C1QTNF5 – Late-onset Retinal Degeneration

C1QTNF5 (CTRP5) is associated with autosomal dominant late-onset retinal degeneration (L-ORD), a macular dystrophy characterized by sub-RPE deposits and photoreceptor atrophy. Six unrelated probands carrying the recurrent S163R variant were identified among a cohort of 213 hereditary maculopathy patients, supporting dominant inheritance and specificity for L-ORD (6 probands (PMID:25082885)).

Genetic evidence includes the single recurrent missense variant c.488C>G (p.Ser163Arg) segregating in affected family members and absent from controls, fulfilling moderate ClinGen criteria for pathogenicity (Moderate genetic evidence, see scores).

Functional characterization demonstrates that wild-type CTRP5 is a secreted, membrane-associated protein localized to apical RPE and ciliary epithelial membranes, whereas the S163R mutant is retained intracellularly, impairing secretion and lattice formation in vitro (PMID:17122142). Porcine pCTRP5 shares 98% amino acid identity and recapitulates human RPE localization, validating cross-species conservation (PMID:22275800).

The heterozygous S163R knock-in mouse develops age-dependent autofluorescent lesions, sub-RPE and Bruch’s membrane deposits indistinguishable from human L-ORD, confirming dominant pathogenesis and providing an in vivo model (Moderate functional evidence, PMID:25814825).

Mechanistic studies reveal that CTRP5 interacts with HTRA1 via a PDZ-binding motif, enhancing HTRA1 proteolytic activity; the S163R mutant resists cleavage, leading to accumulation of CTRP5, HTRA1, and extracellular matrix substrates in Bruch’s membrane (strong mechanistic concordance, PMID:31385385). Further, patient-derived iPSC-RPE harboring the S163R variant exhibit reduced CTRP5 secretion, dysregulated AMPK signaling, defective lipid metabolism, and accumulation of sub-RPE deposits that are ameliorated by metformin or wild-type CTRP5 supplementation (PMID:34887495).

No conflicting reports have been described. Integration of genetic segregation, recurrent variant identification in multiple probands, and extensive concordant functional data supports a Strong gene–disease association. C1QTNF5 S163R testing informs diagnosis and family counseling in L-ORD and may guide therapeutic strategies targeting CTRP5 secretion and HTRA1 modulation.

References

• Investigative ophthalmology & visual science • 2014 • Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss PMID:25082885
• Investigative ophthalmology & visual science • 2006 • CTRP5 is a membrane-associated and secretory protein in the RPE and ciliary body and the S163R mutation of CTRP5 impairs its secretion PMID:17122142
• Molecular vision • 2012 • Cloning, characterization, and expression analysis of the pig (Sus scrofa) C1q tumor necrosis factor-related protein-5 gene PMID:22275800
• Molecular vision • 2015 • Presence of rd8 mutation does not alter the ocular phenotype of late-onset retinal degeneration mouse model PMID:25814825
• Aging cell • 2019 • Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1 PMID:31385385
• Communications biology • 2021 • AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration PMID:34887495

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