WDR45, one gene associated with multiple neurodevelopmental disorders
Yingying Cong1, Vincent So1, Marina A J Tijssen2,3
1Department of Biomedical Sciences of Cells & Systems, Molecular Cell Biology Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Autophagy
|April 12, 2021
Summary
Genetic variants in the WDR45 gene cause neurodegenerative disorders by affecting autophagy and iron homeostasis. This review explores WDR45 functions and disease links, focusing on brain iron accumulation as a potential cause.
Area of Science:
- Genetics and Neurobiology
- Molecular and Cellular Biology
Background:
- The WDR45 gene, located on the X-chromosome, encodes the WD repeat-containing protein WDR45/WIPI4.
- Variants in WDR45 are associated with several neurodegenerative disorders, including ß-propeller protein associated neurodegeneration (BPAN), Rett-like syndrome (RLS), intellectual disability (ID), and various epileptic encephalopathies (e.g., developmental and epileptic encephalopathy [DEE], early-onset epileptic encephalopathy [EOEE], West syndrome).
- The precise function of WDR45 remains largely unknown, but its involvement in autophagy, mitochondrial function, endoplasmic reticulum (ER) stress, and iron homeostasis is suggested.
Purpose of the Study:
- To review and summarize current knowledge on the cellular and physiological functions of WDR45.
- To highlight how genetic variants in WDR45 contribute to the pathophysiology of associated neurodegenerative disorders.
- To critically discuss the potential role of brain iron accumulation as a primary cause of these WDR45-associated diseases.
Main Methods:
- Literature review synthesizing existing research on WDR45 gene variants, protein function, and associated diseases.
- Analysis of the connection between clinical manifestations and potential cellular origins of malfunction.
- Critical discussion of the role of iron accumulation in the pathogenesis of WDR45-related disorders.
Main Results:
- WDR45 variants can lead to defects in macroautophagy/autophagy, mitochondrial dysfunction, ER stress, and imbalanced iron homeostasis.
- These cellular dysfunctions are linked to a spectrum of neurodevelopmental and neurodegenerative conditions.
- Brain iron accumulation is a prominent shared feature across these disorders, prompting investigation into its causal role.
Conclusions:
- WDR45 plays a crucial role in cellular processes, and its dysfunction due to genetic variants underlies several severe neurological disorders.
- Understanding WDR45's function is key to elucidating the pathophysiology of these conditions.
- Further research is needed to confirm whether brain iron accumulation is the primary driver of WDR45-associated neurodegeneration.
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