Language

English

Publication Date

10-1-2025

Journal

Genetics in Medicine

DOI

10.1016/j.gim.2025.101513

PMID

40590205

PMCID

PMC12622366

PubMedCentral® Posted Date

11-18-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Purpose: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants.

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.

Keywords

Humans, Male, Ciliopathies, Female, Phenotype, Pedigree, Loss of Function Mutation, Adult, Cell Cycle Proteins, Alleles, Retinitis Pigmentosa, Child, Cilia, Fibroblasts, Adolescent, Endocrine System Diseases, Ciliopathy, Insulin resistance, Muscle cramps, Renal disease, Syndrome

Published Open-Access

yes

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