Genetics in medicine : official journal of the American College of Medical Genetics

Involvement of DNMT3B in the pathogenesis of Hirschsprung disease and its possible role as a regulator of neurogenesis in the human enteric nervous system.

PMID 24577265


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. 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. 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). 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.