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Genetic Aspect of Hirschsprung’s Disease

  • Kosuke KirinoEmail author
  • Koichiro Yoshimaru
Chapter

Abstract

Hirschsprung’s disease (HSCR) is defined by an absence of enteric neurons of the distal part of the gastrointestinal tract. HSCR results from a failure of the enteric neural crest-derived cells (ENCCs), which give rise to the enteric nervous system (ENS), to migrate, proliferate, differentiate or survive in the bowel wall. This results in clinically severe and sometimes life-threatening bowel obstruction. Developmental biologists and human geneticists are making exceptional progress in understanding the genetic, cellular and molecular events required for normal ENS development, and this progress is in turn leading researchers to explore pathogenesis of HSCR. The objective of this chapter is to provide an overview of the genetics of HSCR, within the context of our current knowledge of ENS development and molecular genetics of human and laboratory models.

Keywords

Hirschsprung’s disease Enteric nervous system Enteric neural crest-derived cells RET GDNF EDNRB EDN3 

References

  1. 1.
    Whitehouse FR, Kernohan JW. Myenteric plexus in congenital megacolon; study of 11 cases. Arch Intern Med (Chic). 1948;82:75–111.CrossRefGoogle Scholar
  2. 2.
    Heanue TA, Pachnis V. Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies. Nat Rev Neurosci. 2007;8:466–79.CrossRefPubMedGoogle Scholar
  3. 3.
    Obermayr F, Hotta R, Enomoto H, Young HM. Development and developmental disorders of the enteric nervous system. Nat Rev Gastroenterol Hepatol. 2013;10:43–57.CrossRefPubMedGoogle Scholar
  4. 4.
    Amiel J, et al. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet. 2008;45:1–14.CrossRefPubMedGoogle Scholar
  5. 5.
    Le Douarin NM, Teillet MA. The migration of neural crest cells to the wall of the digestive tract in avian embryo. J Embryol Exp Morphol. 1973;30:31–48.PubMedGoogle Scholar
  6. 6.
    Burns AJ, Douarin NM. The sacral neural crest contributes neurons and glia to the post-umbilical gut: spatiotemporal analysis of the development of the enteric nervous system. Development. 1998;125:4335–47.PubMedGoogle Scholar
  7. 7.
    Wang X, Chan AK, Sham MH, Burns AJ, Chan WY. Analysis of the sacral neural crest cell contribution to the hindgut enteric nervous system in the mouse embryo. Gastroenterology. 2011;141:992–1002.e1–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Badner JA, Sieber WK, Garver KL, Chakravarti A. A genetic study of Hirschsprung disease. Am J Hum Genet. 1990;46:568–80.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Parisi MA, Kapur RP. Genetics of Hirschsprung disease. Curr Opin Pediatr. 2000;12:610–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Torfs C. An epidemiological study of Hirschsprung disease in a multiracial California population. In: The third international meeting: Hirschsprung disease and related neurocristopathies. France: Evian; 1998.Google Scholar
  11. 11.
    Brooks AS, Oostra BA, Hofstra RM. Studying the genetics of Hirschsprung’s disease: unraveling an oligogenic disorder. Clin Genet. 2005;67:6–14.CrossRefPubMedGoogle Scholar
  12. 12.
    Passarge E. The genetics of Hirschsprung’s disease. Evidence for heterogeneous etiology and a study of sixty-three families. N Engl J Med. 1967;276:138–43.CrossRefPubMedGoogle Scholar
  13. 13.
    Garver KL, Law JC, Garver B. Hirschsprung disease: a genetic study. Clin Genet. 1985;28:503–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Moore SW, Johnson AG. Hirschsprung’s disease: genetic and functional associations of Down’s and Waardenburg syndromes. Semin Pediatr Surg. 1998;7:156–61.CrossRefPubMedGoogle Scholar
  15. 15.
    Burkardt DD, Graham JM Jr, Short SS, Frykman PK. Advances in Hirschsprung disease genetics and treatment strategies: an update for the primary care pediatrician. Clin Pediatr (Phila). 2014;53:71–81.CrossRefGoogle Scholar
  16. 16.
    Griseri P, et al. A common variant located in the 3′UTR of the RET gene is associated with protection from Hirschsprung disease. Hum Mutat. 2007;28:168–76.CrossRefPubMedGoogle Scholar
  17. 17.
