TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa

• DOI: 10.1172/jci.insight.169426
• Publication Date: 2023-09-28T16:00:31Z
• Authors: Béatrice Bocquet; Caroline Borday; Nejla Erkilic; Daria Mamaeva; Alicia Donval; Christel Masson; Karine Parain; Karolina Kaminska; Mathieu Quinodoz; Irene Perea-Romero; Gema Garcia-Garcia; Carla Jimenez-Medina; Hassan Boukhaddaoui; Arthur Coget; Nicolas Leboucq; Giacomo Calzetti; Stefano Gandolfi; Antonio Percesepe; Valeria Barili; Vera Uliana; Marco Delsante; Francesca Bozzetti; Hendrik P.N. Scholl; Marta Corton; Carmen Ayuso; Jose M. Millan; Carlo Rivolta; Isabelle Meunier; Muriel Perron; Vasiliki Kalatzis
• Keywords: MUTATIONS; Induced Pluripotent Stem Cells; Retinal Degeneration; Genetic disease; R; 610; PLATFORM; Retinal Pigment Epithelium; Genetic diseases, Genetics, Ophthalmology, Retinopathy, iPS cells; Retina; PREVALENCE; CILIUM; iPS cells; Ophthalmology; Genetic; DISCOVERY; Genetics; Medicine; Humans; Retinopathy; Retinitis Pigmentosa; Research Article; Adaptor Proteins, Signal Transducing

Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32, which to date has never been associated with an IRD. To validate TBC1D32 as a putative RP causative gene, we combined Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models. Our data showed that TBC1D32 was expressed during retinal development and that it played an important role in retinal pigment epithelium (RPE) differentiation. Furthermore, we identified a role for TBC1D32 in ciliogenesis of the RPE. We demonstrated elongated ciliary defects that resulted in disrupted apical tight junctions, loss of functionality (delayed retinoid cycling and altered secretion balance), and the onset of an epithelial-mesenchymal transition-like phenotype. Last, our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods in TBC1D32 iPSC-derived retinal organoids. Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP. We thus identify TBC1D32 as an IRD-causative gene.