Department of Medicine, McGill University, Montreal, Quebec, Canada H3A 2B4.
Hum Mol Genet. 2011 Nov 15;20(22):4324-33. doi: 10.1093/hmg/ddr359. Epub 2011 Aug 12.
Neural tube defects (NTDs) are a heterogeneous group of common severe congenital anomalies which affect 1-2 infants per 1000 births. Most genetic and/or environmental factors that contribute to the pathogenesis of human NTDs are unknown. Recently, however, pathogenic mutations of VANGL1 and VANGL2 genes have been associated with some cases of human NTDs. Vangl genes encode proteins of the planar cell polarity (PCP) pathway that regulates cell behavior during early stages of neural tube formation. Homozygous disruption of PCP genes in mice results in a spectrum of NTDs, including defects that affect the entire neural axis (craniorachischisis), cranial NTDs (exencephaly) and spina bifida. In this paper, we report the dynamic expression of another PCP gene, Fuzzy, during neural tube formation in mice. We also identify non-synonymous Fuzzy amino acid substitutions in some patients with NTDs and demonstrate that several of these Fuzzy mutations affect formation of primary cilia and ciliary length or affect directional cell movement. Since Fuzzy knockout mice exhibit both NTDs and defective primary cilia and Fuzzy is expressed in the emerging neural tube, we propose that mutations in Fuzzy may account for a subset of NTDs in humans.
神经管缺陷（NTDs）是一组常见的严重先天性畸形，每 1000 例出生中就有 1-2 例。大多数导致人类 NTDs 发病的遗传和/或环境因素尚不清楚。然而，最近 VANGL1 和 VANGL2 基因突变与一些人类 NTDs 有关。Vangl 基因编码平面细胞极性（PCP）途径的蛋白质，该途径调节神经管形成早期的细胞行为。PCP 基因在小鼠中的纯合破坏导致一系列 NTDs，包括影响整个神经轴（颅裂）、颅 NTDs（无脑畸形）和脊柱裂的缺陷。在本文中，我们报告了另一个 PCP 基因 Fuzzy 在小鼠神经管形成过程中的动态表达。我们还在一些 NTDs 患者中发现了非 synonymous Fuzzy 氨基酸取代，并证明这些 Fuzzy 突变中的几个影响初级纤毛的形成和纤毛长度或影响定向细胞运动。由于 Fuzzy 敲除小鼠既表现出 NTDs 又表现出初级纤毛缺陷，并且 Fuzzy 在新出现的神经管中表达，因此我们提出 Fuzzy 中的突变可能导致人类的一部分 NTDs。
