Frequency of Ret mutations in long- and short-segment Hirschsprung disease

Marco Seri, Luo Yin, Virginia Barone, Alessandra Bolino, Iacopo Celli, Renata Bocciardi, Barbara Pasini, Isabella Ceccherini, Margherita Lerone, Ulf Kristoffersson, Lars T. Larsson, Josep Maria Casasa, Daniel T. Cass, Marc Joel Abramowicz, Jean Marie Vanderwinden, Ingrida Kravčenkiene, Ivo Baric, Margherita Silengo, Giuseppe Martucciello, Giovanni Romeo

Research output: Contribution to journalArticlepeer-review


Hirschsprung disease, or congenital aganglionic megacolon, is a genetic disorder of neural crest development affecting 1:5,000 newborns. Mutations in the RET proto-oncogene, repeatedly identified in the heterozygous state in both long- and short-segment Hirschsprung patients, lead to loss of both transforming and differentiating capacities of the activated RET through a dominant negative effect when expressed in appropriate cellular systems. The approach of single-strand conformational polymorphism analysis established for all the 20 exons of the RET proto-oncogene, and previously used to screen for point mutations in Hirschsprung patients allowed us to identify seven additional mutations among 39 sporadic and familial cases of Hirschsprung disease (detection rate 18%). This relatively low efficiency in detecting mutations of RET in Hirschsprung patients cannot be accounted by the hypothesis of genetic heterogeneity, which is not supported by the results of linkage analysis in the pedigrees analyzed so far. Almost 74% of the point mutations in our series, as well as in other patient series, were identified among long segment patients, who represented only 25% of our patient population. The finding of a C620R substitution in a patient affected with total colonic aganglionosis confirms the involvement of this mutation in the pathogenesis of different phenotypes (i.e., medullary thyroid carcinoma and Hirschsprung). Finally the R313Q mutation identified for the first time in homozygosity in a child born of consanguineous parents is associated with the most severe Hirschsprung phenotype (total colonic aganglionosis with small bowel involvement).

Original languageEnglish
Pages (from-to)243-249
Number of pages7
JournalHuman Mutation
Issue number3
Publication statusPublished - 1997


  • Hirschsprung disease
  • mutation detection
  • RET proto-oncogene
  • SSCP analysis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Frequency of Ret mutations in long- and short-segment Hirschsprung disease'. Together they form a unique fingerprint.

Cite this