Wilkin D J, Szabo J K, Cameron R, Henderson S, Bellus G A, Mack M L, Kaitila I, Loughlin J, Munnich A, Sykes B, Bonaventure J, Francomano C A
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Am J Hum Genet. 1998 Sep;63(3):711-6. doi: 10.1086/302000.
More than 97% of achondroplasia cases are caused by one of two mutations (G1138A and G1138C) in the fibroblast growth factor receptor 3 (FGFR3) gene, which results in a specific amino acid substitution, G380R. Sporadic cases of achondroplasia have been associated with advanced paternal age, suggesting that these mutations occur preferentially during spermatogenesis. We have determined the parental origin of the achondroplasia mutation in 40 sporadic cases. Three distinct 1-bp polymorphisms were identified in the FGFR3 gene, within close proximity to the achondroplasia mutation site. Ninety-nine families, each with a sporadic case of achondroplasia in a child, were analyzed in this study. In this population, the achondroplasia mutation occurred on the paternal chromosome in all 40 cases in which parental origin was unambiguous. This observation is consistent with the clinical observation of advanced paternal age resulting in new cases of achondroplasia and suggests that factors influencing DNA replication or repair during spermatogenesis, but not during oogenesis, may predispose to the occurrence of the G1138 FGFR3 mutations.
超过97%的软骨发育不全病例是由成纤维细胞生长因子受体3（FGFR3）基因中的两种突变（G1138A和G1138C）之一引起的，这会导致特定的氨基酸替代，即G380R。软骨发育不全的散发病例与父亲年龄较大有关，这表明这些突变在精子发生过程中更易发生。我们已经确定了40例散发病例中软骨发育不全突变的亲本来源。在FGFR3基因中靠近软骨发育不全突变位点处鉴定出了三种不同的单碱基多态性。本研究分析了99个家庭，每个家庭的孩子都患有软骨发育不全散发病例。在这个群体中，在所有40例亲本来源明确的病例中，软骨发育不全突变都发生在父本染色体上。这一观察结果与父亲年龄较大导致软骨发育不全新病例的临床观察结果一致，并表明影响精子发生过程中而非卵子发生过程中DNA复制或修复的因素可能易导致G1138 FGFR3突变的发生。
