title: Identification of a 4.9-kilo base-pair Alu-mediated founder SDHD deletion in two extended paraganglioma families from Austria.
abstract: Hereditary paraganglioma (PGL) is characterized by the development of highly vascularized paraganglionic tumors as a result of germline mutations in the SDHB, SDHC or SDHD subunit genes of succinate dehydrogenase (SDH; mitochondrial complex II), or in the Von Hippel-Lindau tumor-suppressor gene. Although many PGL mutations have been described, gross SDHD deletions have not yet been implicated as founder mutations and are rarely characterized at the DNA sequence level. We investigated the genetic basis of head and neck PGLs observed in 20 subjects from two unrelated multiplex pedigrees from Austria and identified a 4944-base pair partial SDHD deletion, which escaped PCR-based detection methods. The deletion occurred between Alu elements and was present within the same haplotype context in both pedigrees, indicating a founder effect. The deletion caused tumors only after a paternal transmission similar to other conventional SDHD mutations, suggesting preservation of genomic imprinting mechanisms operating at this locus. These data describe a large SDHD deletion at the genomic sequence level and indicate that gross SDHD deletions could be a founder PGL mutation in certain populations.
authors.affiliation: Division of Clinical Genetics, Innsbruck Medical University, Innsbruck, Austria. andreas.janecke@i-med.ac.at
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Joan E
authors.initials: JE
authors.lastname: Willett-Brozick
authors.forename: Christoph
authors.initials: C
authors.lastname: Karas
authors.forename: Metis
authors.initials: M
authors.lastname: Hasipek
authors.forename: Judith
authors.initials: J
authors.lastname: Loeffler-Ragg
authors.forename: Bora E
authors.initials: BE
authors.lastname: Baysal
mesh_terms: D020087:Alu Elements / Q000235:genetics*; D001317:Austria; D020029:Base Pairing / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005190:Family; D005260:Female; D018703:Founder Effect; D017353:Gene Deletion; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010235:Paraganglioma / Q000201:enzymology* / Q000235:genetics*; D010375:Pedigree; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: C491545:SDHD protein, human; D013385:Succinate Dehydrogenase