title: Involvement of DNMT3B in the pathogenesis of Hirschsprung disease and its possible role as a regulator of neurogenesis in the human enteric nervous system.
abstract: OBJECTIVE
  Hirschsprung disease (OMIM 142623) is a neurocristopathy attributed to a failure of cell proliferation or migration and/or failure of the enteric precursors along the gut to differentiate during embryonic development. Although some genes involved in this pathology are well characterized, many aspects remain poorly understood. In this study, we aimed to identify novel genes implicated in the pathogenesis of Hirschsprung disease.
  
  
  METHODS
  We compared the expression patterns of genes involved in human stem cell pluripotency between enteric precursors from controls and Hirschsprung disease patients. We further evaluated the role of DNMT3B in the context of Hirschsprung disease by inmunocytochemistry, global DNA methylation assays, and mutational screening.
  
  
  RESULTS
  Seven differentially expressed genes were identified. We focused on DNMT3B, which encodes a DNA methyltransferase that performs de novo DNA methylation during embryonic development. DNMT3B mutational analysis in our Hirschsprung disease series revealed the presence of potentially pathogenic mutations (p.Gly25Arg, p.Arg190Cys, and p.Gly198Trp).
  
  
  CONCLUSIONS
  DNMT3B may be regulating enteric nervous system development through DNA methylation in the neural crest cells, suggesting that aberrant methylation patterns could have a relevant role in Hirschsprung disease. Moreover, the synergistic effect of mutations in both DNMT3B and other Hirschsprung disease-related genes may be contributing to a more severe phenotype in our Hirschsprung disease patients.
authors.affiliation: 1] Department of Genetics, Reproduction, and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain [2] Centre for Biomedical Network Research on Rare Diseases, Seville, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Torroglosa
authors.affiliation: 1] Department of Genetics, Reproduction, and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain [2] Centre for Biomedical Network Research on Rare Diseases, Seville, Spain.
authors.forename: María Valle
authors.initials: MV
authors.lastname: Enguix-Riego
authors.affiliation: 1] Department of Genetics, Reproduction, and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain [2] Centre for Biomedical Network Research on Rare Diseases, Seville, Spain.
authors.forename: Raquel María
authors.initials: RM
authors.lastname: Fernández
authors.affiliation: 1] Department of Genetics, Reproduction, and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain [2] Centre for Biomedical Network Research on Rare Diseases, Seville, Spain.
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: Román-Rodriguez
authors.affiliation: Department of Pediatric Surgery, University Hospital Virgen del Rocío, Seville, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Moya-Jiménez
authors.affiliation: Department of Pediatric Surgery, University Hospital Virgen del Rocío, Seville, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de Agustín
authors.affiliation: 1] Department of Genetics, Reproduction, and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain [2] Centre for Biomedical Network Research on Rare Diseases, Seville, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.affiliation: 1] Department of Genetics, Reproduction, and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain [2] Centre for Biomedical Network Research on Rare Diseases, Seville, Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
mesh_terms: D015415:Biomarkers; D016022:Case-Control Studies; D002675:Child, Preschool; D016000:Cluster Analysis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D017615:Enteric Nervous System; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023061:Gene Order; D056426:Genetic Loci; D006627:Hirschsprung Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D039904:Pluripotent Stem Cells / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D015415:Biomarkers; D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B