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WDR45 deficiency shortens axon length in dopaminergic neurons from patient-derived iPSCs
Nana Huang1, Qianqian Ouyang1, Yuxuan Gong1
1Human Phenome Institute, Institute of Medical Genetics and Genomics, MOE Key Laboratory of Contemporary Anthropology, Zhangjiang Fudan International Innovation Center, Fudan University, 825 Zhangheng Road, Shanghai 201203, China.
Insights
Mutations in the WDR45 gene cause β-propeller protein-associated neurodegeneration (BPAN), leading to impaired RNA splicing and shorter neuronal axons. This study reveals iron accumulation in neurons, offering insights into neurodegenerative disease mechanisms.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- β-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder linked to WDR45/WIPI4 gene mutations.
- WDR45 mutations disrupt autophagy, causing brain iron accumulation and neuronal apoptosis, but their effect on neuron performance is unclear.
Purpose of the Study:
- To investigate the pathogenicity of a specific WDR45 intron 6 mutation (c.344+5G>T) in BPAN.
- To analyze the impact of this mutation on dopaminergic neuron development and iron metabolism.
Main Methods:
- Utilized an induced pluripotent stem cell (iPSC) line from a BPAN patient with a de novo WDR45 variant.
- Differentiated patient-derived iPSCs into dopaminergic neurons.
- Performed high-intensity imaging analysis and ferritin accumulation assessment.
Main Results:
- The WDR45 intron 6 mutation impairs RNA splicing, causing a 28 bp insertion and nonsense-mediated mRNA decay.
- Differentiated neurons exhibited significantly shorter axons compared to controls.
- Ferritin accumulation was observed in patient-derived neurons but not in iPSCs.
Conclusions:
- The study elucidates the pathogenic mechanism of a non-canonical splice site mutation in WDR45.
- Findings provide new insights into neurodegeneration in BPAN, highlighting impaired neuronal development and iron dysregulation.
Abstract:
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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