WDR45, one gene associated with multiple neurodevelopmental disorders

Abstract

The WDR45 gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ß-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat β-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in WDR45 can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders.

Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications

“…Pathways include immune system [83], adaptive immune system [84], neutrophil degranulation [85], cytokine signaling in immune system [86] and GPCR ligand binding [87] were responsible for progression of COVID-19 infection. A previous study demonstrated that the expression levels of AHSP (alpha hemoglobin stabilizing protein) [88], IL7R [89], FBXO7 [90], KLRB1 [91], PIP4K2A [92], NFE2 [93], CCR2 [94], CLEC12A [95], NLRP12 [96], PECAM1 [97], TRIM10 [98], ICAM3 [99], EEF1A1 [100], CCR4 [101], PTPRC (protein tyrosine phosphatase receptor type C) [102], CX3CR1 [103], TSPAN32 [104], EOMES (eomesodermin) [105], ATM (ATM serine/threonine kinase) [106], CD28 [107], LRRK2 [108], CCL5 [109], CD33 [110], FCRL3 [111], CCR3 [112], FGL2 [113], GZMA (granzyme A) [114], PICALM (phosphatidylinositol binding clathrin assembly protein) [115], ALOX5 [116], MME (membrane metalloendopeptidase) [117], VIM (vimentin) [118], CD93 [119], GCA (grancalcin) [120], CD226 [121], CD1D [122], TNFSF4 [123], LEF1 [124], TLR4 [125], CCR7 [126], DPP4 [127], NLRC4 [128], ITGB3 [129], RASGRP1 [130], TLR2 [131], DOCK2 [132], CSF1R [133], PRKCB (protein kinase C beta) [134], CAMK4 [135], CXCL5 [136], CD36 [137], P2RY12 [138], LILRB2 [139], CD5 [140], SLC25A37 [141], ADIPOR1 [142], PECAM1 [143], RGS10 [144], RGS18 [145], ANK1 [146], RNF182 [147], NPRL3 [148], NINJ2 [149], KCNA3 [150], ABCG2 [151], MS4A6A [152], WDR45 [153], RAB39B...…”

Cerebral Iron Deposition in Neurodegeneration

“…BPAN (OMIM #300894) manifests as global developmental delay with epilepsy and Rett-like syndrome in childhood and rapid-onset dystonia-parkinsonism and progressive dementia in early adulthood (recently reviewed in [224][225][226]). The WD-domain repeat 45 (WDR45) gene encode a beta-propeller WD repeat protein interacting with phosphoinositides (WIPI4), which is critically involved in the autophagosome-lysosome fusion in neuronal cells [227].…”

“…Another study employing patient-derived fibroblasts found upregulation of DMT1 and downregulation of TfR associated with cellular Fe accumulation induced by nutrient starvation [233]. This pattern of molecular abnormalities led to the hypothesis that mutations in WDR45 may affect ferritinophagy and mitophagy causing deranged Fe recycling with DMT1 upregulation as a proximal cause of Fe accumulation [224]. Impaired ferritinophagy and non-transferrin-bound iron pathway were confirmed to mediate the accumulation of iron in another cellular BPAN model [234] whereby iron was detected mostly in lysosomal vesicles [235].…”

The WIPI Gene Family and Neurodegenerative Diseases: Insights From Yeast and Dictyostelium Models

“…The reason for the variety of clinical manifestations associated to WIPI4 mutations (see Cong et al, 2021 for a comprehensive review of the clinical symptoms) is not yet clear and could be due to the influence of genetic and environmental factors.…”