SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance

Abstract

Lysinuric protein intolerance (LPI, MIM 222700) is an autosomal recessive multisystem disorder found mainly in Finland and Italy. On a normal diet, LPI patients present poor feeding, vomiting, diarrhoea, episodes of hyperammoniaemic coma and failure to thrive. Hepatosplenomegaly, osteoporosis and a life-threatening pulmonary involvement (alveolar proteinosis) are also seen. LPI is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine. Metabolic derangement is characterized by increased renal excretion of CAA, reduced CAA absorption from intestine and orotic aciduria. The gene causing LPI was assigned using linkage analysis to chromosome 14q11.2 near the T-cell receptor alpha/delta chains locus, and a critical region has been defined. We have identified two new transcripts (SLC7A8 and SLC7A7) homologous to amino acid transporters, highly expressed in kidney and mapping in the LPI critical region. Mutational analysis of both transcripts revealed that SLC7A7 (for solute carrier family 7, member 7) is mutated in LPI. In five Italian patients, we found either an insertion or deletion in the coding sequence, which provides evidence of a causative role of SLC7A7 in LPI. Furthermore, we detected a splice acceptor change resulting in a frameshift and premature translation termination in four unrelated Finnish patients. This mutation may represent the founder LPI allele in Finland.

New mutations in the SLC7A7 gene of two chinese sisters with lysinuric protein intolerance

“…However, the major and life‐threatening complications involve the lung are manifested as PAP and fibrosis 1. Only a few papers have been published about LPI specifically presenting as pulmonary symptoms 2. Linkage analysis was used to locate the pathogenic gene of LPI as SLC7A7 mutation which is the solution transport vector.…”

Basolateral LAT-2 Has a Major Role in the Transepithelial Flux of L-Cystine in the Renal Proximal Tubule Cell Line OK

“…The apical amino acid transporters responsible for this residual reabsorption are unknown. Dibasic amino acids leave renal epithelial cells across the basolateral domain via system y ϩ L. The main support for this is the fact that mutations in y ϩ LAT-1 (SLC7A7) cause lysinuric protein intolerance, a disease characterized by dibasic aminoaciduria (15,16). Transport activity reminiscent of system y ϩ L has been described in the basolateral membrane of rat enterocytes (33).…”

“…Second, y ϩ LAT-1 dimerizes with 4F2hc to form the amino acid transporter y ϩ L, which mediates the efflux of cationic amino acids coupled with the influx of neutral amino acids plus sodium (12)(13)(14). Mutations in y ϩ LAT-1 (SLC7A7) cause lysinuric protein intolerance (15,16), an inherited aminoaciduria due to defective dibasic amino acid efflux from the basolateral membrane of proximal tubule epithelial cells (17). Thus, systems b o,ϩ and y ϩ L explain the trans-epithelial transport of dibasic amino acids.…”

Hemophagocytic lymphohistiocytosis and pulmonary alveolar proteinosis in a 13-month-old boy with lysinuric protein intolerance

“…[6] Lysinuric protein intolerance (LPI) is a rare autosomal recessive disease that is caused by mutations in the SLC7A7 gene leading to dysfunction of the cationic amino acid trans-porter (lysine, ornithine, arginine) subunit y+LAT1, which mainly affects intestinal and renal cells. [7,8] Patients with LPI have a highly variable clinical presentation ranging from mild protein intolerance, hepatosplenomegaly and hematologic abnormalities to severe manifestations such as failure to thrive, pulmonary alveolar proteinosis (PAP), kidney failure and immune deficiency. [9] Patients with LPI have an increased susceptibility to HLH and HLH has previously been described in patients with LPI.…”