HUMAN AND MURINE FMR-1 - ALTERNATIVE SPLICING AND TRANSLATIONAL INITIATION DOWNSTREAM OF THE CGG-REPEAT

Fragile X syndrome is associated with massive expansion of a CGG trinu cleotide repeat within the FMR-1 gene and transcriptional silencing of the gene due to abnormal methylation. Partial cDNA sequence of the hu man FMR-1 has been reported. We report here the isolation and characte rization of cDNA clones encoding the murine homologue, fmr-1, which ex hibit marked sequence identity with the human gene, including the cons ervation of the CGG repeat. A conserved ATG downstream of the CGG repe at in human and mouse and an in-frame stop codon in other human 5' cDN A sequences demarcate the FMR-1 coding region and confine the CGG repe at to the 5' untranslated region. We also present evidence for alterna tive splicing of the FMR-1 gene in mouse and human brain and show that one of these splicing events alters the FMR-1 reading frame, predicti ng isoforms with novel carboxy termini.