MOLECULAR ANALYSIS OF MUTATIONS IN THE GENE FMR-1 SEGREGATING IN FRAGILE X-FAMILIES

Molecular genetic analysis of the transmission of mutations in 73 fami lies with fragile X (one of the largest samples evaluated so far) has confirmed previous hypotheses that the fragile X syndrome results from two consecutive mutational steps, designated ''premutation'' and ''fu ll fragile X mutation''. These mutations give rise to expansions of re striction fragments, most probably by amplification of the FMR-1 CGG r epeat. Premutations are identified by small expansions that apparently have no effect on either the clinical or the cellular phenotype. Full mutations are reflected by large expansions and hypermethylation of t he expanded gene region. All males showing large expansions were affec ted. Individuals with full mutations also expressed the fragile X, wit h only one exception. An affected ''mosaic'' male, showing a predomina nce of premutated fragments in his leukocytes, was shown to be fragile -X-negative on different occasions. About 50% of heterozygotes with fu ll mutations were reported by clinicians to be mentally retarded. Conv ersion of the premutation to the full mutation may occur at oogenesis, as previously suggested, or after formation of a zygote at an early t ransitional stage in development when the CGG repeat behaves as a mito tically unstable element on maternally derived/imprinted X chromosomes carrying a premutation of sufficient repeat length.