The WDR45B gene encodes a member of the WD40 repeat-containing proteins superfamily. Proteins of this family consist of a core unit of approximately 40 amino acids ending with Tryptophan (W) and Aspartic Acid (D), hence giving rise to their name. This core unit folds into a 7-bladed beta propeller structure that is responsible for regulating the assembly of multi-protein complexes. By carrying out this function, WD-40 proteins play a key role in several biological processes such as cell cycle control, apoptosis, signal transduction, chromatin assembly, vesicular trafficking and autophagy.
While the specific function of the WDR45B protein is yet to be fully understood, recent studies have suggested a link between WDR45B mutations and a neurodevelopmental disorder characterized by cerebral hypoplasia, mental retardation, spastic quadriplegia and epilepsy. This is further supported by the fact that other WD40 genes have been implicated in similar diseases; namely, WDR62-related primary microcephaly and WDR4-related microcephalic primordial dwarfism.
The gene is located on the long arm of chromosome 17 and spans a length of 33.9 kb of DNA. Its coding sequence is contained within 11 exons and it encodes a 38.1 kDa protein product consisting of 344 amino acids. The gene is ubiquitously expressed in the human body but high expression is seen in the heart, skeletal muscle and pancreas. The truncating mutation p.R225* has been associated with intellectual disability in two different studies.
[See: United Arab Emirates > Suleiman et al., 2017]
Suleiman et al. (2017) described three unrelated families suffering from a distinct neurological phenotype. Family 1 was a consanguineous Emirati family with 3 affected individuals (ages 16 years, 8 years and 9 months). All three patients suffered from developmental delay, spastic quadriplegia and epilepsy. Two patients from a consanguineous Saudi family (ages 20 and 14 years) also suffered from developmental delay, spastic quadriplegia and epilepsy along with microcephaly, while another patient from an unrelated consanguineous Saudi family exhibited developmental delay, spastic quadriplegia and microcephaly. Brain imaging studies revealed a consistent finding of ventriculomegaly, reduced cerebral white matter volume with thin corpus callosum and thinning of cerebral grey matter in all 6 patients. Genetic analysis revealed a novel homozygous c.799C>T (p.Q267*) mutation in the WDR45B gene of patients from family 1 and a known homozygous c.673C>T (p.R225*) mutation in the WDR45B gene of patients from families 2 and 3. Both variants result in a truncated protein and complete loss of function. The authors suggested that WDR45B variants are responsible for a distinct neurodevelopmental disorder characterized by intellectual disability, spastic quadriplegia, epilepsy and cerebral hypoplasia.
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