Mutations in AGBL5, Encoding α-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa

PURPOSE. AGBL5, encoding ATP/GTP binding protein-like 5, was previously proposed as an autosomal recessive retinitis pigmentosa (arRP) candidate gene based on the identification of missense variants in two families. In this study, we performed next-generation sequencing to reveal additional RP cases with AGBL5 variants, including protein-truncating variants. METHODS. Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in three probands. Subsequent Sanger sequencing and segregation analysis were performed in the selected candidate genes. The medical history of individuals carrying AGBL5 variants was reviewed and additional ophthalmic examinations were performed, including fundus photography, fundus autofluorescence imaging, and optical coherence tomography. RESULTS. AGBL5 variants were identified in three unrelated arRP families, comprising homozygous variants in family 1 (c.1775G>A: p.(Trp592*)) and family 2 (complex allele: c.[323C>G; 2659T>C]; p.[(Pro108Arg; *887Argext*1)]), and compound heterozygous variants (c. 752T>G: p.(Val251Gly) and c. 1504dupG: p.(Ala502Glyfs*15)) in family 3. All affected individuals displayed typical RP phenotypes. CONCLUSIONS. Our study convincingly shows that variants in AGBL5 are associated with arRP. The identification of AGBL5 and TTLL5, a previously described RP-associated gene encoding the tubulin tyrosine ligase-like family, member 5 protein, highlights the importance of poly- and deglutamylation in retinal homeostasis. Further studies are required to investigate the underlying disease mechanism associated with AGBL5 variants.