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JCI Insight 2023 Nov 08;821:. doi: 10.1172/jci.insight.169426.
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TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa.

Bocquet B , Borday C , Erkilic N , Mamaeva D , Donval A , Masson C , Parain K , Kaminska K , Quinodoz M , Perea-Romero I , Garcia-Garcia G , Jimenez-Medina C , Boukhaddaoui H , Coget A , Leboucq N , Calzetti G , Gandolfi S , Percesepe A , Barili V , Uliana V , Delsante M , Bozzetti F , Scholl HP , Corton M , Ayuso C , Millan JM , Rivolta C , Meunier I , Perron M , Kalatzis V .

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.

PubMed ID: 37768732
PMC ID: PMC10721274
Article link: JCI Insight

Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: abca4 arl13b arr3 cdh1 cdh3 crx ctnnb1 fancf fn1 ift88 ihh itk lin28a mip mitf otx2 pde6b plec rho rpe rpe65 rpl8 snai1 sox2 tbc1d32 tub tuba4b tubg1 vegfa vim
GO keywords: retinal pigment epithelium development [+]
Antibodies: Arl13b Ab5 Casp3 Ab1 M-Opsin Ab1 Otx2 Ab5 Rho Ab1 S-Opsin Ab1 Tuba4b Ab5
Morpholinos: tbc1d32 MO2 tbc1d32 MO3

Disease Ontology terms: ciliopathy [+]
Phenotypes: tbc1d32 MO2 + NF St 3 [+]

Article Images: [+] show captions
References [+] :
Adly, Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX. 2014, Pubmed