Molecular analysis of cystinosis: Probable Irish origin of the most commonFrench Canadian mutation

Infantile nephropathic cystinosis, an autosomal recessive disease character ized by a lysosomal accumulation of cystine, presents as failure to thrive, rickets and proximal renal tubular acidosis. The cystinosis gene, CTNS, wh ich maps to chromosome 17p13, encodes a predicted 55kDa protein with charac teristics of a lysosomal membrane protein. We have conducted extensive link age analysis in a French Canadian cystinosis cohort identifying a founding haplotype present in approximately half (21/40) of the chromosomes studied. Subsequent mutational analysis, in addition to identifying two novel mutat ions, has unexpectedly revealed a mutation which has been previously found in Irish (but not French) cystinotic families on these 21 French Canadian c hromosomes. Haplotype analysis of two Irish families with this mutation sup ports the hypothesis that Celtic chromosomes represent an extensive portion of cystinosis chromosomes in French Canada. Our analysis underlines the ge netic heterogeneity of the French Canadian population, reflecting a frequen tly unrecognized contribution from non-Gallic sources including the Irish.