Cystinuria is a recessively inherited disease characterized by the excessive urinary excretion of cystine and the dibasic amino acids lysine, arginine, and ornithine. Cystine is the least soluble of these amino acids, and consequently precipitates in the urine, leading to urinary colic, obstruction, secondary urinary tract infection, or, if untreated, renal insufficiency. Based on the urinary levels and intestinal absorption of cystine in obligate heterozygotes, three phenotypes (types I, II, and III) have been defined. Prior to the beginning of the present reporting period, we had mapped a cystinuria susceptibility gene to the short arm of chromosome 2, and had found a total of 5 cystinuria-associated mutations in the amino acid transporter SLC3A1, which is encoded in the appropriate region of chromosome 2. Others have shown that mutations in this gene are seen only in type I cystinuria. Also prior to this year we had determined the genomic structure and promoter sequence of the SLC3AI gene, and had found that cystinuria in Libyan Jewish families is not linked to chromosome 2. Our goal during the last year has been to determine the chromosomal location of thecystinuria susceptibility gene in these Libyan Jewish families. These studies were carried out in Israel by a former fellow, Dr. Elon Pras, with study design and computational assistance from the Genetics Section. Following a genome-wide search involving over 75 microsatellite markers, we found strong evidence for linkage to 7 markers on the long arm of chromosome 19. A maximal lod score of 9.22 was obtained with the marker D19S882. Multipoint linkage data and analysis of recombinants placed the gene in an 8 cM interval, between the markers D19S409 and D19S208. Significant linkage disequilibrium was observed for alleles of 4 markers, and a specific haplotype comprised of alleles at the markers D19S225, D19S208, D19S220, and D19S422 was found in 11 of 17 carrier chromosomes, vs. 1 of 58 Libyan Jewish noncarrier chromosomes. Urinary cystine data in heterozygotes in these families were most consistent with type II cystinuria.
