Variants in the AGBL5 gene are responsible for autosomal recessive Retinitis pigmentosa with hearing loss

The AGBL5 gene encodes for the Cytoplasmic Carboxypeptidase 5 (CCP5), an α-tubulin deglutamylase that cleaves the γ-carboxyl-linked branching point of glutamylated tubulin. To date, pathogenic variants in AGBL5 have been associated only with isolated retinitis pigmentosa (RP). Hearing loss has not been reported in AGBL5-caused retinal disease. In this study, we performed exome sequencing in probands of eight unrelated families from Italy, Spain, Palestine, Switzerland, and Greece. All subjects had a clinical diagnosis of (suspected) Usher syndrome type II for the concurrent presence of RP and post-verbal sensorineural hearing loss (SNHL) that ranged from mild to moderate.We identified biallelic sequence variants in AGBL5 in all analysed subjects. Four of the identified variants were novel. The variants co-segregated with the retinal and auditory phenotypes in additional affected family members. We did not detect any causative variants in known deafness or Usher syndrome genes that could explain the patients' hearing loss. We therefore conclude that SNHL is a feature of a syndromic presentation of AGBL5 retinopathy. This study provides the first evidence that mutations in AGBL5 can cause syndromic RP forms associated with hearing loss, probably due to dysfunction of sensory cilia in the retina and the inner ear.

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Publication Details

Journal
European Journal of Human Genetics
Published
2024-12-13
DOI
https://doi.org/10.1038/s41431-024-01768-8
Citations
2
Primary Topic
Retinal Development and Disorders
Type
article
Field-Weighted Citation Impact
0.47

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article

Variants in the AGBL5 gene are responsible for autosomal recessive Retinitis pigmentosa with hearing loss

Evangelia S. Panagiotou, Lucas Janeschitz‐Kriegl, Hoai Viet Tran, Carlo Rivolta et al.
2 citations
European Journal of Human Genetics
Retinal Development and Disorders
0.47
article

Variants in the AGBL5 gene are responsible for autosomal recessive Retinitis pigmentosa with hearing loss

Evangelia S. Panagiotou, Lucas Janeschitz‐Kriegl, Hoai Viet Tran, Carlo Rivolta, Marianthi Karali, Ana Rodríguez‐Muñoz, Manar Salameh, Sandro Banfi, Karolina Kamińska, Francesco Testa, Alaa AlTalbishi, Hendrik P. N. Scholl, Roberta Zeuli, George Psillas, Mathieu Quinodoz, Francesca Cancellieri, Maria Rosaria Barillari, Gema García‐García, Veronika Vaclavik, Miguel Armengot‐Carceller, Pilar Barberán-Martínez, José M. Millán, Margherita Scarpato, Francesca Simonelli
article en
2 citations

Abstract

The AGBL5 gene encodes for the Cytoplasmic Carboxypeptidase 5 (CCP5), an α-tubulin deglutamylase that cleaves the γ-carboxyl-linked branching point of glutamylated tubulin. To date, pathogenic variants in AGBL5 have been associated only with isolated retinitis pigmentosa (RP). Hearing loss has not been reported in AGBL5-caused retinal disease. In this study, we performed exome sequencing in probands of eight unrelated families from Italy, Spain, Palestine, Switzerland, and Greece. All subjects had a clinical diagnosis of (suspected) Usher syndrome type II for the concurrent presence of RP and post-verbal sensorineural hearing loss (SNHL) that ranged from mild to moderate.We identified biallelic sequence variants in AGBL5 in all analysed subjects. Four of the identified variants were novel. The variants co-segregated with the retinal and auditory phenotypes in additional affected family members. We did not detect any causative variants in known deafness or Usher syndrome genes that could explain the patients' hearing loss. We therefore conclude that SNHL is a feature of a syndromic presentation of AGBL5 retinopathy. This study provides the first evidence that mutations in AGBL5 can cause syndromic RP forms associated with hearing loss, probably due to dysfunction of sensory cilia in the retina and the inner ear.

European Journal of Human GeneticsVol. 33(6)
University of Leicester (GB), King's College London (GB), University of Basel (CH), University of Campania "Luigi Vanvitelli" (IT), Aristotle University of Thessaloniki (GR), AHEPA University Hospital (GR), Ghent University Hospital (BE), St John of Jerusalem Eye Hospital Group (IL), Hospital Universitari i Politècnic La Fe (ES), Cell and Gene Therapy Catapult (GB), Centre for Biomedical Network Research on Rare Diseases (ES), Fondation Asile des Aveugles (CH), Hospital Universitario Doctor Peset (ES), University of Campania "Luigi Vanvitelli" (IT), Telethon Institute Of Genetics And Medicine (IT), Institute of Molecular and Clinical Ophthalmology Basel (CH), Instituto de Investigación Sanitaria La Fe (ES), University of Lausanne (CH)
Engineer Research and Development Center
Good health and well-being
Openalex Percentile: Top 34%
Retinal Development and Disorders
0.47
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