CLINICAL AND MOLECULAR STUDIES OF ACHONDROPLASIS

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This study has three specific aims: 1) the identification and characterization of causes of morbidity and mortality in achondroplasia, 2) molecular genetic studies designed to identify correlations between mutations which cause achondroplasia and related disorders and the phenotypes of affected individuals, and 3) molecular genetic studies designed to identify mutations in other FGFR3 disorders. Molecular genetic studies in our lab have determined that the mutated allele in sporadic cases of achondroplasia is inherited from the paternal chromosome in 38/38 cases. Advanced paternal age may play a role in the high mutation rate observed at this site. Studies of DNA from patients with hypochondroplasia, but without the common hypochondroplasia mutation, have identified an additional FGFR3 mutation, K650N, in two patients. Other patients with hypochondroplasia have not had demonstrable FGFR3 mutations These findings support previous speculation that there may be genetic heterogeneity in hypochondroplasia. A newly identified skeletal dysplasia, with profound growth retardation, mental retardation and acanthosis nigricans, has been found to result from a specific FGFR3 mutation, K650M. To date, the mutation has been found in 3 patients with this phenotype. Efforts are underway to further define the clinical phenotype and elucidate the pathogenesis of the disorder caused by the K650M mutation. Collaborative studies with Dr. Jeffrey Baron of NICHD have identified an FGFR3 alteration associated with generalized short stature. This alteration, which has been found in 5 patients to date, is predicted to alter a known splice site. The pathogenesis of short stature resulting, at least in part, from this alteration is under investigation.