Mutations and Down-Regulation of CDX1 in Children with Anorectal Malformations

Abstract

Background: Anorectal malformations (ARMs) represent a variety of congenital disorders that involve abnormal termination of the anorectum. This study was to reveal relation between CDX1 and human ARMs phenotypes.Methods: 108 Chinese patients and 120 Chinese controls were included in this study. We analyzed the relation between two by PCR, qRT-PCR, western blot and immunofluorescence.Results: Four heterozygous mutations in CDX1 gene were identified in ARMs patients (3.7%, 4/108), no found in controls. CDX1 protein expression was significantly decreased in the ARMs compared with the control anorectum. All samples analyzed in ARMs group exhibited down-regulated CDX1 mRNA expression in comparison to matched normal group, demonstrated significant differences statistically.Conclusion: The findings represented the relation between CDX1 mutations and CDX1 genotype. Furthermore, it was suggested that the downregulation of CDX1 might be related to the development of ARMs.

Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review

“…A previous study showed that adverse pregnancy outcomes mainly occurred in mothers with poor glycemic control during the critical phase of embryogenesis (Dunne et al, ), which is the case in obese women with undiagnosed diabetes in particular. These studies consistently found that nongenetic risk factors are not unique for ARM, as assisted reproduction, multiple pregnancy, preterm delivery, low birth weight, preeclampsia, overweight or obesity, and preexisting diabetes were also found to be associated with other congenital malformations, such as cardiac defects, neural tube defects, and hypospadias (Mili et al, ; Rasmussen et al, ; Correa et al, ; Reefhuis et al, ; Blomberg and Källén, ; Brouwers et al, ; Zhang et al, ; van der Zanden et al, ). This may point to nonspecificity or the relevance of timing of exposure during embryonic development, although the latter seems to be less applicable to these specific risk factors.…”

“…SHH, GLI2, and BMP4 were also identified as candidate genes in a human expression study (Zhang et al, 2009). Only one candidate gene study identified functional mutations in the CDX1 gene, as well as lower CDX1 expression levels in patients with ARM (Zhang et al, 2013). CDX1 is a transcription factor, which is involved in the regulation of proliferation and differentiation of embryonic intestinal tissue and is regulated by the WNT/b-catenin signaling pathway (Lickert et al, 2000).…”

“…SNPs in the EDNRB gene, which induces smooth muscle differentiation, seemed to increase the risks of specific phenotypes of ARM only. Moreover, increased heritability of ARM was found among patients with perineal or vestibular fistulas (Falcone et al, 2007), and SHH, GLI2, BMP4, and CDX1 were identified as candidate genes for mainly high-located ARM (Zhang et al, 2009(Zhang et al, , 2013.…”

“…The majority of these studies did not adjust for confounding, except three studies showing elevated risks of ARM in the first pregnancy (Harris et al, ; Duong et al, ; Wijers et al, ). ARM was almost consistently found to occur more frequently in multiple births than in singletons (Källén, ; Forrester and Merz, ; Miller et al, ; Zhang et al, ; Zwink et al, ; Wijers et al, ); however, these results were not adjusted for confounders, such as assisted reproduction, in any of the studies. Two studies showed a higher rate of isolated ARM, ARM with other congenital malformations, and ARM‐VACTERL among multiple births (Zwink et al, ; Wijers et al, ).…”

“…Candidate genes were also selected based on the knowledge from animal studies, syndromic forms of ARM, or other congenital malformations of the colon. After screening the caudal type homeobox 1 (CDX1) gene, four heterozygous mutations (c.213-214InsGAA, c.6G>C, c.27G>T, c.18A>C) were identified, and lower CDX1 expression levels were found in cases when compared with controls (Zhang et al, 2013). Although the ret protooncogene (RET) is a major gene involved in Hirschsprung's disease, it was not associated with ARM (Wu et al, 2010).…”