PUBLICATION

WDR34 mutation from anencephaly patients impaired both SHH and PCP signaling pathways

Authors
Yin, H., Peng, R., Chen, Z., Wang, H., Zhang, T., Zheng, Y.
ID
ZDB-PUB-200625-4
Date
2020
Source
Journal of Human Genetics   65(11): 985-993 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Adult
  • Anencephaly/genetics*
  • Anencephaly/pathology
  • Animals
  • Carrier Proteins/genetics*
  • Cell Polarity/genetics
  • Congenital Abnormalities/genetics
  • Congenital Abnormalities/pathology
  • Female
  • Gene Expression Regulation, Developmental
  • Genome, Human/genetics
  • Hedgehog Proteins/genetics*
  • Humans
  • Male
  • Neural Tube Defects/genetics*
  • Neural Tube Defects/pathology
  • Young Adult
  • Zebrafish/genetics
PubMed
32576942 Full text @ J. Hum. Genet.
Abstract
Neural tube defects (NTDs) are debilitating human congenital abnormalities due to failure of neural tube closure. Sonic Hedgehog (SHH) signaling is required for dorsal-ventral patterning of the neural tube. The loss of activation in SHH signaling normally causes holoprosencephaly while the loss of inhibition causes exencephaly due to failure in neural tube closure. WDR34 is a dynein intermedia chain component which is required for SHH activation. However, Wdr34 knockout mouse exhibit exencephaly. Here we screened mutations in WDR34 gene in 100 anencephaly patients of Chinese Han population. Compared to 1000 Genome Project data, two potentially disease causing missense mutations of WDR34 gene (c.1177G>A; p.G393S and c.1310A>G; p.Y437C) were identified in anencephaly patients. These two mutations did not affect the protein expression level of WDR34. Luciferase reporter and endogenous target gene expression level showed that both mutations are lose-of-function mutations in SHH signaling. Surprisingly, WDR34 could promote planar cell polarity (PCP) signaling and the G393S lost this promoting effect on PCP signaling. Morpholino knockdown of wdr34 in zebrafish caused severe convergent extension defects and pericardial abnormalities. The G393S mutant has less rescuing effects than both WT and Y437C WDR34 in zebrafish. Our results suggested that mutation in WDR34 could contribute to human NTDs by affecting both SHH and PCP signaling.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping