Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis

Abstract

Hirschsprung disease (HSCR) is a partially penetrant oligogenic birth defect that occurs when enteric nervous system (ENS) precursors fail to colonize the distal bowel during early pregnancy. Genetic defects underlie HSCR, but much of the variability in the occurrence and severity of the birth defect remain unexplained. We hypothesized that nongenetic factors might contribute to disease development. Here we found that mycophenolate, an inhibitor of de novo guanine nucleotide biosynthesis, and 8 other drugs identified in a zebrafish screen impaired ENS development. In mice, mycophenolate treatment selectively impaired ENS precursor proliferation, delayed precursor migration, and induced bowel aganglionosis. In 2 different mouse models of HSCR, addition of mycophenolate increased the penetrance and severity of Hirschsprung-like pathology. Mycophenolate treatment also reduced ENS precursor migration as well as lamellipodia formation, proliferation, and survival in cultured enteric neural crest-derived cells. Using X-inactivation mosaicism for the purine salvage gene Hprt, we found that reduced ENS precursor proliferation most likely causes mycophenolate-induced migration defects and aganglionosis. To the best of our knowledge, mycophenolate is the first medicine identified that causes major ENS malformations and Hirschsprung-like pathology in a mammalian model. These studies demonstrate a critical role for de novo guanine nucleotide biosynthesis in ENS development and suggest that some cases of HSCR may be preventable.

Maternal Risk Factors and Perinatal Characteristics for Hirschsprung Disease

“…9,11 In our study, we found that a parity of ≥3 children increases the risk of having a child with HSCR. On subanalysis for child sex, boys show the same pattern, but not girls, perhaps because of the small sample size and lack of power.…”

“…6 There have been speculations about the role of hypothyroidism, vitamin A deficiency, and maternal intake of Ibumetin or mycophenolate during pregnancy, but none of these associations have been confirmed. [7][8][9][10][11] The purpose of this study was to investigate the maternal risk factors and perinatal characteristics of HSCR in Sweden.…”

Building a second brain in the bowel

“…Some medicines cause HSCR-like disease in mice (20). Human epidemiologic studies identifying nongenetic risks for HSCR may lead to new prevention strategies.…”

“…Vagal ENCDCs migrate through paraxial mesoderm before entering the bowel, and then migrate in a rostral to caudal direction to colonize the entire fetal bowel ( Figure 1A). Vigorous ENCDC proliferation during migration is important for full bowel colonization (19,20). ENCDCs differentiate into at least 20 neuronal subtypes or enteric glia (21), form ganglia, extend neurites, and establish and refine functional neural circuits to control the bowel (ref.…”

“…For example, removal of vagal neural tube segments where ENCDCs originate causes distal intestinal aganglionosis (50,51). RET mutations that reduce ENCDC proliferation or enhance cell death also cause bowel aganglionosis (27,28), as does treatment with mycophenolic acid, an inhibitor of guanine nucleotide synthesis that reduces ENCDC proliferation but does not prevent ENCDCs from migrating (20). Finally, mutations in endothelin receptor B (EDNRB) or its ligand endothelin-3 (EDN3) cause premature differentiation and cell cycle exit (52)(53)(54), leading to HSCR in humans and distal bowel aganglionosis in mice (55,56).…”