Dataset Information

Mechanisms Underlying Morphological and Functional Changes of Cilia in Fibroblasts Derived from Patients Bearing ARL3T31A and ARL3T31A/C118F Mutations

ABSTRACT: ARL3 plays a crucial role in cilia development, while mutations in ARL3 are closely associated with ciliopathies. In a previous study, we reported distinct phenotypes of retinal dystrophy in patients with single ARL3T31A and compound ARL3T31A/C118F mutations, indicating that different mutation types may exert diverse effects on their functions. Here, we generated fibroblasts from patients carrying single ARL3T31A and compound ARL3T31A/C118F mutations, systematically evaluated their cilia morphology and function, and explored the underlying molecular mechanisms by RNA-sequencing. Our results showed that both ARL3T31A and ARL3T31A/C118F mutations led to a decrease in cilia incidence. The compound ARL3T31A/C118F mutations caused significantly elongated cilia and impaired retrograde transport, whereas the single ARL3T31A mutation did not induce significant changes in fibroblasts. Compared to ARL3T31A, ARL3T31A/C118F fibroblasts exhibited a higher enrichment of biological processes related to neuron projection development, tissue morphogenesis, and extracellular matrix (ECM) organization, with noticeable alterations in pathways such as ECM-receptor interaction, focal adhesion, axon guidance, and TGF-β signaling. Core regulated genes including IQUB, UNC13D, RAB3IP, and GRIP1 were specifically downregulated in the ARL3T31A/C118F group, which were further validated. Additionally, we observed that IQUB had a rescuing effect on the overlong cilia observed in ARL3T31A/C118F fibroblasts. These findings suggest that the ARL3T31A/C118F mutation downregulates IQUB, disrupting TGF-β signaling cascades and leading to cilia elongation in ARL3T31A/C118F cells. Our results not only enhance our understanding of ARL3-related diseases but also provide new insights into the analysis of single and compound mutations in genetics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275978 | GEO | 2025/08/30

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Vocal fold (VF) fibrosis, often caused by phonosurgery, radiation, or trauma, leads to irreversible voice dysfunction due to excessive ECM deposition and increased tissue stiffness. VF fibrosis, a significant cause of chronic dysphonia, lacks FDA-approved treatments, highlighting the critical need for novel antifibrotic therapeutic. TGF-β1 is a major driver in the pathological transformation of fibroblasts into contractile myofibroblasts in VF fibrosis via SMAD3, YAP1, and integrin signaling pathways. These pathways lead to increased ACTA2 expression, excessive collagen production, and progressive tissue stiffening. Leveraging the principle that local cells respond to tissue-specific signals, our ECM hydrogel derived from decellularized vocal fold lamina propria (VFLP-ECM) reduced ACTA2 expression in TGF-β1 stimulated vocal fold fibroblasts, showcasing antifibrotic potential. In this study, we evaluated the therapeutic potential of VFLP-ECM hydrogel in a rabbit VF injury model—treatment involved VFLP-ECM or bovine type I collagen injections into VFs 7 days after injury, with evaluations at 28 days post-injury. We compared two VFLP-ECM formulations: a manual process (VFLP (man)) and an accelerated automated method (VFLP (au)). VFLP (man) showed more modulated fibrosis-associated gene expressions when compared to VFLP (au) and collagen. Proteomic analysis revealed that VFLP (man) preserves a broader array of bioactive proteins, such as vitronectin, crucial in TGF-β1 signaling and ECM remodeling. The transcriptomic analysis uncovered a downregulation of key fibrotic markers and potential inhibition of regulators such as SMAD3, YAP1, and MRTFA, alongside the upregulation of SMAD7, an inhibitor of TGF-β signaling. Notably, treatment with VFLP (man) resulted in vocal folds with similar stiffness as uninjured controls, whereas tissues treated with collagen or VFLP (au) remained stiffer, indicating incomplete mechanical recovery. These data provide the first in vivo evidence that VFLP-ECM hydrogel—mainly when produced via manual decellularization—attenuates fibrosis by disrupting biochemical and biomechanical drivers of myofibroblast activation.

Dataset Information

Mechanisms Underlying Morphological and Functional Changes of Cilia in Fibroblasts Derived from Patients Bearing ARL3T31A and ARL3T31A/C118F Mutations

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets