Résumé
Ciliary dysfunctions cause disorders referred to as ciliopathies. To date, pathogenic variants in the TBC1D32 gene have been exclusively associated with the highly severe ciliopathy, oral-facial-digital syndrome (OFD). We here report four patients from three unrelated families with TBC1D32 variants and presenting with retinitis pigmentosa (RP), an inherited retinal disease (IRD) leading to photoreceptor degeneration, but no signs of OFD. Combining Xenopus in vivo approaches and human iPSC-derived retinal models, we identify a novel role for TBC1D32 in ciliogenesis of the retinal pigment epithelium. We demonstrate elongated ciliary defects that result in disrupted apical tight junctions, loss of apical-basal polarity affecting functionality, and onset of an epithelial-mesenchymal transition-like phenotype. Moreover, our data suggest connecting cilium anomalies in phototoreceptors of TBC1D32 iPSC-derived retinal organoids. Overall, we demonstrate that hypomorphic TBC1D32 mutations lead to RP and recommend that TBC1D32 be added to the list of IRD causative genes for variant screening.