title: Hirschsprung associated GDNF mutations do not prevent RET activation.
abstract: Hirschsprung disease (HSCR) is a complex disorder characterised by aganglia of distal gastrointestinal tracts. The highest proportion of both familial and sporadic cases is due to mutations of the RET proto-oncogene. Five germline mutations in the glial cell-line-derived neurotrophic factor (GDNF) gene, one of the RET ligands, have been detected in HSCR patients. Pedigrees analysis and the observed association between these GDNF alterations and RET variants in the same patients raised the question of whether the GDNF gene plays any causative/predisposing role in HSCR pathogenesis. In the present work, we have studied the ability of GDNF proteins, each bearing one of the reported mutations, to activate RET by performing a functional test in cultured neuroblastoma cells. Consistently with the lack of genotype/phenotype correlation in human subjects, our results indicate absence of detectable alterations of mutant GDNF induced RET activation.
authors.affiliation: Laboratorio di Genetica Molecolare, Istituto G. Gaslini, 16148 Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Borghini
authors.forename: Renata
authors.initials: R
authors.lastname: Bocciardi
authors.forename: Giulia
authors.initials: G
authors.lastname: Bonardi
authors.forename: Ivana
authors.initials: I
authors.lastname: Matera
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Santamaria
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
mesh_terms: D000818:Animals; D019556:COS Cells; D029721:Drosophila Proteins; D005838:Genotype; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D029721:Drosophila Proteins; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; C000715470:MAS1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila