL1A2共鉴定出56个杂合突变，其中COL1A1 43个突变，COL1A2 13个突变。在COL1A1和COL1A2的56个致病突变中，发现了24个新突变，其中25个（44.6%）导致了三螺旋Gly-X-Y三联体结构域中甘氨酸的取代。与COL1A1单倍不全（n = 23）相比，影响甘氨酸残基突变的患者具有严重的骨骼表型。在18岁及以上的患者中，COL1A1单倍体功能不全患者的平均身高和股骨颈骨密度高于螺旋突变患者。有趣的是，我们在两个不相关的常染色体隐性OI家族中发现了LEPRE1基因的两个新的复合杂合突变。尽管基因型与表型的相关性尚不清楚，但我们的研究结果有助于了解中国成骨不全患者的遗传基础。
Dominant inheritance of osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2, the genes that encode type I collagen, and CRTAP, LEPRE1, PPIB, FKBP10, SERPINH1, and SP7 mutations were recently detected in a minority of patients with autosomal recessive OI. However, these findings have been mostly restricted to Western populations. The proportion of mutations and the correlations between genotype and phenotype in Chinese patients with OI are completely unknown. In this study, mutation analyses were performed for COL1A1, COL1A2, CRTAP, and LEPRE1 in a cohort of 58 unrelated Chinese patients with OI; the relationship between collagen type I mutations and clinical features was examined. A total of 56 heterozygous mutations were identified in COL1A1 and COL1A2, including 43 mutations in COL1A1 and 13 mutations in COL1A2. Among the 56 causative COL1A1 and COL1A2 mutations, 24 novel mutations were found, and 25 (44.6%) resulted in the substitution of a glycine within the Gly-X-Y triplet domain of the triple helix. Compared with COL1A1 haploinsufficiency (n = 23), patients with mutations affecting glycine residues had a severe skeletal phenotype. In patients 18 years of age or older, on average patients with COL1A1 haploinsufficiency were taller and had higher femoral neck bone mineral density than with patients with helical mutations. Interestingly, we found two novel compound heterozygous mutations in the LEPRE1 gene in two unrelated families with autosomal recessive OI. Although the genotype–phenotype correlation is still unclear, our findings are useful to understand the genetic basis of Chinese patients with OI.