WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells

Abstract

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

WDR81 regulates adult hippocampal neurogenesis through endosomal SARA-TGFβ signaling

“…Mutations of WDR81 are associated with neurological disorders including CAMRQ2 and microcephaly [16,17]. Our previous studies revealed that loss of WDR81 and its interaction partner WDR91 disrupted PtdIns3P-dependent endosome conversion in the endosome-lysosome pathway [12,14].…”

“…In addition, we found that brain-specific Wdr81 knockout mice died quickly after birth, with accumulated p62 bodies in the cortical and striatal neurons [15]. Importantly, WDR81 mutations were initially reported in a consanguineous family suffering from cerebellar ataxia, mental retardation, and quadrupedal locomotion syndrome (CAMRQ2) [16], and later in patients with microcephaly [17]. However, it is unclear whether and how WDR81 regulates hippocampal neurogenesis in the adult mammalian brain.…”

A Novel Homozygous Frameshift WDR81 Mutation associated with Microlissencephaly, Corpus Callosum Agenesis, and Pontocerebellar Hypoplasia

“…These mitotic defects may lead to reduced neurogenic cell divisions, alterations of neural cell fates, or to a failure to maintain the progenitor cell population. 7 Homozygous WDR81 variants in association with fatal congenital hydranencephaly/hydrocephalus have been reported in consanguineous families (►Table 2, Patients 2-4). 14,15,17 Another phenotype with intellectual disability, cerebellar hypoplasia/atrophy, with or without quadrupedal locomotion due to truncal ataxia (disequilibrium syndrome 2, CAMRQ2, OMIM #610185), has also been ascertained with homozygous WDR81 variants in two consanguineous families (►Table 2, Patients 5 and 6).…”

A de novo variant in ADGRL2 suggests a novel mechanism underlying the previously undescribed association of extreme microcephaly with severely reduced sulcation and rhombencephalosynapsis

“…As regards the different phases of mitosis, WDR81 deleterious variants were shown to increase the number of mitotic cells with an accumulation of cells in prometaphase and metaphase resulting in mitotic delay without any impact on mitotic spindle or primary cilia organization [ 13 ]. Variations in the CIT gene encoding citron kinase localizes to the cleavage furrow and midbody, where it functions in cytodieresis.…”