TLCD3B – Cone-Rod Dystrophy

TLCD3B encodes a ceramide synthase implicated in regulating proapoptotic lipid levels critical for neuronal cell survival. Dysregulated ceramide homeostasis has been linked to photoreceptor apoptosis, suggesting TLCD3B as a plausible candidate in inherited retinal dystrophies.

Exome sequencing of patients with vision loss identified four individuals from three unrelated families with early-onset cone-rod dystrophy or maculopathy carrying bi-allelic TLCD3B variants (PMID:33077892). All affected individuals exhibited progressive photopic dysfunction on electroretinography and macular thinning on optical coherence tomography, consistent with cone-rod dystrophy.

The variant spectrum comprises one missense allele, c.166G>A (p.Gly56Ser), and one frameshift allele, c.234del (p.Gln79fs), observed in homozygous or compound heterozygous states across the cohort (PMID:33077892).

Inheritance is autosomal recessive. Segregation data confirm bi-allelic transmission of pathogenic TLCD3B variants without additional affected relatives in sequenced pedigrees.

Functional studies in Tlcd3bKO/KO mice recapitulated the human phenotype, demonstrating significant reduction of cone photoreceptor ERG responses, thinning of the outer nuclear layer, and widespread cone loss across the retina (PMID:33077892). These findings establish a loss-of-function mechanism concordant with patient presentations.

Integration of genetic and in vivo functional evidence supports a strong gene–disease relationship for TLCD3B in autosomal recessive cone-rod dystrophy. TLCD3B should be included in diagnostic gene panels for early-onset photoreceptor dystrophies to enable definitive molecular diagnosis and inform prognosis.

References

• Genetics in medicine • 2021 • Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy. PMID:33077892

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