Abstract
Spina bifida is one of the most common neural tube defects (NTDs) with a complex etiology. Variants in planar cell polarity (PCP) genes have been associated with NTDs including spina bifida in both animal models and human cohorts. In this study, we sequenced all exons of CELSR1 in 192 spina bifida patients from a California population to determine the contribution of CELSR1 mutations in the studied population. Novel and rare variants identified in these patients were subsequently genotyped in 190 ethnically matched control individuals. Six missense mutations not found in controls were predicted to be deleterious by both SIFT and PolyPhen. Two TG dinucleotide repeat variants were individually detected in 2 spina bifida patients but not detected in controls. In vitro functional analysis showed that the two TG dinucleotide repeat variants not only changed subcellular localization of the CELSR1 protein, but also impaired the physical association between CELSR1 and VANGL2, and thus diminished the ability to recruit VANGL2 for cell-cell contact. In total, 3% of our spina bifida patients carry deleterious or predicted to be deleterious CELSR1 mutations. Our findings suggest that CELSR1 mutations contribute to the risk of spina bifida in a cohort of spina bifida patients from California.
Highlights
Neural tube defects (NTDs) are among the most severe and common of all human birth defects
TG dinucleotide repeat variants were identified in spina bifida cases (N = 192), and both of them were absent among the 190 control samples (Table 1 and Figure S2)
These four mutations were mapped to different domains of CELSR1: p.Ala1023Gly and p.Ile1124 were mapped to the cadherin repeats, p.Thr1362Met was mapped to a EGF-like domain and p.Arg2497Cye was mapped to the transmembrane domain of CELSR1 (Table 1)
Summary
Neural tube defects (NTDs) are among the most severe and common of all human birth defects. The most frequent types of NTDs are spina bifida and anencephaly. The etiology of NTDs is complex and involves both environmental and genetic factors. Periconceptional folic acid supplementation reduces 50% to 70% of newborn NTDs [1]; the mechanisms underlying this protective effect remain unclear. In terms of genetic underpinnings, monozygotic twinning and single gene disorders have long been associated with increased risks of NTDs [2]. Numerous exploratory candidate gene studies have highlighted a variety of biological pathways such as the folate and one carbon metabolism and transport [3], DNA repair [4], retinoic acid receptors [5], and the planar cell polarity (PCP) signaling network [6]
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