FRIEDREICHS ATAXIA - A DEFECT IN SIGNAL-TRANSDUCTION

We have previously assigned the mutation causing Friedreich's ataxia ( FRDA) to 9q13 by genetic linkage and fluorescent in situ hybridization analysis, and identified recombination events which position the gene centromeric to D9S5. We report here the extension of a yeast artifici al chromosome contig to span the 860 kb interval immediately proximal to this marker, which includes the D9S886 and D9S887/888 loci reported to flank the FRDA locus, and the construction of a high resolution co smid contig initiated from the D9S888 locus, Exon trapping and cDNA li brary screening strategies have resulted in the isolation of a candida te gene which traverses the centromeric boundary of the FRDA critical region, The gene spans a genomic interval greater than 220 kb with at least two of the coding exons located proximal to the D9S887/888 loci, Expression is complex, with multiple transcripts detected in a variet y of tissues and evidence of alternative splicing and developmental co ntrol, The predicted amino acid sequence for the 2.7 kb transcript rep orted here shows a marked homology to the deduced amino acid sequence of the Saccharomyces cerevisiae MSS4 protein, proposed to function wit hin the phosphoinositide cycle, suggesting a potential role for the hu man homologue in signal transduction, Whilst no evidence for mutation has been detected in this transcript, the sequence represents only one of the shorter alternatively spliced species identified by Northern a nalysis and direct sequencing. This gene remains a strong candidate fo r FRDA.