SLC7A7 – Lysinuric Protein Intolerance

Lysinuric protein intolerance (LPI) is a rare autosomal recessive inborn error of cationic amino acid transport, resulting in impaired absorption of lysine, arginine, and ornithine and secondary urea cycle dysfunction. Patients typically present after weaning with protein-rich food aversion, failure to thrive, hepatosplenomegaly, hematological anomalies, and recurrent hyperammonemic crises (PMID:21308987). The gene SLC7A7 (y+LAT1) encodes the light chain of the heteromeric y⁺L transporter at the basolateral membrane of intestinal and renal epithelial cells. Biallelic pathogenic variants in SLC7A7 underlie LPI by abolishing cationic amino acid transport activity.

Genetic evidence for the SLC7A7–LPI association is definitive based on linkage and mutation analysis in 31 Finnish patients and 1 Spanish patient harboring homozygous or compound heterozygous SLC7A7 variants, segregating with disease in multiple families, and functional transport assays confirming loss of activity ([PMID:10080182]). Case reports and series totaling over 100 patients have identified a broad spectrum of variant classes—missense, nonsense, frameshift, splice-site, large deletions—and recurrent founder alleles, notably the Finnish c.895-2A>T splice variant and Tunisian 1471delTTCT, supporting an autosomal recessive inheritance pattern.

Clinical reports illustrate phenotypic heterogeneity. A Malaysian child with global developmental delay and severe failure to thrive carried a homozygous c.235G>C (p.Gly79Arg) variant confirmed by molecular analysis ([PMID:23358709]). Prenatal and neonatal diagnoses have been achieved by targeted mutation screening, guiding dietary management from birth. Long-term complications include pulmonary alveolar proteinosis, osteoporosis, renal tubular acidosis, and immune dysregulation, emphasizing the need for early recognition and genetic testing.

Functional assays in Xenopus oocytes and mammalian cells demonstrate that missense mutants (e.g., p.Gly54Val, p.Leu334Arg) localize to the membrane but lack transport activity, whereas frameshift and nonsense alleles are retained intracellularly, highlighting loss of function as the primary mechanism ([PMID:10655553], [PMID:11883940]). Expression studies in patient‐derived fibroblasts and lymphoblasts further corroborate transport defects across multiple cell types.

Animal models of Slc7a7 deficiency reinforce human findings. Slc7a7–/– mice exhibit intrauterine growth restriction, neonatal lethality, and postnatal growth failure with markedly reduced plasma IGF-1 and delayed skeletal development, mirroring LPI clinical features ([PMID:17376816], [PMID:37486182]). These models underscore the systemic impact of SLC7A7 loss and provide platforms for therapeutic exploration.

Molecular diagnosis of LPI via SLC7A7 sequencing and deletion/duplication analysis is essential for early dietary interventions (protein restriction, citrulline supplementation, nitrogen scavengers) that mitigate hyperammonemia and improve growth outcomes. Comprehensive functional data and robust genotype–phenotype correlations support definitive clinical validity and utility in guiding management and genetic counseling.

Key take-home: Biallelic loss-of-function SLC7A7 variants cause LPI with a definitive gene–disease relationship; early molecular diagnosis enables targeted dietary and supportive therapies to prevent life-threatening metabolic decompensation.

References

• Nature Genetics • 1999 • Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. PMID:10080182
• Human Molecular Genetics • 2000 • Functional analysis of novel mutations in y(+)LAT-1 amino acid transporter gene causing lysinuric protein intolerance (LPI). PMID:10655553
• European Journal of Pediatrics • 2013 • Hyperexcretion of homocitrulline in a Malaysian patient with lysinuric protein intolerance. PMID:23358709
• American Journal of Physiology. Cell Physiology • 2007 • Slc7a7 disruption causes fetal growth retardation by downregulating Igf1 in the mouse model of lysinuric protein intolerance. PMID:17376816
• Disease Models & Mechanisms • 2023 • Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance. PMID:37486182

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