CLINICAL AND MOLECULAR ASPECTS OF NEPHROPATHIC CYSTINOSIS

Nephropathic cystinosis, an autosomal recessively inherited lysosomal storage disease, results from impaired transport of the disulfide amin o acid cystine out of cellular lysosomes. The consequent accumulation and crystallization of cystine destroys tissues, causing growth retard ation in infancy, renal failure at 10 years of age, and a variety of o ther complications. Early oral therapy with the cystine-depleting agen t cysteamine prevents renal deterioration and enhances growth. Althoug h the lysosomal cystine carrier has been extensively studied, its mole cular structure remains unknown. The lysosomal cystine transporter gen e has been mapped by linkage analysis to human chromosome 17p between polymorphic microsatellite markers D17S1583 and D17S1584. Pertinent re combination events and homozygosity by descent has verified that the c ystinosis gene lies in the 3.6 cM genetic interval between these two m arkers. The cystinosis region has been substantially reduced in size b y the observation of recombination events in cystinosis patients betwe en markers D17S1828 and D17S2167. According to radiation hybrid analys is, these two markers are separated by 10.2 cR(8000) (centirad using 8 000 rad radiation hybrids). Estimates of the physical size of this int erval range from 187 to 510 kb. Four yeast artificial chromosomes have been identified which form a contig covering the original cystinosis region. Two P1 clones together may span the new, smaller interval, mea ning that the cystinosis gene would lie on one of them. Current effort s are being directed toward using these P1 clones to isolate candidate cDNAs by a variety of methods. The ultimate cloning of the cystinosis gene will reveal how functional lysosomal porters are synthesized, ta rgeted, processed, and integrated into the lysosomal membrane.