Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG–repeat

Abstract

Fragile X syndrome is associated with massive expansion of a CGG trinucleotjde repeat within the FMR–1 gene and transcriptional silencing of the gene due to abnormal methylation. Partial cDNA sequence of the human FMR–1 has been reported. We report here the isolation and characterization of cDNA clones encoding the murine homologue, fmr–1, which exhibit marked sequence identity with the human gene, including the conservation of the CGG repeat. A conserved ATG downstream of the CGG repeat in human and mouse and an in–frame stop codon in other human 5′ cDNA sequences demarcate the FMR–1 coding region and confine the CGG repeat to the 5′ untranslated region. We also present evidence for alternative 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, predicting isoforms with novel carboxy termini.