Gastrointestinal Tract: Molecular Genetics of Hirschsprung Disease

Eberhard Passarge, Universitätsklinikum, Leipzig, Germany

Published online: June 2011

DOI: 10.1002/9780470015902.a0005518.pub2

Hirschsprung disease is a complex, heterogeneous disorder, resulting from absence of the intramural intestinal ganglion cells (congenital intestinal aganglionosis) owing to failure of migration from the neural crest during embryonic development. Therefore, Hirschsprung disease is considered a neural crest disorder (neurocristopathy). Nine genes and three signal pathways have been identified in relation to the aetiology of this group of disorders. In addition, disease-related noncoding regions in the RET gene contribute to the causes by interacting with at least one of the other predisposing genes. The disease susceptibility between males and females differs by a factor of 5 (5:1 higher disease frequency in males than in females).

Key Concepts:

  • Hirschsprung disease is currently the best understood multifactorial, nonMendelian genetic disorder.
  • Mutations in the receptor tyrosine kinase gene RET located at human chromosome 10q11.1 play a pivotal role in the etiology, in combination with other genes.
  • A common noncoding variant in intron 1 of the RET gene within a conserved enhancer-like DNA sequence markedly influences the susceptibility to congenital intestinal aganglionosis.
  • This variant reduces enhancer activity in vitro and contributes to the disease risk 20-fold more than other rare alleles, in spite of its low penetrance.
  • The eight other known genes involved in the genetic aetiology account for less than 30% of patients.
  • Three different signal pathways related to ganglion cell migration and intramural intestinal function are involved in the genetic pathogenesis of congenital intestinal aganglionosis: (1) the RET receptor kinase pathway with the RET gene and its ligand GDNF (glial cell line-derived neurotrophic factor), (2) the endothelin type B receptor pathway with the EDNRB receptor and its ligand EDN3 (endothelin-3) and (3) the transcription factor SOX10.
  • A single genetic change in any of the known genes and chromosomal regions predisposing to congenital intestinal aganglionosis is neither sufficient nor necessary to cause the disease.
  • The genetic effects differ in males and females. The frequency of transmission of predisposing factors differs between males and females, resulting in a 5.7-fold and 2.1-fold increase in susceptibility in males and females, respectively.
  • The predisposing RET susceptibility allele differs in world-like frequency. It is virtually absent in Africa (less than 5%) in contrast to Asia (40% in China and Japan) and Europe (25%).
  • In about 12% of patients, congenital intestinal aganglionosis occurs in syndromic form associated with other clinical manifestations outside the GI tract, usually in a monogenetic inheritance pattern.

Keywords: gastrointestinal disorders; embryology of the GI tract; Hirschsprung disease; aganglionosis; multigenic inheritance; intestinal aganglionosis; RET; SOX10; noncoding variant; genetic susceptibility; penetrance

