Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung's disease

Lancet. 2002 Apr 6;359(9313):1200-5. doi: 10.1016/S0140-6736(02)08218-1.


Background: Several genes, including the major susceptibility gene RET, have roles in development of Hirschsprung's disease. Results of genetic-linkage analysis of patients with familial disease with both long-segment and short-segment phenotypes have shown close linkage with the RET locus. We aimed to investigate whether both RET mutations and polymorphisms contribute to phenotype of Hirschsprung's disease.

Methods: We looked at the coding region of all 21 exons of the RET proto-oncogene, including the flanking intronic sequences, by direct DNA sequencing in 76 caucasians from Germany with Hirschsprung's disease.

Findings: 20 different mutations were detected in 18 patients. Mutations were under-represented in patients with a homozygous RET c135A/A genotype in association with short-segment phenotype. Short-segment phenotype also arose if the RET mutation was on the c135A allele; conversely, a RET germline mutation on the c135G allele resulted in long-segment phenotype, particularly in heterozygous c135G/A patients.

Interpretation: These observations lend support to the idea that both RET alleles have a role in pathogenesis of Hirschsprung's disease, in a dose-dependent fashion. We also showed that the c135G/A polymorphism modifies the phenotype by a within-gene interaction between the c135A variant and a mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Drosophila Proteins*
  • Female
  • Germ-Line Mutation* / genetics
  • Hirschsprung Disease / genetics*
  • Humans
  • Male
  • Phenotype
  • Polymorphism, Genetic
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Sequence Analysis


  • Drosophila Proteins
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila