CLINICAL AND MOLECULAR STUDIES OF ACHONDROPLASIS

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This study has two specific aims: 1) the identification and characterization of causes of morbidity and mortality in achondroplasia, and (2) molecular genetic studies designed to identify the gene for achondroplasia and characterize mutations causing the condition, and possible correlations between mutation and disease. Clinical studies to date have focused on children less than five years of age. Previous work has shown that persons in this age group have a substantially increased risk of mortality. In our retrospective study of patients followed at Johns Hopkins and the University of Texas at Houston, we found a 7% mortality rate among children with achondroplasia in the less than five year age group. We have subsequently enrolled 100 children, all less than five at the time they entered the study, to look at neurologic and respiratory complications of achondroplasia. All children entered in the study have had CT or MRI of the head and neck, polysomnography, echocardiography and electrocardiography, and neurologic, developmental, orthopedic and pulmonary consultations. Data analysis is still in progress on the initial evaluations of 100 children. Molecular genetic studies in our lab and others have demonstrated linkage of the achondroplasia gene to markers on the distal tip of 4p. Subsequently, Wasmuth et al showed that mutations in the FGFR3 gene (fibroblast growth factor 3) cause achondroplasia; their studies in 16 patients suggested a high degree of homogeneity of mutations. We have analyzed DNA from 154 unrelated patients with achondroplasia and have confirmed these observations: 150 of them had a G to A mutation at nucleotide 1138, while 3 had a G to C transversion at the same position. Calculations of mutation frequency at this nucleotide suggest that it is the single most highly mutable necleotide known in the human genome.