Functional genetics on congenital intestinal motility disorders

This thesis explores primary pediatric intestinal pseudo-obstruction (PIPO), focusing on the genetic causes and cellular mechanisms behind the neuropathic (ENS defects) and myopathic (smooth muscle dysfunction) forms of the disorder. Chapter 2 identifies the TFAP2B gene as a new candidate for neuropathic PIPO, showing that a deletion in this gene causes abnormal exon splicing and impaired gastrointestinal function in zebrafish models. Chapter 3 investigates Filamin A (FLNA) mutations in myopathic PIPO, demonstrating that the loss of the long FLNA isoform disrupts smooth muscle contraction and intestinal development, leading to congenital short bowel syndrome and delayed motility.
Chapter 4 examines the role of DNA methylation in Hirschsprung disease (HSCR), a common form of neuropathic PIPO, finding hypermethylation in key genes like MAB21L2, which may contribute to the disease by disrupting enteric nervous system (ENS) development. The study suggests that both RET and MAB21L2 interact in the same molecular pathway, offering insights into potential epigenetic influences on HSCR pathogenesis. Finally, Chapter 5 uses patient-derived induced pluripotent stem cells (iPSCs) to model HSCR, highlighting defective migration and proliferation of enteric neural crest cells (ENCCs) caused by genetic variants, and suggesting that genetic correction may be necessary for cell therapy approaches.
Taken together, the thesis contributes new genetic insights into PIPO and HSCR, advancing the understanding of their pathogenesis and offering potential strategies for future therapies, including genetic correction and cell replacement therapies for patients with these disorders.