Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease

Giovanni Romeo, Patrizia Ronchetto, Yin Luo, Virginia Barone, Marco Seri, Isabella Ceccherini, Barbara Pasini, Renata Bocciardi, Margherita Lerone, Helena Kääriäinen, Giuseppe Martucciello

Research output: Contribution to journalArticlepeer-review

Abstract

HIRSCHSPRUNG'S disease is a genetic disorder of neural crest development affecting 1 in 5,000 births. It is characterized by the absence of intramural ganglion cells in the hindgut, which often results in partial to complete intestinal obstruction during the first years of life. An autosomal dominant gene causing this disease was recently mapped to chromosome 10q11.2 (refs 1, 2), using an interstitial deletion of this region isolated in a cell hybrid3,4. It was subsequently localized to a 250-kilobase interval which contains the RET proto-oncogene5. Using flanking intronic sequences as primers6 to amplify 12 of the 20 exons of RET from genomic DNA of 27 Hirschsprung's disease patients, we have now identified four mutations (one frameshift and three missense) that totally disrupt or partially change the structure of the tyrosine kinase domain of the RET protein (Ret). Mutations in the extracellular cysteinerich domain of Ret have been identified previously7,8 in patients with multiple endocrine neoplasia type 2A, and a targeted mutation in the tyrosine kinase domain of the same gene produces intestinal aganglionosis and kidney agenesis in homozygous transgenic mice9. Our results support the hypothesis that KET, in addition to its potential role in tumorigenesis, plays a critical role in the embryogenesis of the mammalian enteric nervous system.

Original languageEnglish
Pages (from-to)377-378
Number of pages2
JournalNature
Volume367
Issue number6461
Publication statusPublished - Jan 27 1994

ASJC Scopus subject areas

  • General

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