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Within-gene interaction between c.135 G/A genotypes and RET proto-oncogene germline mutations in HSCR families.
Eur J Pediatr Surg. 2003 Jun; 13(3):152-7.EJ

Abstract

Hirschsprung disease (HSCR) is considered a model for a complex inheritance disorder. Several genes, including the major HSCR-susceptibility RET proto-oncogene, play an aetiological role in the development of HSCR. Genetic linkage analysis in familial HSCR with both long- and short-segment phenotypes has demonstrated a tight linkage to the RET locus, while the phenotype within a HSCR family is characterised by an incomplete penetrance or a variable extension of the aganglionosis. Therefore, additional genetic alterations of RET are postulated in the aetiology or modification of the HSCR phenotype. In this study, the coding region of all 21 exons of the RET proto-oncogene, including the flanking intronic sequences, were investigated by direct DNA sequencing in a HSCR population. We genotyped the c.135 G/A polymorphism and resolved haplotypes comprising the mutation locus and the c.135 G/A polymorphism. Twenty different mutations were detected in 18 of 76 HSCR patients. In ten families the mutations were inherited from the parents, while only four patients had a positive family history for the disease. Moreover, in all ten families an incomplete penetrance of the HSCR phenotype was observed. We have investigated the effect of the non-mutated wild-type allele as well as the c.135 G/A polymorphism on the phenotype within the HSCR families. Our findings support the notion that both RET alleles are involved in the pathogenesis of a subgroup of HSCR patients in a dose-dependent fashion. Additionally, we have shown a modifying effect of the c.135 G/A polymorphism on the HSCR phenotype within HSCR families.

Authors+Show Affiliations

Department of Paediatric Surgery, University of Technology Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. Guido.Fitze@mailbox.tu-dresden.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12939698

Citation

Fitze, G, et al. "Within-gene Interaction Between C.135 G/A Genotypes and RET Proto-oncogene Germline Mutations in HSCR Families." European Journal of Pediatric Surgery : Official Journal of Austrian Association of Pediatric Surgery ... [et Al] = Zeitschrift Fur Kinderchirurgie, vol. 13, no. 3, 2003, pp. 152-7.
Fitze G, Cramer J, Serra A, et al. Within-gene interaction between c.135 G/A genotypes and RET proto-oncogene germline mutations in HSCR families. Eur J Pediatr Surg. 2003;13(3):152-7.
Fitze, G., Cramer, J., Serra, A., Schreiber, M., Roesner, D., & Schackert, H. K. (2003). Within-gene interaction between c.135 G/A genotypes and RET proto-oncogene germline mutations in HSCR families. European Journal of Pediatric Surgery : Official Journal of Austrian Association of Pediatric Surgery ... [et Al] = Zeitschrift Fur Kinderchirurgie, 13(3), 152-7.
Fitze G, et al. Within-gene Interaction Between C.135 G/A Genotypes and RET Proto-oncogene Germline Mutations in HSCR Families. Eur J Pediatr Surg. 2003;13(3):152-7. PubMed PMID: 12939698.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Within-gene interaction between c.135 G/A genotypes and RET proto-oncogene germline mutations in HSCR families. AU - Fitze,G, AU - Cramer,J, AU - Serra,A, AU - Schreiber,M, AU - Roesner,D, AU - Schackert,H K, PY - 2003/8/27/pubmed PY - 2005/2/11/medline PY - 2003/8/27/entrez SP - 152 EP - 7 JF - European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie JO - Eur J Pediatr Surg VL - 13 IS - 3 N2 - Hirschsprung disease (HSCR) is considered a model for a complex inheritance disorder. Several genes, including the major HSCR-susceptibility RET proto-oncogene, play an aetiological role in the development of HSCR. Genetic linkage analysis in familial HSCR with both long- and short-segment phenotypes has demonstrated a tight linkage to the RET locus, while the phenotype within a HSCR family is characterised by an incomplete penetrance or a variable extension of the aganglionosis. Therefore, additional genetic alterations of RET are postulated in the aetiology or modification of the HSCR phenotype. In this study, the coding region of all 21 exons of the RET proto-oncogene, including the flanking intronic sequences, were investigated by direct DNA sequencing in a HSCR population. We genotyped the c.135 G/A polymorphism and resolved haplotypes comprising the mutation locus and the c.135 G/A polymorphism. Twenty different mutations were detected in 18 of 76 HSCR patients. In ten families the mutations were inherited from the parents, while only four patients had a positive family history for the disease. Moreover, in all ten families an incomplete penetrance of the HSCR phenotype was observed. We have investigated the effect of the non-mutated wild-type allele as well as the c.135 G/A polymorphism on the phenotype within the HSCR families. Our findings support the notion that both RET alleles are involved in the pathogenesis of a subgroup of HSCR patients in a dose-dependent fashion. Additionally, we have shown a modifying effect of the c.135 G/A polymorphism on the HSCR phenotype within HSCR families. SN - 0939-7248 UR - https://www.unboundmedicine.com/medline/citation/12939698/Within_gene_interaction_between_c_135_G/A_genotypes_and_RET_proto_oncogene_germline_mutations_in_HSCR_families_ L2 - http://www.thieme-connect.com/DOI/DOI?10.1055/s-2003-41270 DB - PRIME DP - Unbound Medicine ER -