Ciliopathy due to POC1A deficiency: clinical and metabolic features, and cellular modeling.

Early human evidence such as case series or small samples is exploring possible benefits.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Objective SOFT syndrome (MIM#614813), denoting Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis, is a rare primordial dwarfism syndrome caused by biallelic variants in POC1A, encoding a centriolar protein. SOFT syndrome, characterized by severe growth failure of prenatal onset and dysmorphic features, was recently associated with insulin resistance. This study aims to further explore its endocrinological features and pathophysiological mechanisms. Design/methods We present clinical, biochemical, and genetic features of 2 unrelated patients carrying biallelic pathogenic POC1A variants. Cellular models of the disease were generated using patients' fibroblasts and POC1A-deleted human adipose stem cells. Results Both patients present with clinical features of SOFT syndrome, along with hyperinsulinemia, diabetes or glucose intolerance, hypertriglyceridemia, liver steatosis, and central fat distribution. They also display resistance to the effects of IGF-1. Cellular studies show that the lack of POC1A protein expression impairs ciliogenesis and adipocyte differentiation, induces cellular senescence, and leads to resistance to insulin and IGF-1. An altered subcellular localization of insulin receptors and, to a lesser extent, IGF1 receptors could also contribute to resistance to insulin and IGF1. Conclusions Severe growth retardation, IGF-1 resistance, and centrip

Evidence level

Early human evidence such as case series or small samples is exploring possible benefits.

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