Skip to main content

Molekularbiologie, Grundlagenforschung und Diagnose des Morbus Hirschsprung

Molecular biology, basic research and diagnosis of Hirschsprung’s disease

Zusammenfassung

Das RET-Proto-Onkogen ist das zentrale für die Entstehung eines M. Hirschsprung verantwortliche Gen, wobei RET-Mutationen auch bei anderen pathologischen Läsionen vorkommen. Bei Hirschsprung-Patienten konnten eine Reihe verschiedener RET-Mutationen festgestellt werden. Besondere Aufmerksamkeit sollte denjenigen Patienten gewidmet werden, die Mutationen der Exone für die entscheidenden Zysteinreste aufweisen, welche für MEN2A prädisponieren. Bei diesen Patienten kann der M. Hirschsprung selten mit der Entwicklung neuroendokriner Tumoren, wie mit einem medullären Schilddrüsenkarzinom oder einer MEN2A assoziiert sein. Daher ist eine prophylaktische Thyreoidektomie dann ratsam, wenn eine tumorassoziierte RET-Mutation gefunden wurde. In MEN2A/Hirschsprung-Familien können die RET-Mutationsanalyse, Tumor-Screening und ggf. eine prohylaktische Thyreoidektomie wie bei MEN2A empfohlen werden. Der multigenetische Ursprung des M. Hirschsprung in Abwesenheit einer spezifischen „Standard-Hirschsprung-Mutation“ macht eine genetische Routinediagnostik unmöglich.

Abstract

The proto-oncogene RET is the major gene responsible for Hirschsprung’s disease (HSCR), with RET mutations also implied in different pathologies. A variety of mutations of the RET proto-oncogene have been detected in HSCR patients. Special attention should be paid to rare patients who carry mutations of one of the critical cysteine residues of these exons, known to predispose to MEN2A. In these cases, HSCR can be associated with the development of neuroendocrine tumors such as medullary thyroid carcinoma (MTC) or MEN2A, for which a prophylactic thyroidectomy is advisable in the presence of a tumor causing RET mutation. In combined MEN2A/HSCR families, RET gene testing, tumor screening and prophylactic thyroidectomy are indicated as in MEN2A. The multigenic origin of HSCR and the absence of a “standard” RET mutation associated with HSCR currently make a routine molecular diagnosis impossible.

This is a preview of subscription content, access via your institution.

Abb. 1
Abb. 2

Literatur

  1. Amiel J, Lyonnet S (2001) Hirschsprung disease, associated syndromes, and genetics: a review. J Med Genet 38: 729–739

    Article  PubMed  Google Scholar 

  2. Angrist M, Kauffman E, Slaugenhaupt SA et al. (1993) A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10. Nat Genet 4: 351–356

    Article  PubMed  Google Scholar 

  3. Asai N, Iwashita T, Matsuyama, M Takahashi M (1995) Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 15: 1613–1619

    PubMed  Google Scholar 

  4. Attie T, Pelet A, Edery P et al. (1995) Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet 4: 1381–1386

    PubMed  Google Scholar 

  5. Badner JA, Sieber WK, Garver KL, Chakravarti A (1990) A genetic study of Hirschsprung disease. Am J Hum Genet 46: 568–580

    PubMed  Google Scholar 

  6. Bolande RP (1974) The neurocristopathies. A unifying concept of disease arising in neural crest maldevelopment. Hum Pathol 5: 409–429

    Article  Google Scholar 

  7. Borst MJ, VanCamp JM, Peacock ML, Decker RA (1995) Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung’s disease. Surgery 117: 386–391

    Article  PubMed  Google Scholar 

  8. Carlomagno F, De Vita G, Berlingieri MT et al. (1996) Molecular heterogeneity of RET loss of function in Hirschsprung’s disease. EMBO J 15: 2717–2725

    PubMed  Google Scholar 

  9. Carlson KM, Dou S, Chi D et al. (1994) Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA 91: 1579–1583

    PubMed  Google Scholar 

  10. Ceccherini I, Bocciardi R, Luo Y et al. (1993) On structure and flanking intronic sequences of the human RET proto-oncogene. Biochem Biophys Res Commun 196: 1288–1295

    Article  PubMed  Google Scholar 

  11. Ceccherini I, Hofstra RM, Luo Y et al. (1994) DNA polymorphisms and conditions for SSCP analysis of the 20 ons of the ret proto-oncogene. Oncogene 9: 3025–3029

    PubMed  Google Scholar 

  12. Ceccherini I, Yin L, Pasini B et al. (1993) Close linkage with RET protooncogene and deletion mutation in autosomal dominant hirschusprung disease. Human Mol Gent 11: 1803–1808

