title: Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families.
abstract: Germline mutations in succinate dehydrogenase subunits B, C and D (SDHB, SDHC and SDHD), genes encoding subunits of mitochondrial complex II, cause hereditary paragangliomas and phaeochromocytomas. In SDHB (1p36)- and SDHC (1q21)-linked families, disease inheritance is autosomal dominant. In SDHD (11q23)-linked families, the disease phenotype is expressed only upon paternal transmission of the mutation, consistent with maternal imprinting. However, SDHD shows biallelic expression in brain, kidney and lymphoid tissues (Baysal et al., 2000). Moreover, consistent loss of the wild-type (wt) maternal allele in SDHD-linked tumours suggests expression of the maternal SDHD allele in normal paraganglia. Here we demonstrate exclusive loss of the entire maternal chromosome 11 in SDHD-linked paragangliomas and phaeochromocytomas, suggesting that combined loss of the wt SDHD allele and maternal 11p region is essential for tumorigenesis. We hypothesize that this is driven by selective loss of one or more imprinted genes in the 11p15 region. In paternally, but not in maternally derived SDHD mutation carriers, this can be achieved by a single event, that is, non-disjunctional loss of the maternal chromosome 11. Thus, the exclusive paternal transmission of the disease can be explained by a somatic genetic mechanism targeting both the SDHD gene on 11q23 and a paternally imprinted gene on 11p15.5, rather than imprinting of SDHD.
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Leiden University Medical Centre, Albinusdreef 2, H4Q, 2333 ZA, Leiden, The Netherlands.
authors.forename: Erik F
authors.initials: EF
authors.lastname: Hensen
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Ivonne J H M
authors.initials: IJ
authors.lastname: van Minderhout
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Peter E M
authors.initials: PE
authors.lastname: Taschner
authors.forename: Andel G L
authors.initials: AG
authors.lastname: van der Mey
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Cornelisse
mesh_terms: D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D018392:Genomic Imprinting; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008565:Membrane Proteins / Q000235:genetics*; D008957:Models, Genetic; D010235:Paraganglioma / Q000235:genetics*; D013385:Succinate Dehydrogenase
chemical_list: D008565:Membrane Proteins; C491545:SDHD protein, human; D013385:Succinate Dehydrogenase