title: Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect.
abstract: BACKGROUND
  Pheochromocytoma/paraganglioma occurs almost exclusively after paternal transmission of succinate dehydrogenase D (SDHD) mutations. This parent-of-origin effect has not been fully explained but is accompanied by obligate loss of the maternal copy of chromosome 11. Loss of wild-type SDHD and an additional imprinted gene (hypothesized to be H19) appears necessary for tumor formation. Two previous reports suggested tumor formation after maternal transmission of SDHD mutation, but histological and molecular characterization was unavailable.
  
  
  OBJECTIVE
  We report the first kindred in which histologically confirmed pheochromocytoma/paraganglioma occurred after maternal transmission of an SDHD mutation and investigate the molecular mechanism of tumor formation.
  
  
  METHODS
  The design of the investigation was the study of a three-generation family with SDHD c.242C>T (p.Pro81Leu) mutation.
  
  
  RESULTS
  The index patient had a histologically confirmed pheochromocytoma and an identical SDHD germline mutation (p.Pro81Leu) to her mother (who had a glomus jugulare tumor) and paraganglioma tissue from her maternal grandfather. Tumor DNA from the index patient revealed loss of heterozygosity (LOH) at 11q23, causing loss of the wild-type paternal SDHD allele and LOH affecting maternal 11p15, including H19. These two regions of LOH were separated by a region exhibiting clearly retained heterozygosity, including SDHAF2, a recently reported paraganglioma susceptibility gene.
  
  
  CONCLUSIONS
  Tumor formation can occur after maternal transmission of SDHD, a finding with important clinical implications for SDHD families. Tumor formation in SDHD mutation requires the loss of both the wild-type SDHD allele and maternal 11p15, leading to the predominant but now not exclusive pattern of disease inheritance after paternal SDHD transmission.
authors.affiliation: Department of Endocrinology, Western Infirmary, Glasgow G11 6NT, United Kingdom.
authors.forename: Phey M
authors.initials: PM
authors.lastname: Yeap
authors.forename: Edward S
authors.initials: ES
authors.lastname: Tobias
authors.forename: Eleni
authors.initials: E
authors.lastname: Mavraki
authors.forename: Alexander
authors.initials: A
authors.lastname: Fletcher
authors.forename: Nicola
authors.initials: N
authors.lastname: Bradshaw
authors.forename: E Marie
authors.initials: EM
authors.lastname: Freel
authors.forename: Alexander
authors.initials: A
authors.lastname: Cooke
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Murday
authors.forename: H Rosemarie
authors.initials: HR
authors.lastname: Davidson
authors.forename: Colin G
authors.initials: CG
authors.lastname: Perry
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lindsay
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000483:Alleles; D002880:Chromosomes, Human, Pair 11; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D010375:Pedigree; D010673:Pheochromocytoma / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: D013385:Succinate Dehydrogenase