    Google Scholar 

  13. Chakravarti A (1996) Endothelin receptor-mediated signaling in hirschsprung disease. Hum Mol Genet 5: 303–307

    PubMed  Google Scholar 

  14. Chakravarti A, Lyonnet S (2001) Hirschsprung disease. In: Scriver CR et al. (eds) The Metabolic and Molecular Bases of Inherited Disease. 8th edn. McGraw-Hill, New York, pp 6231-6255

  15. Doray B, Salomon R, Amiel J et al. (1998) Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum Mol Genet 7: 1831

    Article  Google Scholar 

  16. Fewtrell MS, Tam PK, Thomson AH et al. (1994) Hirschsprung’s disease associated with a deletion of chromosome 10 (q11.2q21.2): a further link with the neurocristopathies? J Med Genet 31: 325–327

    PubMed  Google Scholar 

  17. Garcia-Barcelo M, Sham MH, Lee WS et al. (2004) Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease. Clin Chem 50: 93–100

    Article  PubMed  Google Scholar 

  18. Gardner E, Papi L, Easton DF et al. (1993) Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2. Hum Mol Genet 2: 241–246

    Article  PubMed  Google Scholar 

  19. Garret JR, Howerd ER, Nixon HH (1969) Histochemical diagnosis of Hirschsprung’s disease. Lancet 2(7617): 456

    Google Scholar 

  20. Garver KL, Law JC, Garver B (1985) Hirschsprung disease: a genetic study. Clin Genet 28: 503–508

    PubMed  Google Scholar 

  21. Hall BK (1999) The neural crest in development and evolution. Springer, New York

  22. Hall BK,Horstadius S (1988) The neural crest including a fascimile reprint of the neural crest by Sven Horstadius. Oxford University Press, New York

  23. Hofstra RM, Landsvater RM, Ceccherini I et al. (1994) A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367: 375–376

    Article  PubMed  Google Scholar 

  24. Ito S, Iwashita T, Asai N et al. (1997) Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung’s disease phenotype. Cancer Res 57: 2870–2872

    PubMed  Google Scholar 

  25. Iwashita T, Murakami H, Asai N, Takahashi M (1996) Mechanism of ret dysfunction by Hirschsprung mutations affecting its tracellular domain. Hum Mol Genet 5: 1577–1580

    Article  PubMed  Google Scholar 

  26. Le Douarin N, Kalcheim C (1999) The Neural Crest. Cambridge University Press, Cambridge

  27. Le Douarin NM (1984) Cell migrations in embryos. Cell 38: 353–360

    Article  PubMed  Google Scholar 

  28. Luo Y, Ceccherini I, Pasini B et al. (1993) Close linkage with the RET protooncogene and boundaries of deletion mutations in autosomal dominant Hirschsprung disease. Hum Mol Genet 2: 1803–1808

    Article  PubMed  Google Scholar 

  29. Lyonnet S, Bolino A, Pelet A et al. (1993) A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nat Genet 4: 346–350

    Article  PubMed  Google Scholar 

  30. Martucciello G, Bicocchi MP, Dodero P et al. (1992) Total colonic aganglionosis associated with interstitial deletion of the long arm of chromosome 10. Pediatr Surg Intern 7: 308–310

    Google Scholar 

  31. Martucciello G, Ceccherini I, Lerone M,Jasonni V (2000) Pathogenesis of Hirschsprung’s disease. Journ Pediatr Surg 35: 1017–1025

    Article  Google Scholar 

  32. Martucciello G, Favre A, Takahashi M et al. (1995) Immunohistochemical localization of RET protein in Hirschsprung’s disease: J Pediatr Surg 30: 433–436

    Google Scholar 

  33. Martucciello G, Pini Prato A, Puri P et al. (2005) Controversies concerning diagnostic guidelines for anomalies of the enteric nervous system: a report from the fourth International Symposium on Hirschsprung’s disease and related neurocristopathies. J Pediatr Surg 40: 1527–1531

    Article  PubMed  Google Scholar 

  34. Martucciello G, Thompson H, Mazzola C et al. (1998) GDNF deficit in Hirschsprung’s disease. J Pediatr Surg 33: 99–102

    Article  PubMed  Google Scholar 

  35. Meier-Ruge WA, Bruder E (2005) Pathology of chronic costipation in pediatric and adult coloproctology. Pathobiology 72: 1–2

    PubMed  Google Scholar 

  36. Mole SE, Mulligan LM, Healey CS et al. (1993) Localisation of the gene for multiple endocrine neoplasia type 2A to a 480 kb region in chromosome band 10q11.2. Hum Mol Genet 2: 247–252

