新近出版的《新英格兰医学杂志》发表了由复旦大学生命科学学院遗传工程国家重点实验室王红艳教授及其合作者共同完成的“在头部神经管畸形（NTD）出生缺陷人群中首次鉴别出Vangl2基因突变”研究结果。这是科学家首次从患有神经管畸形的人类胚胎中发现这一类型的基因突变，该研究成果为进一步全面、完整研究Vangl2基因对NTD产生的遗传效应，系统研究人类神经管畸形发生的分子机制奠定了基础。
据王红艳介绍，全世界NTD的发病率为1％。~2％。，而在我国部分地区高达6％。~10％。，是我国排名第二的出生缺陷。数年前有人曾猜测Vangl2基因的突变可能导致神经管畸形，但科学界始终未能予以证实。受小鼠的神经管畸形表型研究启发，复旦大学、首都儿科研究所和苏州市立医院的研究团队推测这个Vangl2基因突变很可能直接导致胎儿死亡，因此，在生存的神经管畸形人群中很难检出。于是，研究团队突破既有研究思路，经过两年的努力，终于在因NTD病流产的胎儿中发现Vangl2基因突变，并证实这些突变确实是导致严重的神经管畸形的罪魁祸首。（生物谷Bioon.net）
生物谷推荐原文出处：
NEJM Volume 362:2232-2235 June 10, 2010 Number 23
VANGL2 Mutations in Human Cranial Neural-Tube Defects
Yun-Ping Lei, B.S. Ting Zhang, Ph.D. Hong Li, M.D. Bai-Lin Wu, M.Med., Ph.D. Li Jin, Ph.D. Hong-Yan Wang, Ph.D.
Mutations in more than 200 genes are known to cause neural-tube defects in mice; less is known about the genetic cause of neural-tube defects in humans.1 Kibar and colleagues2 hypothesized that human neural-tube defects are caused by mutations in VANGL1 and VANGL2, genes that affect planar cell polarity and cause neural-tube defects in mice. They identified mutations in VANGL1 but not in VANGL2 in humans.2 We hypothesized that mutations in VANGL2 are lethal to the fetus, and therefore we sequenced VANGL2 in 163 stillborn or miscarried Han Chinese fetuses with neural-tube defects (Table 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) and 508 apparently unrelated healthy Han Chinese infants. We obtained written informed consent from the parents and collected and analyzed samples with the approval of the institutional review board of Fudan University.
We identified three novel missense mutations in VANGL2. All were heterozygous in fetuses with a cranial neural-tube defect: S84F (737CT), R353C (1543CT), and F437S (1796TC). R353C was detected in a male fetus at 21 weeks' gestation. This fetus had anencephaly with occipital and cervical spina bifida. F437S was detected in a male fetus at 24 weeks' gestation with anencephaly, and S84F was detected in a female fetus at 22 weeks' gestation with holoprosencephaly. All three mutations affect conserved residues in VANGL2 proteins across species (see the Figure in the Supplementary Appendix) and were absent in controls. The prevalence of other variants was similar among cases and controls (Table 2 in the Supplementary Appendix).
R353 and F437 are located in the cytoplasmic domain, adjacent to the carboxy-terminal PDZ-binding domain. The mutations R353C and F437S are predicted to affect protein structure, and both affect residues that are highly conserved across species (see the Figure in the Supplementary Appendix). Similarly positioned mutations (D255E and S464N) of Vangl2 in mice have been shown to affect Vangl2 function, and they are predicted to disrupt interactions with the cytoplasmic protein, disheveled (Dvl).3,4 S84F predicts the substitution of a serine residue at position 84 (which is highly conserved across species) with a phenylalanine residue (see the Figure in the Supplementary Appendix). Its association with holoprosencephaly is uncertain.
Using a yeast two-hybrid system, we tested the ability of VANGL2 mutants (carrying either the R353C or the F437S mutation) to bind Dvl. All constructs were stably expressed at similar levels (Figure 1A). F437S completely abrogated interaction with Dvl, whereas R353C diminished but did not abolish this interaction (Figure 1B, 1C, and 1D). In contrast, and serving as a positive control, was the interaction between nonmutant VANGL2 and Dvl.
Because we identified VANGL2 mutations in miscarried fetuses with severe cranial neural-tube defects, we surmise that their lethal effect during in utero development precludes their presence in living persons with less severe defects. Our results provide support for studies that emphasize the role of planar-cell-polarity genes in neural-tube closure, although craniorachischisis, not anencephaly, is the invariable phenotype in mice that are homozygously deficient in Vangl2.5
