Here, we identified compound heterozygous mutations c.731 C > T (p.Ser 244 Leu) and c.2413 G > T (p.Glu 805 X) in the WDR62/MCPH2 gene, which encodes the mitotic centrosomal protein WDR62, in two siblings in a Japanese family with microcephaly using whole-exome sequencing.
Here we utilized CRISPR/Cas9 approaches to generate three strains of WDR62 mutant mice; WDR62V66M/V66M and WDR62R439H/R439H mice recapitulate conserved missense mutations found in humans with microcephaly, with the third strain being a null allele (WDR62stop/stop).
Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum.
It has been reported that WDR62 is the second causative gene of autosomal recessive microcephaly (MCPH2) playing a significant role in spindle formation and the proliferation of neuronal progenitor cells.
We propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2.
WD40-repeat protein 62 (WDR62) was recently identified as a spindle pole protein linked to the neurodevelopmental defect of microcephaly but its roles in mitosis have not been defined.
Thus, modeling microcephaly with cerebral organoids and mice reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly, disruption of which contributes to microcephaly.
Microcephaly 2 (MCPH2) is one of the most frequent subtypes of MCPH.WD repeat-containing protein 62 gene (WDR62) is the most frequently mutated gene in MCPH2 patients.
Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD.