WDR45 gene

The WD repeat domain 45 (WDR45) gene is an X-linked gene and encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids that are typically bracketed by gly-his and trp-asp (GH-WD) and can facilitate the formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation.

The WDR45 gene has a pseudogene on chromosome 4q31.3.

Several alternatively spliced transcript variants encoding different isoforms have been found for this gene, and their biological functions remain largely unclear.

WDR45 is a candidate gene for a wide range of neurodegenerative and neurodevelopmental disorders. The phenotypic spectrum of patients with WDR45 mutations is broad, ranging from mild cognitive impairment in females to severe early-onset epileptic encephalopathies in males. Some patients with mild and relatively static cognitive problems deteriorate in adulthood with the onset of dystonia and dementia. The following partially overlapping phenotypes associated with WDR45 can be distinguished:

SENDA: Static encephalopathy with neurodegeneration in adulthood is the classic phenotype associated with mutations in WDR45. This condition (Haack et al. 2012) refers to patients presenting with an initial non-progressive and "static" intellectual disability with subsequent development of neurodegenerative features in early adulthood that include dementia and dystonia.

BPAN: Some women with WDR45 mutations have phenotypes reminiscent of Rett syndrome or atypical Rett syndrome. Given the properties of the WDR45 protein (beta-propeller structure), disorders associated with WDR45 mutations are termed beta-propeller-associated neurodegeneration (BPAN). In the early phase of the disease, patients were found to have global developmental delay, epilepsy, and stereotypies, i.e., repetitive movements such as hand flapping. The latter in particular reminded the authors of other disorders such as Rett syndrome and atypical Rett syndrome. Epilepsy phenotypes included myoclonic, astatic, and absence seizures. In addition, the authors suggest that neuroimaging may be normal in childhood. In young adulthood, dystonia, parkinsonism, and progressive dementia were noted, and MRI showed iron deposition in the basal ganglia.

Epileptic encephalopathies: Some male patients with early-onset epileptic encephalopathies and de novo mutations in WDR45 were identified.

Due to the widespread use of genetic testing, mutations in WDR45 are often identified in patients before signs of iron storage can be detected. The phenotype of patients with WDR45 mutations by genetic testing can be broad, with males being more affected than females.

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