Agbl5, also known as the gene encoding Cytoplasmic Carboxypeptidase 5 (CCP5), is an α-tubulin deglutamylase. It cleaves the γ-carboxyl-linked branching point of glutamylated tubulin, playing a role in the homeostasis of tubulin glutamylation, which is crucial for normal cell function [2,4,5,7]. Glutamylation is an important post-translational modification of microtubules, and Agbl5 is involved in the tubulin code-related pathway [4].

Mutations in Agbl5 have been associated with autosomal recessive retinitis pigmentosa (arRP) [1,3,5,6,8]. In multiple studies, sequencing in RP patients identified biallelic sequence variants in Agbl5, with affected individuals showing typical RP phenotypes such as progressive peripheral vision loss and nyctalopia [3,5]. A recent study also found that mutations in Agbl5 can cause syndromic RP forms associated with hearing loss, likely due to the dysfunction of sensory cilia in the retina and inner ear [2]. Mouse models with increased glutamylation due to Ccp5 knockout (Ccp5-/-) showed disruption of outer segment architecture in photoreceptor cells, indicating that proper glutamylation levels regulated by Agbl5 are crucial for maintaining the molecular architecture of the photoreceptor cilium [7].

In conclusion, Agbl5 is essential for maintaining tubulin glutamylation homeostasis. Research on Agbl5, especially through knockout mouse models, has revealed its significance in retinal diseases, specifically retinitis pigmentosa, and has provided insights into the role of glutamylation in photoreceptor cell structure and function. Understanding Agbl5 may offer new perspectives for treating these retinal and potentially related syndromic disorders.

References:

1. Patel, Nisha, Aldahmesh, Mohammed A, Alkuraya, Hisham, Al-Hazzaa, Selwa A F, Alkuraya, Fowzan S. 2015. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies. In Genetics in medicine : official journal of the American College of Medical Genetics, 18, 554-62. doi:10.1038/gim.2015.127. https://pubmed.ncbi.nlm.nih.gov/26355662/

2. Karali, Marianthi, García-García, Gema, Kaminska, Karolina, Banfi, Sandro, Millán, José M. 2024. Variants in the AGBL5 gene are responsible for autosomal recessive Retinitis pigmentosa with hearing loss. In European journal of human genetics : EJHG, , . doi:10.1038/s41431-024-01768-8. https://pubmed.ncbi.nlm.nih.gov/39672920/

3. Paredes, Diego I, Bello, Nicholas R, Capasso, Jenina E, Procopio, Rebecca, Levin, Alex V. 2023. Mutations in AGBL5 associated with Retinitis pigmentosa. In Ophthalmic genetics, 45, 275-280. doi:10.1080/13816810.2023.2291687. https://pubmed.ncbi.nlm.nih.gov/38078364/

4. Chen, Jiayi, Zehr, Elena A, Gruschus, James M, Tjandra, Nico, Roll-Mecak, Antonina. 2024. Tubulin code eraser CCP5 binds branch glutamates by substrate deformation. In Nature, 631, 905-912. doi:10.1038/s41586-024-07699-0. https://pubmed.ncbi.nlm.nih.gov/39020174/

5. Astuti, Galuh D N, Arno, Gavin, Hull, Sarah, Webster, Andrew R, Cremers, Frans P M. . Mutations in AGBL5, Encoding α-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa. In Investigative ophthalmology & visual science, 57, 6180-6187. doi:10.1167/iovs.16-20148. https://pubmed.ncbi.nlm.nih.gov/27842159/

6. Kastner, Simone, Thiemann, Ina-Janine, Dekomien, Gabriele, Bagci, Hasan, Epplen, Jörg T. . Exome Sequencing Reveals AGBL5 as Novel Candidate Gene and Additional Variants for Retinitis Pigmentosa in Five Turkish Families. In Investigative ophthalmology & visual science, 56, 8045-53. doi:10.1167/iovs.15-17473. https://pubmed.ncbi.nlm.nih.gov/26720455/

7. Mercey, Olivier, Gadadhar, Sudarshan, Magiera, Maria M, Guichard, Paul, Hamel, Virginie. 2024. Glutamylation imbalance impairs the molecular architecture of the photoreceptor cilium. In The EMBO journal, 43, 6679-6704. doi:10.1038/s44318-024-00284-1. https://pubmed.ncbi.nlm.nih.gov/39528655/

8. Branham, Kari, Matsui, Hiroko, Biswas, Pooja, Sieving, Paul A, Ayyagari, Radha. 2016. Establishing the involvement of the novel gene AGBL5 in retinitis pigmentosa by whole genome sequencing. In Physiological genomics, 48, 922-927. doi:10.1152/physiolgenomics.00101.2016. https://pubmed.ncbi.nlm.nih.gov/27764769/