CTNS – Nephropathic Cystinosis

Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in CTNS, encoding the lysosomal cystine transporter cystinosin. Affected individuals typically present in infancy with proximal renal tubular Fanconi syndrome, failure to thrive, metabolic acidosis, and corneal crystal deposition leading to photophobia. Without treatment, progressive cystine accumulation leads to renal failure by 10 years of age and multiorgan impairment. Early molecular diagnosis enables prompt initiation of cysteamine therapy to deplete intracellular cystine and delay organ damage.

Genetic evidence for CTNS involvement is robust, with over 350 unrelated probands reported across diverse populations since 1998. In an American cohort of 108 nephropathic patients, 44% were homozygous for the 65-kb deletion and an additional 27 pathogenic alleles were identified among the remaining patients (PMID:9792862). A mapping study of 70 affected individuals defined CTNS within a 65-kb deletion interval, identifying 11 distinct deleterious variants segregating with disease (PMID:9537412). Additional series in German–Swiss, Italian, Middle Eastern, and other cohorts confirmed biallelic CTNS lesions in over 250 further families.

The CTNS variant spectrum includes small insertions/deletions leading to frameshifts (e.g., c.696_697dup (p.Val233fsTer)?), nonsense mutations (e.g., c.382C>T (p.Gln128Ter)), splice-site alterations, and the common 57-kb deletion encompassing CARKL. The 57-kb deletion accounts for 44%–65% of alleles in European populations, whereas recurrent hypomorphic and splicing alleles such as c.681G>A (p.Glu227=) predominate in Middle Eastern groups. Founder effects have been demonstrated for major alleles in Karachay, Chechen, and Tunisian populations.

Functional studies corroborate pathogenicity and mechanism. In vitro transport assays of 31 CTNS missense and in-frame deletion mutants showed that infantile cystinosis–associated alleles abolish lysosomal cystine efflux, whereas juvenile or ocular forms retain residual activity (PMID:15128704). Promoter mutations disrupting Sp1 binding reduce CTNS expression without affecting the adjacent CARKL gene (PMID:11505338). A Ctns−/− mouse model recapitulates the renal Fanconi syndrome and uncovers intrinsic osteoblastic and osteoclastic defects leading to osteopenia (PMID:30794806).

There is no substantive conflicting evidence disputing CTNS’s role; nascent data on exonic variants indicate some alleles may alter splicing efficiency, underscoring the need for RNA-level assessment (PMID:38009794).

In summary, CTNS–nephropathic cystinosis meets criteria for a Definitive gene–disease relationship, supported by genetic and functional concordance across hundreds of cases. Routine CTNS sequencing and deletion analysis facilitate early diagnosis and therapeutic intervention, underscoring the clinical utility of genetic testing for this treatable lysosomal disorder.

References

• American Journal of Human Genetics • 1998 • CTNS mutations in an American-based population of cystinosis patients PMID:9792862
• Nature Genetics • 1998 • A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis PMID:9537412
• Human Molecular Genetics • 2004 • Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin PMID:15128704
• 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
• The American Journal of Pathology • 2019 • Intrinsic Bone Defects in Cystinotic Mice PMID:30794806

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