KEYWORDS: Compound heterozygous mutation, Primary Microcephaly, Saudi Family, WDR62.
However, Most of the mutations have been reported in two abnormal spindle microtubule assembly (ASPM) OMIM 608716 genes accounting for more than half of all mutations; and WDR62 gene around 10% of all reported cases related to primary microcephaly.2 WD repeat domain 62 genes (WDR62 - GenBank Accession NM_005682.5) are known to play important role in cerebral cortical development and any mutations in this gene lead to cortical malformations, mental retardation and primary microcephaly.
Recently a compound heterozygous mutations c.731 C > T (p.Ser 244 Leu) and c.2413 G > T (p.Glu 805 X) in the WDR62 gene responsible for the mitotic centrosomal protein WDR62, in a microcephaly family from Japanese.3 We have also reported in our recent study a missense mutation in exon 30 of WDR62changing alanine to aspartate in the protein leading to the typical MCPH2 phenotype.4 Whereas new homozygous splicing variantc.3335+1G>C in the WDR62 gene also reported recently.5 Previously pathogenic mutations reported in WDR62 include missense (e.g.
In this study two rare, missense variants were detected as compound heterozygous state in the WDR62 gene of these patients results as c.797C>T, exon 7 (Ala266Val) and c.1102G>A, exon 9 (Asp368Asn) and these mutation leading to the typical MCPH2 MIM 604317 phenotype in Saudi family.
Compound Heterozygous Mutations in WDR62 Identified through Exome Sequencing: Whole exome sequencing revealed two rare, missense variants detected in heterozygous state in the WDR62 gene of this patient.
Second gene is WD repeat protein 62 (WDR62
) at MCPH 2 (Roberts et al., 1999; Kausar et al., 2011).
WD40-repeat protein 62 (WDR62) mutations are common genetic causes of human autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder characterized by significantly reduced cerebral cortex size at birth .
While studies in mice and immortalized cell lines have greatly contributed to our understanding of WDR62's role in neurogenesis, it is important to further investigate its function within the context of human model systems.
shRNA knockdown was performed using SMARTchoice inducible lentiviral small hairpin RNA (shRNA) targeting human WDR62 (H15) (Dharmacon, catalog number: VSH6376).
Neural induction of H9 cells and/or WDR62 shRNA-transduced H9 cells were set up as described by Denham and Dottori, with some slight modifications .
Microcephalin which corresponds to MCPH1, WDR62
(WD repeat-containing protein 62) at MCPH2, CDK5RAP2 (CDK5 regulatory subunit-associated protein 2) at MCPH3, CEP152 (centrosomal protein, 152-KD) at MCPH4, ASPM (abnormal spindle like microcephaly associated) at MCPH5, CENPJ (centromeric protein J) at MCPH6 and STIL corresponding to MCPH7.4 Mutations at any of these loci are indistinguishable clinically.4
Murat Gunel, chief of the Neurovascular Surgery Program and codirector of the Program on Neurogenetics at Yale University, New Haven, Conn., recently used whole exome sequencing to determine that several distinct types of malformations of cortical development, including microcephaly, pachygyria with cortical thickening, and hypoplasia of the corpus callosum, were all associated with recessive mutations in a single gene, WDR62