Expanding the phenotype of TTLL5-associated retinal dystrophy: a case series

Abstract

Background Inherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone–rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5. Examination of these patients included funduscopic evaluation, spectral-domain optical coherence tomography, short-wavelength autofluorescence, and full-field electroretinography (ffERG). Genetic diagnoses were confirmed using whole exome capture. Protein modeling of the identified variants was performed to explore potential genotype–phenotype correlations. Results Genetic testing revealed five novel variants in TTLL5 in three unrelated patients with retinal dystrophy. Clinical imaging demonstrated features of sectoral cone–rod dystrophy and cone dystrophy, with phenotypic variability seen across all three patients. One patient also developed high-frequency hearing loss during a similar time period as the onset of retinal disease, potentially suggestive of a syndromic disorder. Retinal structure findings were corroborated with functional measures including ffERG findings that supported these diagnoses. Modeling of the five variants suggest that they cause different effects on protein function, providing a potential reason for genotype–phenotype correlation in these patients. Conclusions The authors report retinal phenotypic findings in three unrelated patients with novel mutations causing autosomal recessive TTLL5-mediated retinal dystrophy. These findings broaden the understanding of the phenotypes associated with TTLL5-mediated retinal disease and suggest that mutations in TTLL5 should be considered as a potential cause of sectoral retinal dystrophy in addition to cone–rod and cone dystrophies.

Microtubule‐associated proteins and enzymes modifying tubulin

“…Since TTLL4 targets nontubulin proteins as well, red blood cells from Ttll4‐knockout mice show larger average diameters due to completely lost of glutamylation in nucleosome assembly protein 1 (NAP1) (Ijaz et al, 2017). Mutations or disruption of TTLL5 gene is associated with infertility and retinal dystrophy (Bedoni et al, 2016; Lee et al, 2013; Oh et al, 2022). Loss of Ttll9 leads to infertility in male mice due to decreased sperm count and motility caused by reduced polyglutamylation of tubulin in sperm flagella (Konno et al, 2016).…”