Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2010, vol. 19, nr 1, January-February, p. 83–88

Publication type: original article

Language: English

Study of a Hirschsprung’s Disease Patient Cohort Using Multiplex Ligation-Dependent Probe Amplification

Badania wybranych genów u pacjentów z chorobą Hirschsprunga z użyciem metody MLPA

Robert Śmigiel1,, Damian Bednarczyk1,, Łukasz Łaczmański2,, Anita Rauch3,, Christiane Zweier3,, Dariusz Patkowski4,, Izabela Łaczmańska1,

1 Genetics Department, Wroclaw Medical University, Poland

2 Department of Endocrinology and Diabetology, Wroclaw Medical University, Poland

3 Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

4 Pediatric Surgery Department, Wroclaw Medical University, Poland

Abstract

Background. Hirschsprung’s disease is a congenital disorder with an incidence of 1 per 5000 live births, characterized by the absence of intestinal ganglion cells. The etiology of Hirschsprung’s disease is very heterogeneous (chromosomal, monogenic, oligoand polygenic, as well as multifactorial). Various genes play a role in its etiology, i.e. RET, EDNRB, EDN3, GDNF, SOX10, and ZEB2; new susceptible loci have also been identified.
Material and Methods. The characterized mutations in these genes are mostly small deletions and point mutations in both coding and non-coding regions. Also microdeletions of exons of the critical genes have been reported. The goal of this study was to screen 71 patients with Hirschsprung’s disease for micro-rearrangements in four genes (RET, ZEB2, EDN3, and GDNF) using the MLPA method. Results and
Conclusion. In one case, deletion of all ZEB2 exons was detected and Mowat-Wilson syndrome was diagnosed. In the rest of the patients, no genomic rearrangements were observed in any of the four genes.

Streszczenie

Wprowadzenie. Choroba Hirschsprunga jest wrodzonym schorzeniem jelita występującym z częstością 1 na 5000 żywo urodzonych dzieci, charakteryzuje się brakiem komórek zwojowych w warstwie mięśniowej błony śluzowej oraz w błonie podśluzowej. Etiologia choroby Hirschsprunga jest bardzo heterogenna genetycznie (czynniki chromosomowe, monogenowe, oligoi poligenowe, a także wieloczynnikowość). Zidentyfikowano wiele genów odgrywających znaczącą rolę w etiologii choroby: RET, EDNRB, EDN3, GDNF, SOX10, ZEB2, są opisywane także nowe, istotne loci. Charakterystyczne mutacje w tych genach to najczęściej małe delecje oraz mutacje punktowe, zarówno regionach kodujących, jak i niekodujących. Opisuje się także mikrodelecje w regionach chromosomowych, gdzie są zlokalizowane geny krytyczne dla choroby Hirschsprunga.
Materiał i metody. Ocena molekularna 71 pacjentów z chorobą Hirschsprunga w kierunku mikrorearanżacji genomowych w czterech genach (RET, ZEB2, EDN3 i GDNF) z użyciem metody MLPA. W jednym przypadku wykazano delecję wszystkich egzonów genu ZEB2, rozpoznając jednocześnie u pacjenta zespół Mowat i Wilsona. Wyniki i wnioski. W pozostałych przypadkach nie wykazano istotnych rearanżacji genomowych w czterech badanych genach.

Key words

Hirschsprung’s disease, MLPA, deletions, duplications, RET, ZEB2, EDN3, GDNF, Mowat-Wilson syndrome

Słowa kluczowe

choroba Hirschsprunga, MLPA, delecje, duplikacje, RET, ZEB2, EDN3, GDNF, zespół Mowat-Wilson

References (40)

  1. Badner JA, Sieber WK, Garver KL, Chakravarti A: A genetic study of Hirschsprung disease. Am J Hum Genet 1990, 46, 3, 568–580.
  2. Sieber WK: Hirschsprung’s disease. In: Paediatric Surgery. Eds.: Ravitch MM, YBMP Inc. 1984, 3rd ed., 1035–1058.
  3. Puri P, Ohshiro K, Wester T: Hirschsprung’s disease: a search for etiology. Sem Pediatr Surg 1998, 7, 140–147.
  4. Passarge E: Dissecting Hirschsprung disease. Nat Genet 2002, 31, 11–12.
  5. Brooks AS, Oostra BA, Hofstra RMW: Studying the genetics of Hirschsprung’s disease: unravelling an oligogenic disorder. Clin Genet 2004, 67, 6–14.
  6. Amiel J, Sproat-Emison E, Garcia-Barceo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L, Clement-Ziza M, Munnich A, Kashuk C, West K, Wong K K-Y, Lyonnet S, Chakravarti A, Tam P K-H, Ceccherini I, Hofstra R M W, Fernandez R: Hirschsprung disease: associated syndromes and genetics: a review. J Med Genet 2008, 45, 1–14.
  7. Brunner HG, van Bokhoven H: Genetic players in esophageal atresia and tracheoesophageal fistula. Curr Opin Genet Develop 2005, 15, 341–347.
  8. Smigiel R, Sasiadek M, Jagielski J, Blin N: Aspekty genetyczne choroby Hirschsprunga. Gastroenterol Pol 2000, 7, 3, 203–211.
  9. Yaxiong S, Chengren S: Clinical evaluation of diagnostic methods for Hirschsprung’s disease. Paediatr Surg Int 1986, 1, 218–222.
  10. Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002, 30, 12, e57.
  11. Bolk S, Salomon R, Pelet A, Angrist M, Amiel J, Fornagel M, Attié-Bitach T, Olson JM, Hofstra R, Buys C, Steffann J, Munnich A, Lyonnet S, Chakravarti A: Segregation at three loci explains familial and population risk in Hirschsprung disease. Nat Genet 2002, 31, 89–93.
  12. Emison ES, McCallion AS, Kashuk CS, Bush RT, Grice E, Lin S, Portnoy ME, Cutler DJ, Green ED, Chakravarti A: A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 2005, 434, 857–863.
  13. Romeo G, Ronchetto P, Luo Y, Barone V, Seri M, Ceccherini I, Pasini B, Bocciardi R, Lerone M, Kääriäinen H, Martucciello G: Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994, 367, 377–378.
  14. Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fékété C, Ponder BAJ, Munnich A: Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994, 367, 378–380.
  15. Angrist M, Bolk S, Thiel B, Puffenberger EG, Hofstra RM, Buys CHC, Cass DT, Chakravarti A: Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet 1995, 4, 821–830.
  16. Attie T, Pelet A, Edery P, Eng C, Mulligan LM, Amiel J, Boutrand L, Beldjord C, Nihoul-Fékété C, Munnich A, Ponder BAJ, Lyonnet S: Diversity of RET Proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet 1995, 4, 1381–1386.
  17. Hofstra RM, Wu Y, Stulp RP, Elfferich P, Osinga J, Maas SM, Siderius L, Brooks AS, vd Ende JJ, Heydendael VM, Severijnen RS, Bax KM, Meijers C, Buys CH: RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. Hum Mutat 2000, 15, 5, 418–429.
  18. Smigiel R, Patkowski D, Slezak R, Czernik J, Sasiadek M: The role of RET gene in the pathogenesis of Hirschsprung disease. Med Wieku Rozw 2004, 8, 3, 663–675.
  19. Borrego S, Ruiz A, Saez E, Gimm O, Gao X, Lopez-Alonso M, Hernández A, Wright FA, Antiñolo G, Eng C: RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease. J Med Genet 2000, 37, 572–578.
  20. Fitze G, Cramer J, Ziegler A, Schierz M, Schreiber M, Kuhlisch E, Roesner D, Schackert HK: Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung disease. Lancet 2002, 359, 1200–1205.
  21. Smigiel R, Lebioda A, Patkowski D, Czernik J, Dobosz T, Pesz K, Kaczmarz M, Sasiadek MM: Single nucleotide polymorphisms in the RET gene and their correlations with Hirschsprung disease phenotype. J Appl Genet 2006, 47, 3, 261–267.
  22. Bolk S, Pelet A, Hofstra R, Angrist M, Salomon R, Croaker D, Buys CHCM, Lyonnet S, Chakravartiet A: A human model for multigenic inheritance: Phenotypic expression in Hirschsprung disease requires both the RET gene and new 9q31 locus. PNAS 2000, 97, 268–273.
  23. Bolk SG, Salomon R, Pelet A, Angrist M, Amiel J, Fornagel M, Attié-Bitach T, Olson JM, Hofstra R, Buys C, Steffann J, Munnich A, Lyonnet S, Chakravarti A: Segregation at three loci explains familial and population risk in Hirschsprung disease. Nat Genet 2002, 31, 89–93.
  24. Pusch CM, Sasiadek MM, Blin N: Hirschsprung, RET-SOX and beyond: the challenge of examining non-mendelian traits (Review). Int J Mol Med 2002, 10, 4, 367–370.
  25. Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M, Chakravarti A: A Missence Mutation of the Endothelin-B Receptor Gene in Multigenic Hirschsprung‘s Disease. Cell 1994, 79, 1257–1266.
  26. Svensson PJ, Anvret M, Molander ML, Nordenskjöld A: Phenotypic Variation in a Family with Mutations in Two Hirschsprung-related Genes (RET and Endothelin Receptor B). Hum Genet 1998, 103, 145–148.
  27. Bidaud C, Salomon R, Van Camp G, Pelet A, Attie T, Eng C, Bonduelle M, Amiel J, Nihoul-Fekete C, Willems PJ, Munnich A, Lyonnet S: Endothelin-3 Gene Mutations in Isolated and Sydromic Hirschsprung Disease. Eur J Hum Genet 1997, 5, 247–251.
  28. Bolk S, Angrist M, Xie J, Yanagisawa M, Silvestri JM, Weese-Mayer DE, Chakravarti A: Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome. Nat Genet 1996, 13, 395–396.
  29. Salomon R, Attie T, Pelet A, Bidaud C, Eng C, Amiel J, Sarnacki S, Goulet O, Ricour C, Nihoul-Fekete C, Munnich A, Lyonnet S: Gerline Mutations of the RET Ligand GDNF are Not Sufficient to Cause Hirschsprung Disease. Nat Genet 1996, 14, 345–347.
  30. Mowat DR, Croaker GDH, Cass DT, Kerr BA, Chaitow J, Ades J, Chia NL, Wilson MJ: Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. J Med Genet 1998, 35, 617–623.
  31. Amiel J, Espinosa-Parrilla Y, Steffann J, Gosset P, Pelet A, Prieur M, Boute O, Choiset A, Lacombe D, Philip N, Le Merrer M, Tanaka H, Till M, Touraine R, Toutain A, Vekemans M, Munnich A, Lyonnet S: Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures. Am J Hum Genet 2001, 69, 1370–1377.
  32. Zweier C, Albrecht B, Mitulla B, Behrens R, Beese M, Gillessen-Kaesbach G, Rott HD, Rauch A: “MowatWilson” syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomaliesmental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene. Am J Med Genet 2002, 108, 177–181.
  33. Śmigiel R, Jakubiak A: Zespół Mowata i Wilsona – aspekty kliniczne i genetyczne. Standardy Medyczne – Pediatria 2009, 4, 6, 629–634.
  34. Cacheux V, Dastot-Le Moal F, Kääriäinen H, Bondurand N, Rintala R, Boissier B, Wilson M, Mowat D, Goossens M: Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease. Hum Mol Genet 2001, 10, 1503–1510.
  35. Engenheiro E, Møller RS, Pinto M, Soares G, Nikanorova M, Carreira IM, Ullmann R, Tommerup N, Tümer Z: Mowat-Wilson syndrome: an underdiagnosed syndrome? Clin Genet 2008, 73, 6, 579–584.
  36. Zweier C, Thiel CT, Dufke A, Crow J, Meinecke P, Suri M, Ala-Mello S, Beemer F, Bernasconi S, Bianchi P, Bier A, Devriendt K, Dimitrov B, Firth H, Gallagher RC, Garavelli L, Gillessen-Kaesbach G, Hudgins L, Kääriäinen H, Karstens S, Krantz I, Mannhardt A, Medne L, Mücke J, Kibaek M, Krogh LN, Peippo M, Rittinger O, Schulz S, Schelley SL, Temple IK, Dennis NR, Van der Knaap MS, Wheeler P, Yerushalmi B, Zenker M, Seidel H, Lachmeijer A, Prescott T, Kraus C, Lowry RB, Rauch A: Clinical and mutation
  37. Ishihara N, Yamada K, Yamada Y, Miura K, Kato J, Kuwabara N, Hara Y, Kobayashi Y, Hoshino K, Nomura Y, Mimaki M, Ohya K, Matsushima M, Nitta H, Tanaka K, Segawa M, Ohki T, Ezoe T, Kumagai T, Onuma A, Kuroda T, Yoneda M, Yamanaka T, Saeki M, Segawa M, Saji T, Nagaya M, Wakamatsu N: Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1. J Med Genet 2004, 41, 387–393.
  38. Smigiel R, Patkowski D, Czyzewska M, Szafranska A, Rauch A, Zweier C, Sasiadek MM: Severe clinical course of Hirschsprung disease in Mowat-Wilson syndrome patient. J Appl Genet 2010, 51, 1.
  39. Serra A, Gorgens H, Alkada K, Ziegler A., Fitze A, Schackert HK: Analysis of RET, ZEB2, EDN3 and GDNF genomic rearrangements in 80 patients with Hirschsprung Disease (using multiplet ligation-dependent probe amplification). Ann Hum Genet 2009, 73, 147–151.
  40. Moore SW, Johnson AG: Hirschsprung’s disease: genetic and functional associations of Down’s and Waardenburg syndromes. Semin Pediatr Surg 1998, 7, 3, 156–161.
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