新近出版的《新英格蘭醫(yī)學雜志》發(fā)表了由復旦大學生命科學學院遺傳工程國家重點實驗室王紅艷教授及其合作者共同完成的“在頭部神經(jīng)管畸形（NTD）出生缺陷人群中首次鑒別出Vangl2基因突變”研究結果,。這是科學家首次從患有神經(jīng)管畸形的人類胚胎中發(fā)現(xiàn)這一類型的基因突變，該研究成果為進一步全面,、完整研究Vangl2基因對NTD產(chǎn)生的遺傳效應,，系統(tǒng)研究人類神經(jīng)管畸形發(fā)生的分子機制奠定了基礎。

據(jù)王紅艷介紹,，全世界NTD的發(fā)病率為1％,。~2％。,，而在我國部分地區(qū)高達6％。~10％,。,，是我國排名第二的出生缺陷。數(shù)年前有人曾猜測Vangl2基因的突變可能導致神經(jīng)管畸形,，但科學界始終未能予以證實,。受小鼠的神經(jīng)管畸形表型研究啟發(fā)，復旦大學,、首都兒科研究所和蘇州市立醫(yī)院的研究團隊推測這個Vangl2基因突變很可能直接導致胎兒死亡,，因此，在生存的神經(jīng)管畸形人群中很難檢出,。于是,，研究團隊突破既有研究思路，經(jīng)過兩年的努力,，終于在因NTD病流產(chǎn)的胎兒中發(fā)現(xiàn)Vangl2基因突變,，并證實這些突變確實是導致嚴重的神經(jīng)管畸形的罪魁禍首,。（生物谷Bioon.net）

生物谷推薦原文出處：

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