Journal
HUMAN MUTATION
Volume 34, Issue 8, Pages 1094-1101Publisher
WILEY
DOI: 10.1002/humu.22338
Keywords
neural tube defects; NTD; SEC24B; COPII vesicle
Categories
Funding
- National Science Fund for Distinguished Young Scholars [81025003]
- 973 Program [2010CB529601, 2013CB945403, 2012CB944604]
- Program for Innovative Research Team in University [IRT1010]
- Ministry of Education of China [20110071110026]
- Commission for Science and Technology of Shanghai Municipality [10JC1401300, 11XD1400900]
- National Natural Science Foundation of China [31000542]
- Scientific Research Foundation for Returned Scholars, Ministry of Education of China
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Neural tube defects (NTDs) are severe birth malformations that affect one in 1,000 live births. Recently, mutations in the planar cell polarity (PCP) pathway genes had been implicated in the pathogenesis of NTDs in both the mouse model and in human cohorts. Mouse models indicate that the homozygous disruption of Sec24b, which mediates the ER-to-Golgi transportation of the core PCP gene Vangl2 as a component of the COPII vesicle, will result in craniorachischisis. In this study, we found four rare missense heterozygous SEC24B mutations (p.Phe227Ser, p.Phe682Leu, p.Arg1248Gln, and p.Ala1251Gly) in NTDs cases that were absent in all controls. Among them, p.Phe227Ser and p.Phe682Leu affected its protein stability and physical interaction with VANGL2. Three variants (p.Phe227Ser, p.Arg1248Gln, and p.Ala1251Gly) were demonstrated to affect VANGL2 subcellular localization in cultured cells. Further functional analysis in the zebrafish including overexpression and dosage-dependent rescue study suggested that these four mutations all displayed loss-of-function effects compared with wild-type SEC24B. Our study demonstrated that functional mutations in SEC24B might contribute to the etiology of a subset of human NTDs and further expanded our knowledge of the role of PCP pathway-related genes in the pathogenesis of human NTDs.
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