Abstract
WNT5A is one of the most highly investigated non-canonical Wnt ligands and is involved in the embryonic heart development, especially in formation of the cardiac conotruncal region by regulating the migration and differentiation of cardiac neural crest (CNC) and second heart field (SHF) cells. No study to date has comprehensively characterized the WNT5A regulatory variants in patients with congenital heart malformations (CHMs). The association between regulatory variants of the WNT5A gene and CHMs was examined in case-control association study in 1,210 CHMs and 798 controls. Individuals carrying a homozygous genotype CC (rs524153) or GG (rs504849) had a similarly reduced risk of conotruncal malformations. The homozygous genotypes (CC for rs524153 and GG for rs504849) were associated with a lower WNT5A transcriptional level compared with the transcriptional level of those with wild-type genotypes. Further functional analysis revealed that an additional upstream single nucleotide polymorphisms (SNP) rs371954924 (–5244GCCA > CC) in a linkage disequilibrium (LD) block with the above genotyped SNPs decreased WNT5A expression through the attenuated binding affinity with the transcription factor SOX9. This is the first demonstration that genetic variants in the regulatory regions of WNT5A play a vital role in sporadic conotruncal malformations susceptibility through the changeable expression of the WNT5A gene.
Highlights
WNT5A is one of the most highly investigated non-canonical Wnt ligands and is involved in the embryonic heart development, especially in formation of the cardiac conotruncal region by regulating the migration and differentiation of cardiac neural crest (CNC) and second heart field (SHF) cells
To verify the rs371954924 (GCCA/CC) is within one linkage disequilibrium (LD) with others three common single nucleotide polymorphisms (SNP) located in the regulatory region of WNT5A, we randomly selected 119 samples, including 89 congenital heart malformations (CHMs) and 30 controls from our samples, and genotyped the four SNPs by Sanger sequencing
Wnt5a was expressed in SHF progenitors, and it act in an auto- and/or paracrine fashion to regulated oriented cells migration into an epithelial-like sheet, which generated a pushing force to deploy SHF cells rostrally into the OFT11
Summary
WNT5A is one of the most highly investigated non-canonical Wnt ligands and is involved in the embryonic heart development, especially in formation of the cardiac conotruncal region by regulating the migration and differentiation of cardiac neural crest (CNC) and second heart field (SHF) cells. Further functional analysis revealed that an additional upstream single nucleotide polymorphisms (SNP) rs371954924 (–5244GCCA > CC) in a linkage disequilibrium (LD) block with the above genotyped SNPs decreased WNT5A expression through the attenuated binding affinity with the transcription factor SOX9 This is the first demonstration that genetic variants in the regulatory regions of WNT5A play a vital role in sporadic conotruncal malformations susceptibility through the changeable expression of the WNT5A gene. We identified a functional SNP at –5244GCCA/CC (rs371954924) that reduced the risk of conotruncal defects by influencing WNT5A expression These results confirmed that functional genetic variants of WNT5A contribute significantly to CHM susceptibility
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