Asn540Lys mutation in fibroblast growth factor receptor 3 and phenotype inhypochondroplasia

Hypochondroplasia is characterized by a disproportionate short stature with rhizomelic shortening of the limbs. Amino acid substitutions Asn540Lys, As n540Thr and Ile538Val in the fibroblast growth factor receptor 3 (FGFR3) ar e considered to cause hypochondroplasia. In this study we examined the FGFR 3 gene for the previously described hypochondroplasia mutations and the phe notype of 23 probands with clinically and radiologically diagnosed hypochon droplasia. For the phenotype comparison, the patients were divided into two groups: Group 1: hypochondroplasia with Asn540Lys substitution; Group 2,: hypochondroplasia with no mutations identified so far. A three-generation f amily negative for the known hypochondroplasia mutations was examined with polymorphic markers flanking the FGFR1, FGFR2 and FGFR3 genes. Nine (39%) o f 23 probands were found to be heterozygous for the Asn540Lys substitution. The individuals positive for the Asn540Lys substitution were significantly more disproportionate than the individuals without this mutation. In this respect, a genotype-phenotype correlation was found in our patients. Howeve r, some individuals belonging to the group without mutations identified so far showed similarly abnormal proportions. Genotyping/haplotyping in the th ree-generation family with hypochondroplasia showed that FGFR1, FGFR2 and F GFR3 genes were not linked to the hypochondroplasia phenotype in this famil y, thus further confirming the genetic heterogeneity of hypochondroplasia. Conclusion: Individuals with hypochondroplasia heterozygous for the Asn540L ys substitution are significantly more disproportionate than individuals wi thout this mutation. Our study further confirms the clinical and genetic he terogeneity of hypochondroplasia.