Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy.
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Vulto-van Silfhout Anneke T, Jazet Ingrid M, Yzer Suzanne, Pas Jeroen, Demirdas Serwet, van Rossum Elisabeth F C, Thiadens Alberta A H J, van Beek Ronald, Haer-Wigman Lonneke, Barge-Schaapveld Daniela Q C M, Brasch-Andersen Charlotte, Frost Simon, Bauwens Miriam, De Baere Elfride, Balikova Irina, Van den Broeck Filip, Weisz-Hubshman Monika, Joset Pascal, Miny Peter, Filges Isabel, Kohl Susanne, De Angeli Pietro, Kühlewein Laura, Bodenbender Jan-Philipp, Haack Tobias, Poths Karin, Fernandez-Caballero Lidia, Corton Marta, Blanco Kelly Fiona, Ayuso Carmen, Martínez-Esteban Peggy, Vissing John, Díaz-Manera Jordi, Straub Volker, Töpf Ana, Lin Siying, Arno Gavin, Macken William L, Spillane Jennifer, Ramachandran Radha, de Vrieze Erik, van Ham Tjakko, Roosing Susanne, Oud Machteld M
Аннотация
METHODS: We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines.
RESULTS: Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies.
CONCLUSION: We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies.