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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 seen1. LPI is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine1. 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 α/δ chains locus, and a critical region has been defined2. 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 Finland2.

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Figure 1: Families and haplotype data for four LPI families originating from a highly restricted region of southern Italy.
Figure 2: Sequence and expression analysis SLC7A7.
Figure 3: Mutation 197Δ543 in family 1.
Figure 4: Segregation of mutation 1625insATCA in families 2, 3 and 4.
Figure 5: Segregation of mutation 1136-2A>T in Finnish patients.

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Stylianos E. Antonarakis, Brian G. Skotko, … Roger H. Reeves

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Acknowledgements

We thank the families for contributing to this project; G. Parenti and M.R. Larocca for patient-care support; M.R. Tuzzi and E. Conti for technical assistance; B. Franco, S. Banfi and G. Casari for helpful suggestions; M. Smith for preparation of the manuscript; and the YAC Screening Center at San Raffaele Biomedical Science Park. Telethon Grant E.652 is gratefully acknowledged. This work was supported by MURST Cofin 1998 to G.S. and by the BIOMED2 CT97-BMH4-2284 EC grant (EURO-IMAGE) to A.B.

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Correspondence to Giuseppe Borsani or Gianfranco Sebastio.

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Borsani, G., Bassi, M., Sperandeo, M. et al. SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. Nat Genet 21, 297–301 (1999). https://doi.org/10.1038/6815

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