Involvement of the WNT and FGF signaling pathways in non-isolated anorectal malformations: sequencing analysis of WNT3A, WNT5A, WNT11, DACT1, FGF10, FGFR2 and the T gene

Int J Mol Med. 2012 Dec;30(6):1459-64. doi: 10.3892/ijmm.2012.1124. Epub 2012 Sep 7.

Abstract

Anorectal malformations (ARMs) comprise a broad spectrum of anomalies, including anal atresia, congenital anal fistula and persistence of the cloaca. Research suggests that genetic factors play an important role in ARM development. However, few genetic variants have been identified. Embryogenesis is orchestrated by crosstalk of the wingless-type MMTV integration site family (WNT) and fibroblast growth factor (FGF) signaling pathways in a process that involves several intracellular cascades. Studies in mice have implicated several genes from these pathways in the etiology of ARMs. We performed sequencing analysis of seven of these previously reported genes in 78 patients with ARMs occurring within the context of at least one additional congenital anomaly. No associations were identified with variants in WNT3A, WNT5A, WNT11, DACT1, FGF10 or the T gene. In the FGFR2 gene, three novel heterozygous nucleotide substitutions were identified. Further investigations, including the study of family members, revealed that these variants were not causally related to the phenotype in the present ARM cohort. Mutations in the seven investigated genes may nonetheless be a cause of ARMs in rare cases. However, further studies should consider genes encoding other proteins in the WNT/FGF signaling pathways as possible candidates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Anorectal Malformations
  • Anus, Imperforate / genetics*
  • Anus, Imperforate / metabolism
  • Brachyury Protein
  • DNA Mutational Analysis
  • Fetal Proteins / genetics
  • Fibroblast Growth Factor 10 / genetics
  • Fibroblast Growth Factors / metabolism*
  • Genetic Association Studies
  • Humans
  • Nuclear Proteins / genetics
  • Point Mutation
  • Proto-Oncogene Proteins / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics*
  • T-Box Domain Proteins / genetics
  • Wnt Proteins / genetics
  • Wnt Signaling Pathway*
  • Wnt-5a Protein
  • Wnt3A Protein / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • DACT1 protein, human
  • FGF10 protein, human
  • Fetal Proteins
  • Fibroblast Growth Factor 10
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • T-Box Domain Proteins
  • WNT3A protein, human
  • WNT5A protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • Wnt11 protein, human
  • Wnt3A Protein
  • Fibroblast Growth Factors
  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2
  • Brachyury Protein