title: High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations.
abstract: OBJECTIVE
  Germline SDHB, SDHC, and/or SDHD mutations have been reported in familial and apparently sporadic paragangliomas (PGLs). There is, however, some variation in the prevalence, penetrance, and phenotypic expression of the succinate dehydrogenase (SDH) mutated gene among different populations. We sought to determine whether germline mutations in SDHB, SDHC, and/or SDHD play a role in cervical PGLs from northern Spain, where this disorder is particularly frequent, and whether there is any difference with respect to the data published in other populations.
  
  
  METHODS
  Thirty-six sporadic cervical PGLs and four familial PGLs were investigated by PCR-single-strand conformation polymorphism analysis and sequencing. Computational biology was applied to address the structural-conformational changes behind missense mutations and, simultaneously, infer the possible consequences in protein function.
  
  
  RESULTS
  Eight sporadic cases (22.2%) carried pathogenic germline mutations, six of which were in SDHB and two in SDHD. Three families had mutations in SDHD and one in SDHB. Seven of 11 different pathogenic mutations (64%) affected SDHB. Ten mutations were novel. Missense mutations were primarily found in SDHB and frameshift mutations in SDHD. Missense SDHB mutations seemed to alter the enzymatic activity by hampering the electron transfer. SDH-linked tumors occurred mainly in males (P = 0.0033), occurred at a younger age (P < 0.0001), were usually multifocal (P = 0.0011), and exhibited a larger size (P = 0.0341).
  
  
  CONCLUSIONS
  A significant proportion of sporadic cervical PGLs arise as a consequence of intrinsic genetic factors. At variance with previous reports, SDHB is frequently mutated in sporadic cervical PGLs and the mutations do not entail a deleterious behavior. Therefore, SDHB genetic testing may be considered in all subjects presenting with solitary cervical PGL and no family history.
authors.affiliation: Institute of Molecular Pathology and Immunology of University of Porto, University of Porto, 4200-465 Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Lima
authors.forename: Tália
authors.initials: T
authors.lastname: Feijão
authors.forename: André
authors.initials: A
authors.lastname: Ferreira da Silva
authors.forename: Isabel
authors.initials: I
authors.lastname: Pereira-Castro
authors.forename: Gregorio
authors.initials: G
authors.lastname: Fernandez-Ballester
authors.forename: Valdemar
authors.initials: V
authors.lastname: Máximo
authors.forename: Agustin
authors.initials: A
authors.lastname: Herrero
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
authors.forename: Manuel
authors.initials: M
authors.lastname: Sobrinho-Simões
authors.forename: Ginesa
authors.initials: G
authors.lastname: Garcia-Rostan
mesh_terms: D000483:Alleles; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000453:epidemiology / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology*; D008967:Molecular Biology; D020125:Mutation, Missense / Q000235:genetics; D010235:Paraganglioma / Q000453:epidemiology / Q000235:genetics*; D019683:Penetrance; D010641:Phenotype; D012189:Retrospective Studies; D013030:Spain / Q000453:epidemiology; D013329:Structure-Activity Relationship; D013385:Succinate Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D013385:Succinate Dehydrogenase