HUMAN MUTATION 29(1), 14^21, 2008 MUTATION UPDATE Lysinuric Protein Intolerance: Update and Extended Mutation Analysis of the SLC7A7 Gene Maria Pia Sperandeo, Generoso Andria, and Gianfranco Sebastio à Department of Pediatrics, Federico II University, Naples, Italy Communicated by Ronald J.A. Wanders Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y 1 LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. Coexpression of 4F2hc (the heavy chain subunit) and y 1 LAT-1 induces y 1 L activity (CAA transport). So far a total of 43 different mutations of the SLC7A7 gene, nine of which newly reported here, have been identified in a group of 130 patients belonging to at least 98 independent families. The mutations are distributed along the entire gene and include all different types of mutations. Five polymorphisms within the SLC7A7 coding region and two variants found in the 5 0 UTR have been identified. A genuine founder effect mutation has been demonstrated only in Finland, where LPI patients share the same homozygous mutation, c.895–2A4T. LPI patients show extreme variability in clinical presentation, and no genotype–phenotype correlations have been defined. This phenotypic variability and the lack of a specific clinical presentation have caused various misdiagnoses. At the biochemical level, the elucidation of SLC7A7 function will be necessary to understand precise disease mechanisms and develop more specific and effective therapies. In this review, we summarize the current knowledge of SLC7A7 mutations and their role in LPI pathogenesis. Hum Mutat 29(1), 14–21, 2008. r r 2007 Wiley-Liss, Inc. KEY WORDS: lysinuric protein intolerance; SLC7A7; aminoaciduria; y 1 L activity; cationic amino acid transport; mutation INTRODUCTION Lysinuric protein intolerance (LPI; MIM] 222700) is an inherited aminoaciduria caused by defective cationic amino acid (CAA; arginine, lysine, ornithine) transport at the basolateral membrane of epithelial cells in the intestine and kidney [Simell, 2001]. LPI is more prevalent in Finland (1/76,000 births) but clusters of LPI families are also known in southern Italy and Japan, and sporadic cases have been described worldwide [Sperandeo et al., 2000; Shoji et al., 2002; Norio, 2003]. Major symptoms include vomiting, diarrhea, failure to thrive, hepatosplenomegaly, bone marrow abnormalities, osteoporosis, episodes of coma, mental retardation, lung involvement (mainly as alveolar proteinosis), altered immune response and chronic renal disease [Palacin et al., 2001; Simell, 2001]. Impairment of both intestinal absorption and renal reabsorption of CAA cause a metabolic derangement characterized by low plasma CAA concentrations, increased CAA urinary excretion, and dysfunction of the urea cycle leading to hyperammonemia and orotic aciduria. Dysfunction of the urea cycle has been observed in hepatocytes [Rajantie et al., 1983], possibly explained by low availability of plasma ornithine. The diagnosis of LPI is often difficult due to vague clinical presentation and lack of readily accessible laboratory tests. Therefore it is not surprising that LPI is mainly diagnosed in countries such as Finland, Italy, and Japan, where clinicians are accustomed to it. Classical symptoms of protein intolerance may remain unnoticed during the first and second decades of life due to unconscious avoidance of dietary protein. Nevertheless, infants affected by LPI commonly present gastrointestinal symptoms (feeding difficulties, vomiting, and diarrhea) soon after weaning [Simell, 2001]. The disease was considered relatively benign thanks to treatment based on a low-protein diet and oral supplementation of citrulline, a neutral amino acid that can ameliorate urea cycle dysfunction by its conversion to arginine. However, the natural history of LPI is now showing that this treatment is insufficient to prevent severe complications, which represent the major causes of morbidity and mortality. In addition, the pathogenic mechanisms underlying severe clinical complications of LPI (such as alveolar Published online 31 August 2007 in Wiley InterScience (www. interscience.wiley.com). DOI 10.1002/humu.20589 Received 29 December 2006; accepted revised manuscript 31 May 2007. Grant sponsor: Ministero dell’Universita' e della Ricerca (MURST), Rome; Grant sponsor: Co¢nanziamento (COFIN) 2005; Grant sponsor: European Genomics Initiative on Disorders of Plasma Membrane Amino Acid Transporters (EUGINDAT) EC FPVI; Grant number: LSHM- CT-2003 -502852 à Correspondence to: Gianfranco Sebastio, Department of Pedia- trics, Federico II University,Via Sergio Pansini, 5, 80131 Naples, Italy. E-mail: sebastio@unina.it r r 2007 WILEY-LISS, INC.