️ Episode 72: The POC5 Syndrome — A Ciliopathy Linking Retina, Muscles and Metabolism

In this episode of Base by Base, we explore a multi-institutional study by Vulto-van Silfhout et al. (2025), published in Genetics in Medicine, that uncovers a novel syndromic ciliopathy caused by bi-allelic loss-of-function variants in the POC5 gene. The research describes twelve families with a rare constellation of clinical features—including rod-cone dystrophy, severe insulin-resistant diabetes, partial lipodystrophy, renal impairment, and muscle cramps—all tied to defective POC5 function.

The POC5 protein plays a central role in centriole maturation and cilium assembly. Through comprehensive clinical characterization, RNA analysis, and immunofluorescence studies in patient-derived fibroblasts, the authors demonstrate mislocalization of POC5 and aberrant centriolar structure. While primary ciliogenesis and sonic hedgehog (SHH) signaling appeared preserved, affected individuals exhibited systemic abnormalities that strongly align with ciliopathy phenotypes.

This work not only broadens the phenotypic spectrum associated with POC5 deficiency—beyond previously reported retinitis pigmentosa—but also highlights the underrecognized link between ciliary dysfunction and adipose tissue abnormalities. Particularly striking is the presence of partial lipodystrophy and metabolic dysregulation, features rarely associated with classical ciliopathies, suggesting a distinct role of POC5 in adipocyte development and endocrine homeostasis.

Conclusion:
The study defines a new multi-organ ciliopathy driven by POC5 loss, linking ciliary biology with retinal integrity, neuromuscular function, and systemic metabolism. This discovery paves the way for improved diagnostic strategies for patients presenting with overlapping ocular, endocrine, and neuromuscular symptoms—and reinforces the relevance of ciliopathy research in metabolic diseases.

Reference:
Vulto-van Silfhout AT, Jazet IM, Yzer S, et al. (2025). Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine and neuromuscular ciliopathy. Genetics in Medicine. https://doi.org/10.1016/j.gim.2025.101513

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/