SLC7A7 genomic structure and novel variants in three Japanese lysinuric protein intolerance families

Lysinuric protein intolerance (LPI) is a rare inherited disease caused by d efective transport of the dibasic amino acids at the basolateral membranes of epithelial cells in the renal tubules and small intestine. The metabolic defect leads to brain dysfunction caused by hyperammonemia with a function al impairment of the urea cycle. Recently, mutations in the human SLC7A7 cD NA coding for y(+)LAT-1, which express dibasic amino acid transport activit y, were reported to be responsible for LPI. In the present study, we examin ed the genomic structure of SLC7A7 by DNA sequencing of PCR products, and d etermined that the gene had 11 exons and 10 introns spanning about 18 kb of genomic DNA. We also identified an alternative RNA splicing at the 5' untr anslated region of the SLC7A7 mRNA in human peripheral blood leukocytes, cu ltured lymphoblasts, and fibroblasts. As a result of mutational analysis of SLC7A7 in three Japanese LPI families, we found a nonsense mutation (R410X ), a splicing mutation(911+1G>A) in intron 4, and four silent polymorphisms (201C/T, 445A/G, 784C/T, 946T/C). Identification of the genomic structure of SLC7A7 may provide a molecular basis for a genetic survey for LPI. Hum M utat 15:367-372, 2000. (C) 2000 Wiley-Liss, Inc.