    Emison ES, et al. A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature. 2005;434:857–63.CrossRefPubMedGoogle Scholar
  18. 18.
    Schuchardt A, D’Agati V, Larsson-Blomberg L, Costantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature. 1994;367:380–3.CrossRefPubMedGoogle Scholar
  19. 19.
    Sanchez MP, et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature. 1996;382:70–3.CrossRefPubMedGoogle Scholar
  20. 20.
    Pichel JG, et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature. 1996;382:73–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Moore MW, et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature. 1996;382:76–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Cacalano G, et al. GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron. 1998;21:53–62.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Angrist M, Bolk S, Halushka M, Lapchak PA, Chakravarti A. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet. 1996;14:341–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Young HM, et al. GDNF is a chemoattractant for enteric neural cells. Dev Biol. 2001;229:503–16.CrossRefPubMedGoogle Scholar
  25. 25.
    Natarajan D, Marcos-Gutierrez C, Pachnis V, de Graaff E. Requirement of signalling by receptor tyrosine kinase RET for the directed migration of enteric nervous system progenitor cells during mammalian embryogenesis. Development. 2002;129:5151–60.PubMedGoogle Scholar
  26. 26.
    Heuckeroth RO, et al. Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron. 1999;22:253–63.CrossRefGoogle Scholar
  27. 27.
    Rossi J, et al. Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor alpha2. J Clin Invest. 2003;112:707–16.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Doray B, et al. Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum Mol Genet. 1998;7:1449–52.CrossRefPubMedGoogle Scholar
  29. 29.
    Baynash AG, et al. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell. 1994;79:1277–85.CrossRefGoogle Scholar
  30. 30.
    Hosoda K, et al. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell. 1994;79:1267–76.CrossRefPubMedGoogle Scholar
  31. 31.
    Yanagisawa H, et al. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development. 1998;125:825–36.PubMedGoogle Scholar
  32. 32.
    Barlow A, de Graaff E, Pachnis V. Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET. Neuron. 2003;40:905–16.CrossRefPubMedGoogle Scholar
  33. 33.
    Leibl MA, et al. Expression of endothelin 3 by mesenchymal cells of embryonic mouse caecum. Gut. 1999;44:246–52.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Carrasquillo MM, et al. Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nat Genet. 2002;32:237–44.CrossRefPubMedGoogle Scholar
  35. 35.
    McCallion AS, Stames E, Conlon RA, Chakravarti A. Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb. Proc Natl Acad Sci U S A. 2003;100:1826–31.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Garcia-Barcelo MM, et al. Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung’s disease. Proc Natl Acad Sci U S A. 2009;106:2694–9.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Tang CS, et al. Mutations in the NRG1 gene are associated with Hirschsprung disease. Hum Genet. 2012;131:67–76.CrossRefPubMedGoogle Scholar
  38. 38.
    Tang CS, et al. Genome-wide copy number analysis uncovers a new HSCR gene: NRG3. PLoS Genet. 2012;8:e1002687.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Borrego S, Ruiz-Ferrer M, Fernandez RM, Antinolo G. Hirschsprung’s disease as a model of complex genetic etiology. Histol Histopathol. 2013;28:1117–36.PubMedGoogle Scholar
  40. 40.
    Jiang Q, et al. Functional loss of semaphorin 3C and/or semaphorin 3D and their epistatic interaction with ret are critical to Hirschsprung disease liability. Am J Hum Genet. 2015;96:581–96.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Bodian M, Carter C. A family study of Hirschsprung disease. Ann Hum Genet. 1963;26:261.CrossRefGoogle Scholar
  42. 42.
    Parisi MA, et al. Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease? Am J Med Genet. 2002;108:51–6.CrossRefPubMedGoogle Scholar
  43. 43.
