FZD6 is a novel gene for human neural tube defects.
FZD6 is a novel gene for human neural tube defects.
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DOI：
10.1002/humu.21643
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发表时间：
2012-02
期刊：
影响因子：
3.9
通讯作者：
Capra, Valeria
中科院分区：
文献类型：
--
作者：
De Marco, Patrizia;Merello, Elisa;Rossi, Andrea;Piatelli, Gianluca;Cama, Armando;Kibar, Zoha;Capra, Valeria
神经管缺陷（NTDs）是中枢神经系统的严重畸形，每1000个活产儿中就有1个受到影响。小鼠模型有助于确定NTDs中有缺陷的信号通路，包括平面细胞极性（PCP），也称为非规范卷曲/凌乱通路。基于双Fzd3/Fzd6−/−突变小鼠中NTDs的高渗透发生率，我们通过对473名NTDs患者和639名种族匹配的对照组进行重测序，研究了人类同源物Fzd3和Fzd6的作用。虽然我们无法证明FZD3基因的显著贡献，但我们发现了5个罕见的FZD6变异，这些变异在所有对照中都不存在，并通过计算分析预测它们具有功能效应：1个新移码突变（c. 1843_1844insa）， 3个错义变化（p.Arg405Gln, p.Arg511Cys, p.Arg511His）， 1个影响基因3 ' -非翻译区（UTR）的替换（c.*20C>T）。与对照组相比，病例中预测的FZD6有害变异的总体发生率高出5.1倍，导致ntd突变负担显著增加。该研究表明，FZD6中罕见的非同义变异可能导致人类的NTDs，并扩大了PCP途径与NTDs之间的突变谱。[j] .科学通报，2012。©2011 Wiley期刊公司
Neural tube defects (NTDs) are severe malformations of the central nervous system, affecting 1 of 1,000 live births. Mouse models were instrumental in defining the signaling pathways defective in NTDs, including the planar cell polarity (PCP), also called noncanonical Frizzled/Disheveled pathway. Based on the highly penetrant occurrence of NTDs in double Fzd3/Fzd6−/− mutant mice, we investigated the role of the human orthologues, FZD3 and FZD6, by resequencing a cohort of 473 NTDs patients and 639 ethnically matched controls. While we could not demonstrate a significant contribution of FZD3 gene, we identified five rare FZD6 variants that were absent in all controls and predicted to have a functional effect by computational analysis: one de novo frameshift mutation (c.1843_1844insA), three missense changes (p.Arg405Gln, p.Arg511Cys p.Arg511His), and one substitution (c.*20C>T) affecting the 3′-untranslated region (UTR) of the gene. The overall rate of predicted deleterious variants of FZD6 was 5.1-fold higher in cases compared to controls, resulting in a significantly increased NTDs mutation burden. This study demonstrates that rare nonsynonymous variants in FZD6 may contribute to NTDs in humans and enlarges the spectrum of mutations that link PCP pathway to NTDs. Hum Mutat 33:384–390, 2012. © 2011 Wiley Periodicals, Inc.
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