CTNS – Nephropathic Infantile Cystinosis

Infantile nephropathic cystinosis is an autosomal recessive lysosomal storage disorder caused by biallelic mutations in the CTNS gene encoding the cystine exporter cystinosin. Early-onset renal Fanconi syndrome, failure to thrive, rickets and progressive renal failure define the clinical phenotype, with intracellular cystine accumulation diagnostic by leukocyte cystine measurement. Linkage analysis in 18 cystinosis families refined the CTNS locus to chromosome 17p13 within a 1 cM interval, with no evidence of genetic heterogeneity, confirming CTNS as the causative gene (PMID:8644713).

Genetic evidence is robust: in a cohort of 25 infantile patients, 12 carried two truncating alleles and 13 harbored missense or in-frame deletions disrupting transmembrane domains, consistent with loss of transporter function (PMID:10556299). A French Canadian founder haplotype encompassing 21 of 40 disease chromosomes and shared with Irish families carrying c.473T>C (p.Leu158Pro) illustrates population-specific alleles (PMID:10482956). The common 57-kb deletion accounts for 59 % of Dutch alleles, underscoring recurrent large-scale rearrangements in CTNS (PMID:11528232).

Functional assays confirm pathogenicity via multiple mechanisms. Promoter mutations (e.g., -295G>C) abolish Sp1 binding and reduce CTNS expression in reporter assays (PMID:11505338). Transport studies of 31 patient-derived variants demonstrated that 16 of 19 infantile cystinosis mutations abolish lysosomal cystine efflux, whereas milder juvenile alleles retain residual activity (PMID:15128704). An ER-associated degradation pathway for misfolded cystinosin(Δ7) was delineated, and chemical chaperones restored folding and decreased cystine levels by ~70 % in vitro (PMID:37561577). In Ctns⁻/⁻ mice, cystinosin deficiency directly impairs osteoblast and osteoclast function, causing bone loss independent of renal failure (PMID:30794806).

No conflicting reports of CTNS acting outside nephropathic cystinosis have been substantiated. Taken together, decades of genetic mapping, variant discovery in >100 unrelated patients, concordant functional and animal studies yield a definitive association.

Key take-home: Comprehensive CTNS molecular analysis enables early diagnosis, informs prognosis based on residual transporter activity, and guides emerging precision therapies such as chemical chaperones.

References

• American journal of human genetics • 1996 • High-resolution mapping of the gene for cystinosis, using combined biochemical and linkage analysis. PMID:8644713
• Human molecular genetics • 1999 • Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin. PMID:10556299
• European journal of human genetics : EJHG • 1999 • Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation. PMID:10482956
• Nephron • 2001 • The molecular basis of Dutch infantile nephropathic cystinosis. PMID:11528232
• American journal of human genetics • 2001 • The promoter of a lysosomal membrane transporter gene, CTNS, binds Sp-1, shares sequences with the promoter of an adjacent gene, CARKL, and causes cystinosis if mutated in a critical region. PMID:11505338
• Human molecular genetics • 2004 • Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. PMID:15128704
• The American journal of pathology • 2019 • Intrinsic Bone Defects in Cystinotic Mice. PMID:30794806
• The Journal of clinical investigation • 2023 • ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine. PMID:37561577

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