WDR45 deficiency shortens axon length in dopaminergic neurons from patient-derived iPSCs

Sep 23, 2025Human molecular genetics

WDR45 deficiency may shorten the length of dopamine neuron fibers made from patient stem cells

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Abstract

Mutations in the WDR45 gene may disrupt RNA splicing, leading to significant neuronal changes, including shorter axons and ferritin accumulation.

The WDR45 gene is linked to β-propeller protein-associated neurodegeneration, characterized by developmental delay and intellectual disability.
Depletion of WDR45 disrupts the process that clears damaged cell components, causing iron build-up in the brain.
An intron 6 mutation in WDR45 was found to impair RNA splicing, resulting in a truncated protein and subsequent mRNA decay.
Differentiated dopaminergic neurons from patient-derived iPSCs exhibited significantly shorter axons compared to the original stem cells.
Ferritin accumulation was observed in the induced neurons but not in the iPSCs from the same patient.

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β-propeller protein-associated neurodegeneration (BPAN) is characterized by global developmental delay, intellectual disability, and epileptic encephalopathies in infancy or early childhood caused by WDR45/WIPI4 gene mutations. WDR45 depletion disrupted autophagy, leading to iron accumulation in the brain and contributing to neuronal apoptosis. The impact on neuron performance remains unknown. Our previous study established the iPSC cell line derived from a girl patient with a de novo variant c.344 + 5G > T in WDR45 (FDHPIi001). This study demonstrated that this intron 6 mutation impairs RNA splicing, resulting in a 28 bp insertion and nonsense-mediated mRNA decay (NMD) of truncated WDR45. Upon differentiating the iPSCs into dopaminergic neurons, we observed significantly shorter neuronal axons using high-intensity imaging analysis. Additionally, there was significant ferritin accumulation in the induced neurons but not in the iPSCs from the same patient. This research has elucidated the pathogenicity of a non-canonical splice site mutation in WDR45 and has provided deeper insights into the pathologies of neurodegenerative diseases caused by WDR45 defects.

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WDR45 deficiency shortens axon length in dopaminergic neurons from patient-derived iPSCs

Abstract

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