Prinos P, Costa T, Sommer A, Kilpatrick M W, Tsipouras P
Department of Pediatrics, University of Connecticut Health Center, Farmington 06030, USA.
Hum Mol Genet. 1995 Nov;4(11):2097-101. doi: 10.1093/hmg/4.11.2097.
Hypochondroplasia is a genetic disorder of disproportionate short stature. Linkage analysis provisionally placed hypochondroplasia in the chromosome 4p 16.3 region, a location to which the FGFR3 gene has been mapped. The genotyping of a three-generation family showed no recombinants between the hypochondroplasia phenotype and three highly polymorphic markers flanking the FGFR3 gene. Mutation analysis was performed by RT-PCR and direct sequencing. Primers covering most of the coding sequence of the FGFR3 gene were used for RT-PCR of FGFR3 mRNA and PCR amplification of genomic DNA. A C-->A transversion was detected in nucleotide 1659 predicting an N540K substitution in exon 11 which encodes part of the TK1 domain. The same mutation was found in an individual suspected to be an achondroplasia/hypochondroplasia compound phenotype and affected individuals from three other unrelated families. A second mutation, a C-->G transversion, also in nucleotide 1659 was detected in all affected individuals of another family. The latter also predicts an N540K substitution. These findings establish that a common mutation in the FGFR3 gene underlies hypochondroplasia.
软骨发育不全是一种身材不成比例矮小的遗传性疾病。连锁分析初步将软骨发育不全定位于染色体4p16.3区域，成纤维细胞生长因子受体3（FGFR3）基因已被定位到该位置。对一个三代家族进行基因分型，结果显示软骨发育不全表型与FGFR3基因两侧的三个高度多态性标记之间没有重组。通过逆转录聚合酶链反应（RT-PCR）和直接测序进行突变分析。用于FGFR3信使核糖核酸（mRNA）的RT-PCR及基因组脱氧核糖核酸（DNA）的聚合酶链反应（PCR）扩增的引物覆盖了FGFR3基因的大部分编码序列。在第1659位核苷酸处检测到一个C→A颠换，预测在编码TK1结构域一部分的第11外显子中有一个N540K替换。在一个疑似软骨发育不全/软骨发育不全复合表型的个体以及来自其他三个无亲缘关系家族的受影响个体中发现了相同的突变。在另一个家族的所有受影响个体中检测到第二个突变，同样在第1659位核苷酸处，是一个C→G颠换。后者也预测有一个N540K替换。这些发现证实FGFR3基因中的一个常见突变是软骨发育不全的基础。
