title: Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease.
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 hybrid. It was subsequently localized to a 250-kilobase interval which contains the RET proto-oncogene. Using flanking intronic sequences as primers 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 cysteine-rich domain of Ret have been identified previously 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 mice. Our results support the hypothesis that RET, in addition to its potential role in tumorigenesis, plays a critical role in the embryogenesis of the mammalian enteric nervous system.
authors.affiliation: Istituto Giannina Gaslini, Genova-Quarto, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Romeo
authors.forename: P
authors.initials: P
authors.lastname: Ronchetto
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: V
authors.initials: V
authors.lastname: Barone
authors.forename: M
authors.initials: M
authors.lastname: Seri
authors.forename: I
authors.initials: I
authors.lastname: Ceccherini
authors.forename: B
authors.initials: B
authors.lastname: Pasini
authors.forename: R
authors.initials: R
authors.lastname: Bocciardi
authors.forename: M
authors.initials: M
authors.lastname: Lerone
authors.forename: H
authors.initials: H
authors.lastname: Kääriäinen
mesh_terms: D001483:Base Sequence; D002879:Chromosomes, Human, Pair 10; D029721:Drosophila Proteins; D005260:Female; D016368:Frameshift Mutation; D006627:Hirschsprung Disease / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: 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