TTLL5 – Cone-Rod Dystrophy

Cone-rod dystrophy (CORD) is an inherited retinal dystrophy characterized by progressive loss of cone and rod photoreceptors leading to visual impairment and color vision defects. Tubulin tyrosine ligase-like family member 5 (TTLL5) has been implicated in CORD and cone dystrophy through recessive loss-of-function variants. Mechanistically, TTLL5 mediates glutamylation of the photoreceptor-specific RPGR(ORF15) isoform, an essential post-translational modification for photoreceptor integrity. Initial genetic evidence arose from multi-patient case series identifying biallelic TTLL5 variants in individuals with COD/CORD and early-onset severe retinal dystrophy. Subsequent animal and cellular studies confirmed that loss of TTLL5-dependent glutamylation of RPGR underlies cone photoreceptor degeneration.

In an international cohort, five unrelated patients harboring biallelic TTLL5 variants were described, presenting with either late-teenage onset COD or CORD and one case of early-onset severe retinal dystrophy; eight distinct variants including two large multi-exon deletions and a homozygous truncating allele c.1920G>A (p.Trp640Ter) were reported ([PMID:34203883]). Four adults exhibited classical COD/CORD phenotypes while the youngest patient displayed severe, early-onset degeneration, underscoring phenotypic variability. Genetic screening combined targeted NGS and CNV analysis, revealing that TTLL5 should be assessed in patients lacking pathogenic alleles in known retinal dystrophy genes.

A separate study identified five homozygous TTLL5 variants in eight affected individuals from six consanguineous families, including missense p.(Glu543Lys) and frameshift p.(Met712fs). Segregation analysis confirmed autosomal recessive inheritance and revealed variable extra-ocular manifestations, such as reduced sperm motility in male patients ([PMID:28173158]). The predominance of truncating alleles, splice-site changes and CNVs supports a haploinsufficiency mechanism in CORD.

The TTLL5 variant spectrum in CORD comprises missense, nonsense, frameshift, splice-site mutations, and large deletions, with recurrent truncating alleles across populations. Standardized HGVS nomenclature facilitates variant reporting; for example, c.1920G>A (p.Trp640Ter) represents a recurrent stop-gain allele. Hypomorphic missense variants may modulate disease severity and contribute to syndromic features when combined with additional gene defects.

Functional assays demonstrate that TTLL5 specifically glutamylates RPGR(ORF15), and Ttll5-deficient mice exhibit loss of RPGR glutamylation, mislocalization of cone opsins, and progressive photoreceptor degeneration analogous to human CORD ([PMID:27162334]). Patient-derived TTLL5 mutant constructs show impaired RPGR glutamylation in cell models, linking the biochemical defect to retinal pathology.

Integration of these data yields a Strong gene-disease association: autosomal recessive TTLL5 variants cause CORD via loss of glutamylation of RPGR. Current evidence meets ClinGen criteria for a Strong association with robust segregation, multi‐family cohorts, and concordant functional data. Key take-home: Biallelic TTLL5 variants lead to CORD by impairing TTLL5-mediated RPGR glutamylation, providing a diagnostic marker and potential therapeutic target.

References

• International journal of molecular sciences • 2021 • Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy. PMID:34203883
• Human molecular genetics • 2016 • Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility. PMID:28173158
• Proceedings of the National Academy of Sciences of the United States of America • 2016 • Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations. PMID:27162334

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