HIGH-RESOLUTION MAPPING OF THE GENE FOR CYSTINOSIS, USING COMBINED BIOCHEMICAL AND LINKAGE ANALYSIS

Infantile nephropathic cystinosis is an autosomal recessive disorder c haracterized biochemically by an abnormally high intracellular content of free cystine in different organs and tissues due to a transport de fect of cystine through the lysosomal membrane. Affected children pres ent with the Fanconi syndrome and usually develop progressive renal fa ilure within the Ist decade of life. Measurement of free cystine in pu rified polymorphonuclear leukocytes provides an accurate method for di agnosis and detection of heterozygous carriers. In order to localize t he gene locus for cystinosis we performed linkage analysis in 18 cysti nosis families. However, since 17 of these were simplex families, we d ecided to include the phenotypes of the heterozygous carriers previous ly determined by their leukocyte cystine content in the linkage analys is. This approach allowed us to obtain highly significant results, con firming the localization of the cystinosis gene locus recently mapped to the short arm of chromosome 17 by the Cystinosis Collaborative Rese arch Group. Crucial recombination events allowed us to refine the inte rval of the cystinosis gene to a genetic distance of 1 cM. No evidence of genetic heterogeneity was found. Our results demonstrate that the use of the previously determined phenotypes of heterozygous carriers i n linkage analysis provides a reliable method for the investigation of simplex families in autosomal recessive traits.