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Eur J Pediatr Surg 2011; 21(06): 389-394
DOI: 10.1055/s-0031-1291357
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

The Role of Ret Genomic Variants in Infantile Hypertrophic Pyloric Stenosis

A. Serra
1   University of Ulm, Paediatric Surgery, Ulm, Germany
,
K. Schuchardt
2   University of Dresden, Paediatric Surgery, Dresden, Germany
,
J. Genuneit
3   University of Ulm, Institute of Epidemiology and Medical Biometry, Ulm, Germany
,
C. Leriche
1   University of Ulm, Paediatric Surgery, Ulm, Germany
,
H. S. Görgens
4   University of Dresden, Surgical Research, Dresden, Germany
,
H.-K Schackert
4   University of Dresden, Surgical Research, Dresden, Germany
,
G. Fitze
2   University of Dresden, Paediatric Surgery, Dresden, Germany
› Author Affiliations
Further Information

Publication History

received 13 May 2011

accepted after revision 21 September 2011

Publication Date:
14 December 2011 (online)

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Abstract

Infantile hypertrophic pyloric stenosis (IHPS) is a common childhood pathology affecting approximately 1–5 children pro 1 000 newborns, with a genetic background as suggested by the familial occurrence. RET is a candidate gene for IHPS due to its role in the development of the intrinsic innervation and ganglia of the smooth musculature and the association of RET variants with another motility disorder (Hirschsprung’s disease). Accordingly, we investigated RET-IHPS associations through sequencing of the complete RET coding region in 32 IHPS patients. Genotype frequencies were compared between patients and 48 controls using the Cochran-Armitage trend test or Fischer’s test for exact p-values. We found 19 RET variants in IHPS, including polymorphisms in the promoter region (c.-200 G>A and c.-196C>A). There was no statistically significant difference between the frequencies of the variants in both groups. There was no deviation from the Hardy-Weinberg equilibrium, yet a significant correlation (linkage disequilibrium) for variants in the promoter region, in exons 11, 13, 14 and 19 and in the 3’ UTR. We conclude that RET variants are present in IHPS patients yet show no significant statistical association with the IHPS phenotype, suggesting at best an adjuvant role for RET in IHPS.

Key words

infantile hypertrophic pyloric stenosis - RET proto-oncogene - mutations - polymorphisms
 