Figure 1. Abdominal distension owing to megacolon in a child (a) and in an infant (b). Photograph in (b) courtesy of Dr. Lester Martin, Cincinnati (1965) figure from Passarge and Bruder, 2007.
Figure 2. Functional domains of the RET Receptor Tyrosine Kinase in relation to types of mutations (MEN – Multiple Endocrine Neoplasia). The numbers indicate amino acid positions along the RET protein.
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 References
    Amiel J, Sproat-Emison E, Garcia-Barcelo M et al. (2008) Hirschsprung disease, associated syndromes and genetics: a review. Journal of Medical Genetics 45: 1–14.
    Amiel J, Laudier B, Attie-Bitach T et al. (2003) Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nature Genetics 33: 459–460.
    Angrist M, Kauffman E, Slaugenhaupt SA et al. (1993) A gene for Hirschsprung disease (magacolon) in the pericentric region of chromosome 10. Nature Genetics 4: 351–356.
    Bodian M and Carter CO (1963) Family study of Hirschsprung's disease. Annals of Human Genetics 29: 261–277.
    Bolande R (1974) The neurocristopathies: a unifying concept of disease arising in neural crest maldevelopment. Human Pathology 5: 409–429.
    Bolk S, Pelet A, Hofstra RMW et al. (2000) A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both RET gene and a new 9q31 locus. Proceedings of the National Academy of Sciences of the United States of America 97: 268–273.
    Bolk Gabriel S, Salomon R, Pelet A et al. (2002) Segregation at three loci explains familial and population risk in Hirschsprung disease. Nature Genetics 31: 89–93.
    Borrego S, Saez ME, Ruiz A et al. (1999) Specific polymorphism in the RET proto-oncogene are overrepresented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression. American Journal of Human Genetics 65: 1200–1205.
    Burzynski GM, Nolte IM, Osinga J et al. (2004) Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2. European Journal of Human Genetics 12: 604–612.
    Carrasquillo MM, McCallion AS, Puffenberger EG et al. (2002) Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nature Genetics 32: 237–244.
    book Chakravarti A and Lyonnet S (2001) "Hirschsprung disease". In: Scriver CR, Beaudet AL, Sly WS et al. (ed.) The Metabolic and Molecular Bases of Inherited Disease, 8th edn, pp. 6231–6255. New York, NY: McGraw-Hill Medical Publishing Division.
    Emison ES, McCallion AS, Kashuk CS et al. (2005) A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434: 857–863.
    Fitze G, Appelt H, König IR et al. (2003) Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR). Human Molecular Genetics 12: 3207–3214.
    Grice EA, Rochelle ES, Chakravarti A et al. (2005) Evaluation of the RET regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer. Human Molecular Genetics 14: 3837–3845.
    Griseri P, Pesce B, Patrone G et al. (2002) A rare haplotype of the RET proto-oncogene is a risk modifying allele in Hirschsprung disease. American Journal of Human Genetics 71: 969–974.
    book Hamilton WJ, Boyd JD and Mossman HW (1952) (reprinted 1957) Human Embryology: Prenatal Development of Form and Function. Cambridge, UK: W Heffer.
    Heanue TA and Pachnis V (2007) Enteric nervous system development and Hirschsprungs disease: advances in genetic and stem cell studies. Nature Reviews Neuroscience 8: 466–479.
    van Heyningen V (1994) One gene – four syndromes. Nature 367: 319–321.
    book Hinrichsen KV (ed.) (1990) Human-Embryologie. Lehrbuch und Atlas der vorgeburtlichen Entwicklung des Menschen. Berlin, Germany: Springer-Verlag.
    Hirschsprung H (1889) Stuhlträgheit Neugeborener infolge von Dilatation und Hypertrophie des Colons. Jahrbuch fuer Kinderheilkunde 27: 1–7.
    Hofstra RMW, Wu Y and Osinga J (1994) A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367: 375–376.
    Hüther W (1954) Die Hirschsprung'sche Krankheit als Folge einer Entwicklungsstörung der intramuralen Ganglien. Beitraege zur Pathologischen Anatomie und Allgemeinen Pathologie 114: 161–191.
    Jacobi A (1869) On some important causes of constipation in infants. American Journal of Obstetricians 2: 96–113.
    book Klein M and Burd R (1999) "Hirschsprung's disease". In: Wyllie RY and Ams JS (eds) Pediatric Gastrointestinal Diseases, p. 489. Philadelphia, PA: WB Saunders.
    Lyonnet S, Bolino A, Pelt A et al. (1993) A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nature Genetics 4: 346–350.
    book Madsen CM (1964) Hirschsprung's Disease. Copenhagen, Denmark: Munksgaard.
    book McCallion AS and Chakravarti A (2008) "RET and Hirschsprung disease and multiple endocrine neoplasia type 2". In: Epstein CJ, Erickson RP and Wynshaw-Boris A (eds) Inborn Errors of Development. The molecular Basis of Clinical Disorders of Morphogenesis, 2nd edn, pp. 512–520. Oxford: Oxford University Press.
    book McKusick VA (1998) Mendelian Inheritance in Man. A Catalog of Human Genes and Genetic Disorders, 12th edn. Baltimore, MD: Johns Hopkins University Press. (see online version OMIM).
    book Moore KL and Persauld TVN (2008) The Developing Human, 8th edn. Philadelphia, PA: WB Saunders.
