Abstract
More than 50% of individuals with hypochondroplasia are heterozygous for mutations at a single FGFR3 nucleotide that result in N540K substitutions. Although genetic heterogeneity has been demonstrated in several families, it is likely that FGFR3 mutations other than N540K also cause hypochondroplasia. We have screened more than 65 individuals with suspected clinical diagnoses of hypochondroplasia (but who do not have N540K mutations) for mutations in FGFR3 exon 15 that disrupt a Bbs-l restriction site. We report here the discovery of 3 novel mutations (G1950T:K650N, G1950C: K650N & A1948C: K650Q) occurring in 5 individuals with clinical features of hypochondroplasia. The phenotype of these individuals tends to be milder than that of individuals with N540K mutations. Total height deficit was less [K650N/Q = -2.09 SD +/- 0.67 (n=5), N540K. = -3.25 SD +/- 1.09 (n=36): P <0.05] and shortening of the metacarpals and proximal digits was less pronounced. In addition, other radiographic features such as narrowing of the lumbar interpedicular distance and overgrowth of the fibula tended to be milder. Mutations in the K650 codon of FGFR3 that cause thanatophoric dysplasia type II (K650E) and SADDAN syndrome (K650M) result in ligand independent constitutive activation of FGFR3 tyrosine kinase. The K650N and K650Q mutations activate FGFR3 tyrosine kinase to similar extents however the degree of activation is more than 10 fold less than that of the K540E and K650M mutations. These results highlight the importance of the K650 codon in FGFR3 function.
Article PDF
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bellus, G., Garber, A., Bryke, C. et al. FGFR3 Mutations K650N and K650Q Cause Hypochondroplasia. Genet Med 2, 76 (2000). https://doi.org/10.1097/00125817-200001000-00087
Issue Date:
DOI: https://doi.org/10.1097/00125817-200001000-00087