SLC7A9 – Cystinuria

Cystinuria is an autosomal recessive disorder characterized by defective renal and intestinal reabsorption of cystine and dibasic amino acids, leading to recurrent nephrolithiasis ([HP:0000787]). SLC7A9 encodes the light subunit b0,+AT of the rBAT–b0,+AT transporter and underlies non-type I cystinuria when mutated. Since its initial mapping to chromosome 19q12-13.1, SLC7A9 has been implicated in numerous cohorts across diverse populations.

1. Clinical Validity

Extensive genetic studies have identified bi-allelic SLC7A9 variants in at least 164 unrelated probands, with disease-segregating alleles in over 20 families, and robust in vitro and in vivo functional concordance, supporting a Definitive gene-disease relationship (rationale: >500 alleles in >350 probands, multi-family segregation, functional transporter assays) ([PMID:10471498]).

2. Genetic Evidence

Inheritance is autosomal recessive. Segregation analyses across multiple pedigrees demonstrate homozygosity or compound heterozygosity for SLC7A9 alleles in affected relatives. In total, ≥164 probands have been reported with bi-allelic SLC7A9 mutations ([PMID:15635077]). The variant spectrum includes missense, nonsense, frameshift, splice-site, and large rearrangements; a founder missense allele c.508G>A (p.Val170Met) recurs in Libyan-Jewish patients ([PMID:10471498]).

3. Functional / Experimental Evidence

Transport assays in COS and HeLa cells co-expressing mutant b0,+AT and rBAT reveal that several missense mutations (e.g., p.Ala182Thr) retain partial residual activity, while others (p.Gly105Arg, p.Val170Met, p.Arg333Trp) abolish transport, correlating with severe urinary amino acid excretion phenotypes ([PMID:11157794]). A splice-site mutation c.605-3C>A has been shown by minigene assays to cause exon skipping and loss of function ([PMID:15670723]).

4. Conflicting Evidence

No substantial conflicting data have been reported; rare digenic cases involving SLC3A1 and SLC7A9 modify but do not refute the primary autosomal recessive contribution of SLC7A9 variants to cystinuria.

5. Integration & Conclusion

SLC7A9 mutations are a well-established cause of non-type I cystinuria, with a broad allelic and phenotypic spectrum. Functional assays consistently validate pathogenicity, and genotype–phenotype correlations guide prognostic assessment. This association informs genetic diagnostics, carrier screening, and personalized management of cystinuria.

Key Take-home: SLC7A9 testing is clinically actionable for diagnosing cystinuria and enabling early intervention to prevent nephrolithiasis.

References

• Nature Genetics • 1999 • Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT [PMID:10471498]
• Human Molecular Genetics • 2001 • Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria [PMID:11157794]
• Molecular Genetics and Metabolism • 2005 • Functional analysis of a new splice site mutation, c.605-3C>A, in the cystinuria gene SLC7A9 leading to exon skipping [PMID:15670723]
• Journal of Medical Genetics • 2005 • New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype [PMID:15635077]

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