    Okamoto E and Ueda T (1967) Embryogenesis of intramural ganglion of the gut and its relation to Hirschsprung's disease. Journal of Pediatric Surgery 2: 437–443.
    Passarge E (1967) The genetics of Hirschsprung's disease: evidence for heterogeneous etiology and a study of sixty three families. New England Journal of Medicine 276: 138–143.
    Passarge E (2002) Dissecting Hirschsprung disease. Nature Genetics 31: 11–12.
    book Passarge E (2007) "Gastrointestinal tract and hepatobiliary duct system". In: Rimoin DL, Connor JM, Pyeritz RE and Korf BR (eds) Emery and Rimoin's Principles and Practice of Medical Genetics, 5th edn, pp. 1533–1548. Edinburgh, UK: Churchill Livingstone-Elsevier.
    Passarge E and Bruder E (2007) Genetische Grundlagen des Morbus Hirschsprung. Der Pathologe 28: 113–118.
    Pingault V, Bondurand N, Lemort M et al. (2001) A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes? Journal of Medical Genetics 38: 205–209.
    Puffenberger EG, Kauffman ER, Bolk S et al. (1994a) Identity-by-descent and association mapping of a recessive gene for Hirschsprung's disease on human chromosome 13q22. Human Molecular Genetics 3: 1217–1225.
    Puffenberger EG, Hosoda K, Washington SS et al. (1994b) A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell 79: 1257–1266.
    Wakamatsu N, Yamada Y, Yamada K et al. (2001) Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nature Genetics 27: 369–370.
    Whitehouse FR and Kernohan JW (1948) Myenteric plexus in congenital megalcolon. Archives in International Medicine 82: 75–111.
    Yntema CC and Hammond DWS (1954) The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo. Journal of Computational Neurolology 101: 515–534.
    Zuelzer WW and Wilson JL (1948) Functional intestinal obstruction of congenital neurogenic basis in infancy. American Journal of Diseases of Children 75: 40–64.
 Further Reading
    Amiel J, Espinosa-Parilla Y, Steffann J et al. (2001) Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures. American Journal of Human Genetics 69: 1370–1377.
    Badner JA, Sieber WK, Garver KL and Chakravarti A (1990) A genetic study of Hirschsprung disease. American Journal of Human Genetics 46: 568–580.
    Eketjall S and Ibanez CF (2002) Functional characterization of mutations in the GDFN gene of patients with Hirschsprung disease. Human Molecular Genetics 11: 325–329.
    Garcia-Barceló MM, Fong P-Y, Tang CS et al. (2008) Mapping of a Hirschsprung¢s disease locus in 3p21. European Journal of Human Genetics 16: 833–840.
    book Grosveld IL (2008) Hirschsprung's Disease: A Historical Perspective – 1691–2005. Heidelberg–Berlin–New York: Springer-Verlag.
    Hofstra RMW, Wu Y and Stulp RP (2000) RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. Human Mutation 15: 418–429.
    Passarge E (1972) Genetic heterogeneity and recurrence risk of Hirschsprung disease. Birth Defects Original Article Series 8(2): 63–67.
    Passarge E (1993) Wither polygenic inheritance: mapping Hirschsprung disease. Nature Genetics 4: 325–326.
    book Passarge E (2007) "Hirschsprung disease: genetic dissection of a complex disorder". In: Mayo O and Leach C (eds) Fifty Year of Human Genetics, pp. 235–246. Kent Town, Australia: Wakefield Press.
 Web Links
    ePath EDN3 (endothelin 3); LocusID: 1908. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1908
    ePath EDN3 (endothelin 3); MIM number: 131242. OMIM: http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?131242
    ePath EDNRB (endothelin receptor type B); LocusID: 1910. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1910
    ePath EDNRB (endothelin receptor type B); MIM number: 131244. OMIM: http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?131244
    ePath GDNF (glial cell derived neurotrophic factor); LocusID: 2668. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2668
    ePath GDNF (glial cell derived neurotrophic factor); MIM number: 600837. OMIM: http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600837
    ePath OMIM (Online Mendelian Inheritance in Man). http://www.ncbi.nlm.nih.gov/Omim/
    ePath RET (ret proto-oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease)); LocusID: 5979. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5979
    ePath RET (ret proto-oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease)); MIM number: 164761. OMIM: http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?164761
    ePath SOX10 (SRY (sex determining region Y)-box 10); LocusID: 6663. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=6663
    ePath SOX10 (SRY (sex determining region Y)-box 10); MIM number: 602229. OMIM: http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602229

Related Sub-Topics:

Neurobiology of Disease | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease
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Article Title: Gastrointestinal Tract: Molecular Genetics of Hirschsprung Disease
 
How to Cite close
Passarge, Eberhard(Jun 2011) Gastrointestinal Tract: Molecular Genetics of Hirschsprung Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005518.pub2]