    Okamoto N, et al. Hydrocephalus and Hirschsprung’s disease with a mutation of L1CAM. J Hum Genet. 2004;49:334–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Spouge D, Baird PA. Hirschsprung disease in a large birth cohort. Teratology. 1985;32:171–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Brooks AS, Breuning MH, Meijers C. Spectrum of phenotypes associated with Hirschsprung disease: an evaluation of 239 patients from a single institution. In: The third international meeting: Hirschsprung disease and related neurocristopathies. France: Evian; 1998.Google Scholar
  46. 46.
    Herbarth B, et al. Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease. Proc Natl Acad Sci U S A. 1998;95:5161–5.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Southard-Smith EM, Kos L, Pavan WJ. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet. 1998;18:60–4.CrossRefPubMedGoogle Scholar
  48. 48.
    Dutton KA, et al. Zebrafish colourless encodes sox10 and specifies non-ectomesenchymal neural crest fates. Development. 2001;128:4113–25.PubMedGoogle Scholar
  49. 49.
    Bondurand N, Natarajan D, Thapar N, Atkins C, Pachnis V. Neuron and glia generating progenitors of the mammalian enteric nervous system isolated from foetal and postnatal gut cultures. Development. 2003;130:6387–400.CrossRefPubMedGoogle Scholar
  50. 50.
    Britsch S, et al. The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. 2001;15:66–78.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Paratore C, Eichenberger C, Suter U, Sommer L. Sox10 haploinsufficiency affects maintenance of progenitor cells in a mouse model of Hirschsprung disease. Hum Mol Genet. 2002;11:3075–85.CrossRefPubMedGoogle Scholar
  52. 52.
    Kelsh RN. Sorting out Sox10 functions in neural crest development. Bioessays. 2006;28:788–98.CrossRefPubMedGoogle Scholar
  53. 53.
    Benailly HK, et al. PMX2B, a new candidate gene for Hirschsprung’s disease. Clin Genet. 2003;64:204–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Wakamatsu N, et al. Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet. 2001;27:369–70.CrossRefPubMedGoogle Scholar
  55. 55.
    Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF. The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature. 1999;399:366–70.CrossRefPubMedGoogle Scholar
  56. 56.
    Elworthy S, Pinto JP, Pettifer A, Cancela ML, Kelsh RN. Phox2b function in the enteric nervous system is conserved in zebrafish and is sox10-dependent. Mech Dev. 2005;122:659–69.CrossRefPubMedGoogle Scholar
  57. 57.
    Van de Putte T, et al. Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease-mental retardation syndrome. Am J Hum Genet. 2003;72:465–70.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Brooks AS, et al. Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems. Am J Hum Genet. 2005;77:120–6.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Puffenberger EG, et al. Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet. 1994;3:1217–25.CrossRefPubMedGoogle Scholar
  60. 60.
    Carrasquillo MM, et al. Genome-wide association study in Mennonites identifies multiple genes for oligogenic Hirschsprung disease. Am J Hum Genet. 2002;71:193.CrossRefGoogle Scholar
  61. 61.
    Angrist M, et al. Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate gene for Hirschsprung disease susceptibility. Genomics. 1998;48:354–62.CrossRefPubMedGoogle Scholar
  62. 62.
    Attie T, et al. Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet. 1995;4:2407–9.CrossRefPubMedGoogle Scholar
  63. 63.
    de Pontual L, et al. Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease. Hum Mutat. 2007;28:790–6.CrossRefPubMedGoogle Scholar
  64. 64.
    Gui H, et al. Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes. Genome Biol. 2017;18:48.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lai FP, et al. Correction of Hirschsprung-associated mutations in human induced pluripotent stem cells via clustered regularly interspaced short palindromic repeats/Cas9, restores neural crest cell function. Gastroenterology. 2017;153:139–153.e8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Pediatric Surgery, Graduate School of Medical ScienceKyushu UniversityFukuokaJapan

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