SLC3A1 – Cystinuria

Cystinuria is an autosomal recessive disorder of renal and intestinal amino acid transport, resulting in recurrent cystine nephrolithiasis and risk of renal impairment. The disease manifests with increased urinary excretion of cystine and dibasic amino acids leading to stone formation, hematuria and sometimes progressive renal insufficiency. Treatment relies on high fluid intake, urinary alkalinization, and cystine‐binding thiol agents to prevent stone recurrence. The classical form (type A) is caused by biallelic mutations in the SLC3A1 gene encoding the heavy subunit rBAT of the b⁰,+ transporter PMID:8054986.

SLC3A1 mutations have been identified in multiple case series and cohorts, with over 130 distinct point mutations including missense, nonsense, frameshift and splice‐site variants. The most frequently reported allele, c.1400T>C (p.Met467Thr), accounts for up to 30% of cystinuria chromosomes in some European populations PMID:8054986; other recurrent variants include c.808C>T (p.Arg270Ter) and c.1500+1G>T. A large cohort study of 85 probands of Italian and Greek origin identified 62 unique SLC3A1 variants, underpinning extensive allelic heterogeneity PMID:18752446.

Genetic linkage to chromosome 2p in 17 unrelated families and segregation of SLC3A1 variants with cystinuria in multiple sibships firmly establish autosomal recessive inheritance PMID:7539209. Compound heterozygotes and homozygotes exhibit similar stone phenotypes, while heterozygotes generally remain asymptomatic carriers. Segregation analysis across these families revealed perfect concordance between biallelic SLC3A1 mutations and biochemical cystinuria, confirming gene–disease causality.

Functional assays in Xenopus oocytes and mammalian cells demonstrate that pathogenic SLC3A1 variants markedly reduce cystine transport activity. Mutants such as p.Thr341Ala and p.Glu268Lys decrease uptake to 54–63% of wild‐type levels, while p.Met467Thr and p.Met467Lys show impaired trafficking and endoplasmic reticulum retention, abrogating cystine transport at the apical membrane PMID:7575432; PMID:9083097.

No studies to date have refuted the SLC3A1–cystinuria association, and no phenotypes other than cystine stone disease have been consistently linked to SLC3A1 variants. Experimental concordance across in vitro transport assays and in vivo clinical segregation underlies the mechanistic basis of disease.

In summary, biallelic loss‐of‐function variants in SLC3A1 cause type A cystinuria through impaired cystine reabsorption. Comprehensive mutation screening and functional validation enable precise genetic diagnosis, inform family counseling, and guide therapeutic strategies to prevent recurrent nephrolithiasis and preserve renal function.

References

• American Journal of Human Genetics • 1995 • Mutations in the SLC3A1 transporter gene in cystinuria. PMID:7539209
• Nature Genetics • 1994 • Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. PMID:8054986
• Genetic Testing • 2008 • Twenty-four novel mutations identified in a cohort of 85 patients by direct sequencing of the SLC3A1 and SLC7A9 cystinuria genes. PMID:18752446
• The Biochemical Journal • 1995 • Mutations of the basic amino acid transporter gene associated with cystinuria. PMID:7575432
• The Journal of Biological Chemistry • 1997 • An intracellular trafficking defect in type I cystinuria rBAT mutants M467T and M467K. PMID:9083097

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