title: Genetic characterization and structural analysis of VHL Spanish families to define genotype-phenotype correlations.
abstract: Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. This gene, located in the 3p25-26 chromosome, is a tumor suppressor gene associated with the inhibition of angiogenesis and apoptosis, cell cycle exit, fibronectin matrix assembly, and proteolysis. To define the molecular basis of VHL in a Spanish population, we studied 33 patients suspected of suffering familial or de novo VHL disease and two familial pheochromocytoma cases. Sequence analysis of the coding regions of the VHL gene revealed germline sequence variants in 68.7% (24 out of 35) of the patients, and four of them presented with undescribed germline alterations: g.5429-5430insG, p.Leu128Arg, p.Tyr175Cys, and p.Tyr175Asn. For the remaining 11 patients who showed negative for point mutations, we performed Southern blot analysis and detected gross rearrangements in eight cases (22.8% of the index cases). Our results support the relevance of VHL gene analysis in familial pheochromocytoma cases and also in those with no familial history. In order to investigate the relevance of different amino acid changes in the VHL phenotype, we also analyzed the genotype-phenotype correlations using structural analysis to assess protein stability and complexes. The association of clear cell renal carcinoma (CCRC) development with a relatively high loss of structural stability in pVHL missense-mutants was consistent. Structural stability data in the genotype-phenotype correlations therefore provides us with a better understanding of VHL clinical implications. It is also a suitable approach to the evaluation of unknown significance changes.
authors.affiliation: Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz-Llorente
authors.affiliation: Structural and Computational Biology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Bravo
authors.affiliation: Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Arancha
authors.initials: A
authors.lastname: Cebrián
authors.affiliation: Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
authors.affiliation: Cancer Epidemiology Service, National Center for Epidemiology, Carlos III Institute of Health, Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Pollan
authors.affiliation: Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Tellería
authors.affiliation: Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.affiliation: Human Genetics Department, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.affiliation: Human Genetics Department, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodríguez-López
authors.affiliation: Department of Neurosurgery, Hospital Rio Hortega, Valladolid, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: de Campos
authors.affiliation: Pediatric Neurosurgery Department, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Muñoz
authors.affiliation: Department of Internal Medicine, Hospital Severo Ochoa, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lacambra
authors.affiliation: Human Genetics Department, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.affiliation: Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002292:Carcinoma, Renal Cell / Q000235:genetics; D002648:Child; D005260:Female; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D046911:Macromolecular Substances; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D013030:Spain; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics*
chemical_list: D046911:Macromolecular Substances; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human