Oldridge M, Wilkie A O, Slaney S F, Poole M D, Pulleyn L J, Rutland P, Hockley A D, Wake M J, Goldin J H, Winter R M
Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
Hum Mol Genet. 1995 Jun;4(6):1077-82. doi: 10.1093/hmg/4.6.1077.
Craniosynostosis, which affects approximately 1 in 2000 children, is the result of the abnormal development and/or premature fusion of the cranial sutures. Studies of mutations in patients with craniosynostosis have shown that the family of fibroblast growth factor receptor genes are extremely important in the correct formation of the skull, and digits. Mutations in the third immunoglobulin domain of fibroblast growth factor receptor 2 (FGFR2), in part of the molecule corresponding to a tissue specific isoform (IIIc), can cause both Crouzon and Pfeiffer syndromes. Two specific mutations in the linking region between the second and third immunoglobulin domains of FGFR2 occur in Apert syndrome. We present here mutations associated with the Crouzon syndrome, also in the third immunoglobulin domain but in an upstream exon. This exon is expressed in both tissue isoforms. Five different mutations were detected in 11 unrelated individuals. A cysteine to phenylalanine change was found in six individuals. This cysteine forms half of the disulphide bridge maintaining the secondary structure of the immunoglobulin domain. The first deletion within an FGFR gene is reported. Together with mutations in exon IIIc these account for 25 mutations out of 40 Crouzon patients studied in our combined series (5).
颅缝早闭影响约两千分之一的儿童，是颅缝异常发育和/或过早融合的结果。对颅缝早闭患者的突变研究表明，成纤维细胞生长因子受体基因家族在颅骨和手指的正常形成中极为重要。成纤维细胞生长因子受体2（FGFR2）第三免疫球蛋白结构域中的突变，在分子的一部分对应于一种组织特异性异构体（IIIc），可导致克鲁宗综合征和 Pfeiffer 综合征。FGFR2第二和第三免疫球蛋白结构域之间连接区域的两种特定突变发生在Apert综合征中。我们在此展示与克鲁宗综合征相关的突变，同样在第三免疫球蛋白结构域，但在外显子上游。该外显子在两种组织异构体中均有表达。在11名无亲缘关系的个体中检测到五种不同的突变。在六名个体中发现了半胱氨酸到苯丙氨酸的变化。该半胱氨酸构成维持免疫球蛋白结构域二级结构的二硫键的一半。报告了FGFR基因内的首次缺失。连同外显子IIIc中的突变，在我们联合系列研究的40名克鲁宗患者中，这些突变占25个（5）。
