title: Genetic analysis of RET, GFR alpha 1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A.
abstract: Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germline missense mutations in the RET proto-oncogene. This locus encodes a receptor tyrosine kinase whose activation requires the formation of a multimeric receptor complex including GDNF as a ligand and GFR alpha 1 as a coreceptor. In order to explore the role of RET, GFR alpha 1 and GDNF genes in the variation of phenotypes observed in MEN2A families, we analysed germline mutations of these genes in 4 unrelated Spanish MEN2A families (23 cases studied). We found 2 novel variants corresponding to a single change in position + 47 (intron 12) of RET and position +22 (intron 7) of GFR alpha 1. Furthermore, we observed strong co-segregation between 2 polymorphisms of RET [G691S (exon 11) and S904S (TCC-TCG, exon 15) (100%, Fisher's exact test, p< 0.001)]. More interestingly, we found that these polymorphisms occurred at a significantly high frequency in patients with age at onset < 20 years old (Kruskal-Wallis's and Fisher's exact test, p = 0.007). These findings suggest that the G691S and S904S variants of RET may somehow play a role on the age of onset of MEN 2A.
authors.affiliation: Unidad de Biología Celular, Centro Nacional de Biología Fundamental, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Gil
authors.forename: Marta
authors.initials: M
authors.lastname: Azañedo
authors.forename: Marina
authors.initials: M
authors.lastname: Pollán
authors.forename: Eva
authors.initials: E
authors.lastname: Cristobal
authors.forename: Begoña
authors.initials: B
authors.lastname: Arribas
authors.forename: Luis
authors.initials: L
authors.lastname: García-Albert
authors.forename: Alfredo
authors.initials: A
authors.lastname: García-Sáiz
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Maestro
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
authors.forename: Javier
authors.initials: J
authors.lastname: Menárguez
authors.forename: José M
authors.initials: JM
authors.lastname: Rojas
mesh_terms: D000483:Alleles; D004252:DNA Mutational Analysis; D029721:Drosophila Proteins; D005260:Female; D005787:Gene Frequency; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D008297:Male; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D009154:Mutation; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013030:Spain
chemical_list: D029721:Drosophila Proteins; C495039:GDNF protein, human; C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; 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