  • References

  • 1 Abel RM, Bishop AE, Dore CJ et al. A quantitative study of the morphological and histochemical changes within the nerves and muscle in infantile hypertrophic pyloric stenosis. J Ped Surg 1998; 33 (05) 682-687
    CrossrefPubMedGoogle Scholar
  • 2 Chung E, Curtis D, Chen G et al. Genetic evidence for the neuronal nitric oxide synthase gene (NOS1) as a susceptibility locus for infantile pyloric stenosis. Am J Hum Genet 1996; 58: 363-370
    PubMedGoogle Scholar
  • 3 Mitchel LE, Risch N. The genetics of infantile hypertrophic pyloric stenosis: a reanalysis. Am J Dis Chil 1993; 147: 1203-1211
    PubMedGoogle Scholar
  • 4 Serra A, Schuchardt K, Genuneit J et al. Genomic variants in the coding region of NOS1 in infantile hypertrophic pyloric stenosis. J Pediatr Surg 2011; 46: 1903-1908
    CrossrefPubMedGoogle Scholar
  • 5 Vanderwinden JM, Mailleux P, Schiffmann SN et al. Nitric oxide synthase activity in infantile hypertrophic pyloric stenosis. New Engl J Med 1992; 327: 511-515
    CrossrefPubMedGoogle Scholar
  • 6 Huang PL, Dawson TM, Bredt DS et al. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 1993; 75: 1273-1286
    CrossrefPubMedGoogle Scholar
  • 7 Saur D, Vanderwinden JM, Seidler B et al. Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis. Proc Nat Acad Sci 2004; 101: 1662-1667
    CrossrefPubMedGoogle Scholar
  • 8 Soderhall C, Nordenskjold A. Neuronal nitric oxide synthase, nNOS, is not linked to infantile hypertrophic pyloric stenosis in 3 families. [Letter] Clin Genet 1998; 53: 421-422
    PubMedGoogle Scholar
  • 9 Lagerstedt-Robinson K, Svenningsson A, Nordenskjöld A. No association between a promoter NOS1 polymorphism (rs41279104) and infantile hypertrophic pyloric stenosis. J Hum Genet 2009; 54 (12) 706-708
    CrossrefPubMedGoogle Scholar
  • 10 Amiel J, Attié T, Jan D et al. Heterozygous endothelin-B receptor (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet 1996; 5: 355-357
    CrossrefPubMedGoogle Scholar
  • 11 Edery P, Lyonnet S, Mulligan LM et al. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994; 367 (6461) 319-320
    CrossrefPubMedGoogle Scholar
  • 12 Fitze G, Cramer J, Ziegler A et al. Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung’s disease. Lancet 2002; 359 (9313) 1200-1205
    CrossrefPubMedGoogle Scholar
  • 13 Garcia-Barcelo M, Ganster RW, Lui VC et al. TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung’s disease. Hum Mol Genet 2005; 14 (02) 191-204
    CrossrefPubMedGoogle Scholar
  • 14 de Pontual L, Pelet A, Trochet D et al. Mutations of the RET gene in isolated and syndromic Hirschsprung’s disease in human disclose major and modifier alleles at a single locus. J Med Genet 2006; 43: 419-423
    PubMedGoogle Scholar
  • 15 Guarino N, Shima H, Oue T et al. Glial-derived growth factor signaling pathway in infantile hypertrophic pyloric stenosis. J Pediatr Surg 2001; 36 (09) 1468-1469
    PubMedGoogle Scholar
  • 16 Guo SW, Thompson EA. Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 1992; 48: 361-372
    CrossrefPubMedGoogle Scholar
  • 17 Mehta CR, Patel NR. A network algorithm for performing Fisher’s exact test in contingency tables. Journal of the American Statistical Association 1983; 78: 427-434
    CrossrefPubMedGoogle Scholar
  • 18 Abel RM, Bishop AE, Dore CJ et al. A quantitative study of the morphological and histochemical changes within the nerves and muscle in infantile hypertrophic pyloric stenosis. J Ped Surg 1998; 33 (05) 682-687
    CrossrefPubMedGoogle Scholar
  • 19 Sy ED, Shan YS, Lin CH et al. Immature intrinsic nerve innervations of pyloric muscle in idiopathic hypertrophic pyloric stenosis. J Formos Med Assoc 2004; 103 (07) 558-561
    PubMedGoogle Scholar
  • 20 Guarino N, Shima H, Oue T et al. Glial-derived growth factor signalling pathway in infantile hypertrophic pyloric stenosis. J Ped Surg 2000; 35 (06) 835-839
    CrossrefPubMedGoogle Scholar
  • 21 Martucciello G, Thompson H, Mazzola C et al. GDNF deficit in Hirschsprung’s disease. J Pediat Surg 1998; 33 (01) 99-102
    CrossrefPubMedGoogle Scholar
  • 22 Romeo G, Ronchetto P, Luo Y et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994; 367 (6461) 377-378
    CrossrefPubMedGoogle Scholar
  • 23 Lyonnet S, Bolino A, Pelet A et al. A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nat Genet 1993; 4 (04) 346-350
    CrossrefPubMedGoogle Scholar
  • 24 Fitze G, Appelt H, König IR et al. Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR). Hum Mol Genet 2003; 12 (24) 3207-3214
    CrossrefPubMedGoogle Scholar
  • 25 Basel-Vanagaite L, Pelet A, Steiner Z et al. Allele dosage-dependent penetrance of RET proto-oncogene in an Israeli-Arab inbred family segregating Hirschsprung disease. Eur J Hum Genet 2007; 15: 242-245
    CrossrefPubMedGoogle Scholar
  • 26 Chung E, Coffey R, Parker K et al. Linkage analysis of infantile pyloric stenosis and markers from chromosome 9q11-q33: no evidence for a major gene in this candidate region. J Med Genet 1993; 30: 393-395
    CrossrefPubMedGoogle Scholar
  • 27 Chung E, Curtis D, Chen G et al. Genetic evidence for the neuronal nitric oxide synthase gene (NOS1) as susceptibility locus for infantile pyloric stenosis. Am J Hum Genet 1996; 58: 363-370
    PubMedGoogle Scholar
  • 28 Abel RM, Bishop AE, Moscoso G et al. The ontogeny of innervation of the human pylorus. J Pediatr Surg 1998; 33 (04) 613-618
    CrossrefPubMedGoogle Scholar
  • 29 Takahashi T. Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract [review]. J Gastroenterol 2003; 38: 421-430
    CrossrefPubMedGoogle Scholar
  • 30 Kusafuka T, Puri P. Altered messenger RNA expression of the neuronal nitric oxide synthase gene in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1997; 12: 576-579
    CrossrefPubMedGoogle Scholar
  • 31 Miao X, Garcia-Barceló MM, So MT et al. Lack of association between nNOS -84G>A polymorphism and risk of infantile hypertrophic pyloric stenosis in a Chinese population. J Pediatr Surg 2010; 45 (04) 709-713
    CrossrefPubMedGoogle Scholar
  • 32 Page AJ, O’Donnell TA, Cooper NJ et al. Nitric oxide as an endogenous peripheral modulator of visceral sensory neuronal function. J Neurosci 2009; 29 (22) 7246-7255
    CrossrefPubMedGoogle Scholar
  • 33 Sivarao DV, Mashimo H, Goyal RK. Pyloric sphincter dysfunction in nNOS -/- and W/Wv mutant mice: animal models of gastroparesis and duodeno-gastric reflux. Gastroenterology 2008; 135 (04) 1258-1266
    CrossrefPubMedGoogle Scholar
  • 34 Everett KV, Chioza BA, Georgula C et al. Genome-wide high-density SNP-based linkage analysis of infantile hypertrophic pyloric stenosis identifies loci on chromosomes 11q14-q22 and Xq23. Am J Hum Genet 2008; 82: 756-762
    CrossrefPubMedGoogle Scholar