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


RESULTS
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.


CONCLUSIONS
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.
Fitze
Guido
G
Department of Paediatric Surgery, University of Technology Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany. Guido.Fitze@mailbox.tu-dresden.de
Cramer
Jakob
J
Ziegler
Andreas
A
Schierz
Mandy
M
Schreiber
Matthias
M
Kuhlisch
Eberhard
E
Roesner
Dietmar
D
Schackert
Hans K
HK
D000483:Alleles; D029721:Drosophila Proteins; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017421:Sequence Analysis
D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila