Nature Genetics
10, 357 - 359 (1995)
doi:10.1038/ng0795-357
A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasiaGary A. Bellus1, Iain McIntosh1, 2, E. Anne Smith1, Arthur S. Aylsworth3, Ilkka Kaitila4, William A. Horton5, Giselle A. Greenhaw6, Jacqueline T. Hecht6
& Clair A. Francomano1, 2
1Center for Medical Genetics, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
2Medical Genetics Branch, National Center for Human Genome Research, National Institutes of Health, Bethesda, Maryland 20892, USA
3Department of Pediatrics and the Brain and Development Research Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
4Department of Clinical Genetics, Helsinki University Hospital, Helsinki, SF-00290, Finland
5Department of Research, Shriner's Hospital for Crippled Children, Portland, Oregon 97201, USA
6Department of Pediatrics, University of Texas Medical School, Houston, Texas 77225, USA Correspondence should be addressed to C.A.F. Hypochondroplasia (MIM 146000) is an autosomal dominant skeletal dysplasia with skeletal features similar to but milder than those seen in achondroplasia1−4. Within the past year, the achondroplasia locus has been mapped to 4p16.3 (refs 5−7) and mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been identified in patients with the disorder8,9. More than 95% of 242 cases reported so far are accounted for by a single Gly380Arg mutation8−11. McKusick et al.12 proposed that achondroplasia and hypochondroplasia are allelic based on the similarities in phenotype between the two disorders and the identification of a severely dwarfed individual whose father had achondroplasia and whose mother had hypochondroplasia. There is also genetic linkage evidence that hypochondroplasia and achondroplasia map to the same locus6,13. We therefore began a systematic screening of FGFR3 to detect mutations in patients with hypochondroplasia. We now report a single FGFR3 mutation found in 8 out of 14 unrelated patients with hypochondroplasia. This mutation causes a C to A transversion at nucleotide 1620, resulting in an Asn540Lys substitution in the proximal tyrosine kinase domain.
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