CTNS – Cystinosis

Cystinosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in CTNS, which encodes the seven-transmembrane lysosomal cystine transporter cystinosin. Accumulation of cystine in lysosomes leads to proximal tubular dysfunction manifesting as renal Fanconi syndrome, failure to thrive, vomiting (HP:0002013), weight loss (HP:0001824), and dehydration (HP:0001944) in infancy, with corneal cystine crystals causing photophobia and visual impairment. The infantile nephropathic form presents before 1 year of age, while intermediate and ocular forms have later onset and milder manifestations ([PMID:19580442]).

Genetic evidence for CTNS involvement in cystinosis includes autosomal recessive segregation in multiple consanguineous pedigrees. Thirty-two distinct CTNS mutations were identified in nephropathic patients by targeted sequencing ([PMID:10571941]), and mutation screening in 108 additional individuals revealed 14 novel coding and splicing defects across infantile, juvenile, and ocular phenotypes ([PMID:12442267]). Homozygous and compound heterozygous loss-of-function alleles consistently segregate with disease in families, confirming gene-disease association.

The variant spectrum exceeds 140 unique pathogenic alleles, including frameshift, nonsense, splice-site, in-frame deletions, and missense changes. A Northern European founder 57-kb deletion is common in Caucasians but absent in Turkish and South African cohorts. The intronic splice variant c.971-12G>A recurs in black South African patients ([PMID:25326109]). In an Indian kindred, the in-frame deletion c.809_811del (p.Ser270del) was homozygous in the proband and heterozygous in both parents ([PMID:19580442]).

Functional assays demonstrate that 16 of 19 infantile-associated missense or in-frame variants abolish H⁺-driven cystine transport in vitro, whereas alleles linked to juvenile or ocular forms retain residual activity, correlating with clinical severity ([PMID:15128704]). Electrophoretic mobility shift and reporter assays show that promoter mutations disrupting the Sp1 motif (c.-303G>T, c.-295G>C) drastically reduce CTNS expression without affecting the adjacent CARKL promoter ([PMID:11505338]).

Animal models further corroborate pathogenesis: Ctns⁻/⁻ knockout mice exhibit reduced trabecular bone volume, decreased osteoblast and osteoclast parameters, and lower serum bone turnover markers, indicating intrinsic skeletal defects independent of renal Fanconi syndrome ([PMID:30794806]).

Integration of genetic, biochemical, and in vivo data defines CTNS loss-of-function as the definitive cause of cystinosis. Molecular diagnosis via CTNS sequencing and cystine quantitation informs early initiation of cysteamine therapy, improving renal and systemic outcomes. Key take-home: Comprehensive CTNS variant analysis is essential for confirming cystinosis, guiding genetic counseling, and enabling precision treatment.

References

• Genetic testing and molecular biomarkers • 2009 • An Indian boy with nephropathic cystinosis: a case report and molecular analysis of CTNS mutation PMID:19580442
• Human mutation • 1999 • CTNS mutations in patients with cystinosis PMID:10571941
• Human mutation • 2002 • Identification of 14 novel CTNS mutations and characterization of seven splice site mutations associated with cystinosis PMID:12442267
• 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

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