    Article  PubMed  Google Scholar 

  37. Moore SW, Johnson G (2005) Acetylcholinesterase in Hirschsprung’s disease. Pediatr Surg Int 21: 255–263

    Article  PubMed  Google Scholar 

  38. Mulligan LM, Eng C, Attie T et al. (1994) Diverse phenotypes associated with on 10 mutations of the RET proto-oncogene. Hum Mol Genet 3: 2163–2167

    Article  PubMed  Google Scholar 

  39. Mulligan LM, Eng C, Healey CS et al. (1994) Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 6: 70–74

    Article  PubMed  Google Scholar 

  40. Mulligan LM, Kwok JB, Healey CS et al. (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363: 458–460

    Article  PubMed  Google Scholar 

  41. Okamoto E, Ueda T (1967) Embriogenesis of intramural ganglia of the gut and its relation to Hirschsprung’s disease. J Pediatr Surg 2: 437–443

    Article  Google Scholar 

  42. Pasini B, Borrello MG, Greco A et al. (1995) Loss of function effect of RET mutations causing Hirschsprung disease. Nat Genet 10: 35–40

    Article  PubMed  Google Scholar 

  43. Pelet A, Geneste O, Edery P et al. (1998) Various mechanisms cause RET-mediated signaling defects in Hirschsprung’s disease. J Clin Invest 101: 1415–142

    PubMed  Google Scholar 

  44. Peters Van der Sanden MJH, Kirby ML, Gittenberger de Groot A et al. (1993) Ablation of various regions within the avian vagal crest has differential effects on ganglion formation in the fore mid and hindgut. Dev Dyn 196: 183–194

    PubMed  Google Scholar 

  45. Romeo G, Ceccherini I, Celli J et al. (1998) Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med 243: 515–520

    Article  PubMed  Google Scholar 

  46. Romeo G, Ronchetto P, Luo Y et al. (1994) Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature 367(6461): 377–378

    Article  PubMed  Google Scholar 

  47. Santoro M, Carlomagno F, Romano A et al. (1995) Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 267: 381–383

    Article  PubMed  Google Scholar 

  48. Santoro M, Rosati R, Greco M et al. (1990) The RET proto-oncogene is consistently pressed in human pheochromocytoma and medullary thyroid carcinoma. Oncogene 5: 1595–1598

    PubMed  Google Scholar 

  49. Seri M, Yin L, Barone V et al. (1997) Frequency of RET mutations in long- and short-segment Hirschsprung disease. Hum Mutat 9: 243–249

    Article  PubMed  Google Scholar 

  50. Sijmons RH, Hofstra RMW, Wijburg FA, Links TP, Zwierstra RP, Vermey A, Aronson DC, Tan-Sindhunata G, Brouwers-Smalbraak GJ, Maas SM, CHCM Buys (1998) Oncological implications of RET gene mutations in Hirschsprung disease. Gut 43: 542–547

    PubMed  Google Scholar 

  51. Takahashi M, Buma Y, Hiai H (1989) Isolation of ret proto-oncogene cDNA with an amino-terminal signal sequence. Oncogene 4: 805–806

    PubMed  Google Scholar 

  52. Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H (1988) Cloning and pression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3: 571–578

    PubMed  Google Scholar 

  53. Takahashi M, Burma Y, Taniguchi M (1991) Identification of the ret proto oncogene products in neuroblastoma and leukemia cells. Oncogene 6: 297–301

    PubMed  Google Scholar 

  54. Trupp M, Arenas E, Fainzilber M et al. (1996) Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381: 785–789

    Article  PubMed  Google Scholar 

  55. Tsuzuki T, Takahashi M, Asai N et al. (1995) Spatial and temporal pression of the ret proto-oncogene product in embryonic, infant and adult tissues. Oncogene 10: 191–198

    PubMed  Google Scholar 

  56. Yin L, Seri M, Barone V et al. (1996) Prevalence and parental origin of de novo RET mutations in Hirschsprung’s disease. Eur J Hum Genet 4: 356–358

    PubMed  Google Scholar 

Download references

Interessenkonflikt

Keine Angaben.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G. Martucciello.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Martucciello, G., Luinetti, O., Romano, P. et al. Molekularbiologie, Grundlagenforschung und Diagnose des Morbus Hirschsprung. Pathologe 28, 119–124 (2007). https://doi.org/10.1007/s00292-007-0897-7

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-007-0897-7

Schlüsselwörter

  • Morbus Hirschsprung
  • Genetik
  • RET-Proto-Onkogen
  • Neuroendokrine Tumoren

Keywords

  • Hirschsprung’s disease
  • Genetics
  • RET proto oncogen
  • Neuroendocrine tumors