title: A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2.
abstract: Mutations of the RET proto-oncogene are found in the majority of patients with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). A minority of cases, however, have no detectable RET mutation and there is considerable phenotypic variation within and among MEN 2 families with the same RET mutation, suggesting a role for other loci in this disease. A candidate for such a gene is glial cell line-derived neurotrophic factor receptor alpha 4 (GFRA4), which encodes a cell surface-bound co-receptor (GFR alpha 4) required for interaction of RET with its ligand persephin. The GFRA4 gene has multiple alternative splices leading to three distinct protein isoforms that are prominently expressed in thyroid. We postulated that mutations of GFRA4 contribute to MEN 2 in the absence of RET mutations or modify the RET mutation phenotype. We screened patients with MEN 2 or MEN 2-like phenotypes, with and without RET mutations, for variants of GFRA4. We identified 10 variants, one of which was over represented in, and two of which were found exclusively in, our patient populations. One of these was a single-base substitution upstream of the GFR alpha 4 coding region, where it may alter gene expression. The second was a 7 bp insertion, which results in a change in reading frame for all three GFR alpha 4 isoforms. This would cause a relative shift in membrane bound and soluble forms of GFR alpha 4, which would significantly alter the formation of RET signalling complexes. Our data suggest a model of wild-type GFR alpha 4 isoform expression that includes both activating and inhibiting co-receptors for RET.
authors.affiliation: Department of Pathology, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: Judith B
authors.initials: JB
authors.lastname: Vanhorne
authors.forename: Scott D
authors.initials: SD
authors.lastname: Andrew
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Harrison
authors.forename: Sherryl A M
authors.initials: SA
authors.lastname: Taylor
authors.forename: Bradley
authors.initials: B
authors.lastname: Thomas
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McDonald
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ainsworth
authors.forename: Lois M
authors.initials: LM
authors.lastname: Mulligan
mesh_terms: D000595:Amino Acid Sequence; D005786:Gene Expression Regulation; D005820:Genetic Testing; D005838:Genotype; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics*; D009419:Nerve Tissue Proteins; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000494:pharmacology; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C491860:GFRA4 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C000715470:MAS1 protein, human; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases