Karali Marianthi, García-García Gema, Kaminska Karolina, AlTalbishi Alaa, Cancellieri Francesca, Testa Francesco, Barillari Maria Rosaria, Panagiotou Evangelia S, Psillas George, Vaclavik Veronika, Tran Viet H, Janeschitz-Kriegl Lucas, Scholl Hendrik Pn, Salameh Manar, Barberán-Martínez Pilar, Rodríguez-Muñoz Ana, Armengot Miguel, Scarpato Margherita, Zeuli Roberta, Quinodoz Mathieu, Simonelli Francesca, Rivolta Carlo, Banfi Sandro, Millán José M
Medical Genetics, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', 80138, Naples, Italy.
Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania 'Luigi Vanvitelli', 80131, Naples, Italy.
Eur J Hum Genet. 2024 Dec 13. doi: 10.1038/s41431-024-01768-8.
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.
AGBL5基因编码细胞质羧肽酶5（CCP5），一种α-微管蛋白去谷氨酰胺酶，可切割谷氨酰化微管蛋白的γ-羧基连接分支点。迄今为止，AGBL5中的致病变异仅与孤立性视网膜色素变性（RP）相关。AGBL5所致视网膜疾病中尚未有听力损失的报道。在本研究中，我们对来自意大利、西班牙、巴勒斯坦、瑞士和希腊的8个无关家族的先证者进行了外显子组测序。所有受试者均因同时存在RP和轻度至中度的言语后感觉神经性听力损失（SNHL）而被临床诊断为（疑似）II型Usher综合征。我们在所有分析的受试者中均鉴定出AGBL5的双等位基因序列变异。其中4个鉴定出的变异是新的。这些变异在其他受影响的家庭成员中与视网膜和听觉表型共分离。我们在已知的耳聋或Usher综合征基因中未检测到任何可解释患者听力损失的致病变异。因此，我们得出结论，SNHL是AGBL5视网膜病变综合征表现的一个特征。本研究提供了首个证据，表明AGBL5突变可导致与听力损失相关的综合征性RP形式，这可能是由于视网膜和内耳中感觉纤毛功能障碍所致。
