The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency

BackgroundThe SDHA, SDHB, SDHC and SDHD genes encode the subunits of succinate dehydrogenase (succinate: ubiquinone oxidoreductase), a component of both the Krebs cycle and the mitochondrial respiratory chain. SDHA, a flavoprotein and SDHB, an iron-sulfur protein together constitute the catalytic domain, while SDHC and SDHD encode membrane anchors that allow the complex to participate in the respiratory chain as complex II. Germline mutations of SDHD and SDHB are a major cause of the hereditary forms of the tumors paraganglioma and pheochromocytoma. The largest subunit, SDHA, is mutated in patients with Leigh syndrome and late-onset optic atrophy, but has not as yet been identified as a factor in hereditary cancer.DescriptionThe SDH mutation database is based on the recently described Leiden Open (source) Variation Database (LOVD) system. The variants currently described in the database were extracted from the published literature and in some cases annotated to conform to current mutation nomenclature. Researchers can also directly submit new sequence variants online. Since the identification of SDHD, SDHC, and SDHB as classic tumor suppressor genes in 2000 and 2001, studies from research groups around the world have identified a total of 120 variants. Here we introduce all reported paraganglioma and pheochromocytoma related sequence variations in these genes, in addition to all reported mutations of SDHA. The database is now accessible online.ConclusionThe SDH mutation database offers a valuable tool and resource for clinicians involved in the treatment of patients with paraganglioma-pheochromocytoma, clinical geneticists needing an overview of current knowledge, and geneticists and other researchers needing a solid foundation for further exploration of both these tumor syndromes and SDHA-related phenotypes.

[1]  P. Devilee,et al.  Further Localization of the Gene for Hereditary Paragangliomas and Evidence for Linkage in Unrelated Families , 1994, European journal of human genetics : EJHG.

[2]  M. Taniwaki,et al.  Direct evidence for expression of type II flavoprotein subunit in human complex II (succinate-ubiquinone reductase). , 2003, Biochemical and biophysical research communications.

[3]  B. Lemire,et al.  The Saccharomyces cerevisiae mitochondrial succinate:ubiquinone oxidoreductase. , 2002, Biochimica et biophysica acta.

[4]  D. Evans,et al.  Germline SDHD mutation in familial phaeochromocytoma , 2001, The Lancet.

[5]  M. Mascalchi,et al.  Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X , 2005, Journal of Medical Genetics.

[6]  I. Fokkema,et al.  LOVD: Easy creation of a locus‐specific sequence variation database using an “LSDB‐in‐a‐box” approach , 2005, Human mutation.

[7]  M. Taniwaki,et al.  Characterization of the human SDHD gene encoding the small subunit of cytochrome b (cybS) in mitochondrial succinate-ubiquinone oxidoreductase. , 1999, Biochimica et biophysica acta.

[8]  Ourania Horaitis,et al.  Time for a unified system of mutation description and reporting: a review of locus-specific mutation databases. , 2002, Genome research.

[9]  K. Sotlar,et al.  Active succinate dehydrogenase (SDH) and lack of SDHD mutations in sporadic paragangliomas. , 2005, Anticancer research.

[10]  M. Brändle,et al.  A novel succinate dehydrogenase subunit B gene mutation, H132P, causes familial malignant sympathetic extraadrenal paragangliomas. , 2004, The Journal of clinical endocrinology and metabolism.

[11]  C. Eng,et al.  The pressure rises: update on the genetics of phaeochromocytoma. , 2002, Human molecular genetics.

[12]  C. Eng,et al.  Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. , 2004, JAMA.

[13]  E. Jordanova,et al.  Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families , 2004, Oncogene.

[14]  D. Evans,et al.  Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility , 2003, Clinical endocrinology.

[15]  P. Maaswinkel-Mooy,et al.  GENOMIC IMPRINTING IN HEREDITARY GLOMUS TUMOURS: EVIDENCE FOR NEW GENETIC THEORY , 1989, The Lancet.

[16]  H. Neumann,et al.  Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas. , 2005, Endocrine-related cancer.

[17]  B. Devlin,et al.  Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. , 2000, Science.

[18]  P. Rustin,et al.  Hereditary Paraganglioma/Pheochromocytoma and Inherited Succinate Dehydrogenase Deficiency , 2005, Hormone Research in Paediatrics.

[19]  E S Husebye,et al.  Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. , 2001, American journal of human genetics.

[20]  W. Rubinstein,et al.  Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas , 2002, Journal of medical genetics.

[21]  S. Antonarakis,et al.  Corrigendum: Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion , 2002, Human mutation.

[22]  J. Benítez,et al.  Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma , 2002, European Journal of Human Genetics.

[23]  P. Rustin,et al.  Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. , 2002, The Journal of clinical endocrinology and metabolism.

[24]  J. Weber,et al.  A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter. , 1992, Human molecular genetics.

[25]  Ulrich Müller,et al.  Mutations in SDHC cause autosomal dominant paraganglioma, type 3 , 2000, Nature Genetics.