Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility.

2.50
Hdl Handle:
http://hdl.handle.net/10541/78893
Title:
Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility.
Authors:
Astuti, Dewi; Hart-Holden, Niki; Latif, Farida; Lalloo, Fiona; Black, G C; Lim, Caron; Moran, Anthony; Grossman, Ashley B; Hodgson, Shirley V; Freemont, Anthony J; Ramsden, Richard T; Eng, Charis; Evans, D Gareth R; Maher, Eamonn R
Abstract:
BACKGROUND: Germline mutations in three subunits of mitochondrial complex II (SDHB, SDHC and SDHD) may be associated with susceptibility to phaeochromocytoma (PC) and/or head and neck paraganglioma (HNPGL). METHODS: To further define the role of SDH subunit mutations in these disorders, we analysed a series of 22 probands with PC and evidence of genetic susceptibility (seven with familial PC only, one with familial PC and HNPGL, 10 sporadic cases with multiple PC and four cases of isolated paediatric onset PC) for germline SDHB, SDHC and SDHD mutations. In addition, we analysed 34 cases of HNPGL (30 isolated cases with single tumours, three isolated cases with multiple tumours and one familial case with multiple tumours) for somatic and germline mutations in SDHB, SDHC and SDHD. RESULTS: We identified four germline mutations (three SDHB and one SDHD, three novel) in the 22 PC probands. Combining these results with our previous series, we have detected germline SDHB or SDHD mutations in 2/12 (17%) of familial PC only kindreds, 4/5 (80%) of familial PC and HNPGL cases, 1/10 of sporadic multiple PC cases and 2/4 (50%) of paediatric PCs. No somatic mutations were detected in the HNPGL tumours, but four cases with multiple HNPGL had the common P81L germline SDHD mutation. Intriguingly a silent SNP (c.204C > T) in SDHD was significantly more common in HNPGL cases (6/34) than in controls (1/100, P = 0.0011). Combining our results with those from two other large studies in which both SDHB and SDHD have been analysed, SDHB mutations were most commonly associated with phaeochromocytoma susceptibility and SDHD with the development of HNPGL (P = 0.025). However, germline SDHB and SDHD mutations demonstrate considerable phenotypic variability and genotype-phenotype correlations are complex. CONCLUSION: The significantly lower frequency (P = 0.028) of germline SDH subunit mutations in familial PC only cases compared to those with familial PC and HNPGL suggests that further PC susceptibility gene(s) remain to be identified.
Affiliation:
Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham, UK.
Citation:
Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. 2003, 59 (6):728-33 Clin. Endocrinol.
Journal:
Clinical Endocrinology
Issue Date:
Dec-2003
URI:
http://hdl.handle.net/10541/78893
DOI:
10.1046/j.1365-2265.2003.01914.x
PubMed ID:
14974914
Type:
Article
Language:
en
ISSN:
0300-0664
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorAstuti, Dewi-
dc.contributor.authorHart-Holden, Niki-
dc.contributor.authorLatif, Farida-
dc.contributor.authorLalloo, Fiona-
dc.contributor.authorBlack, G C-
dc.contributor.authorLim, Caron-
dc.contributor.authorMoran, Anthony-
dc.contributor.authorGrossman, Ashley B-
dc.contributor.authorHodgson, Shirley V-
dc.contributor.authorFreemont, Anthony J-
dc.contributor.authorRamsden, Richard T-
dc.contributor.authorEng, Charis-
dc.contributor.authorEvans, D Gareth R-
dc.contributor.authorMaher, Eamonn R-
dc.date.accessioned2009-08-27T13:22:30Z-
dc.date.available2009-08-27T13:22:30Z-
dc.date.issued2003-12-
dc.identifier.citationGenetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. 2003, 59 (6):728-33 Clin. Endocrinol.en
dc.identifier.issn0300-0664-
dc.identifier.pmid14974914-
dc.identifier.doi10.1046/j.1365-2265.2003.01914.x-
dc.identifier.urihttp://hdl.handle.net/10541/78893-
dc.description.abstractBACKGROUND: Germline mutations in three subunits of mitochondrial complex II (SDHB, SDHC and SDHD) may be associated with susceptibility to phaeochromocytoma (PC) and/or head and neck paraganglioma (HNPGL). METHODS: To further define the role of SDH subunit mutations in these disorders, we analysed a series of 22 probands with PC and evidence of genetic susceptibility (seven with familial PC only, one with familial PC and HNPGL, 10 sporadic cases with multiple PC and four cases of isolated paediatric onset PC) for germline SDHB, SDHC and SDHD mutations. In addition, we analysed 34 cases of HNPGL (30 isolated cases with single tumours, three isolated cases with multiple tumours and one familial case with multiple tumours) for somatic and germline mutations in SDHB, SDHC and SDHD. RESULTS: We identified four germline mutations (three SDHB and one SDHD, three novel) in the 22 PC probands. Combining these results with our previous series, we have detected germline SDHB or SDHD mutations in 2/12 (17%) of familial PC only kindreds, 4/5 (80%) of familial PC and HNPGL cases, 1/10 of sporadic multiple PC cases and 2/4 (50%) of paediatric PCs. No somatic mutations were detected in the HNPGL tumours, but four cases with multiple HNPGL had the common P81L germline SDHD mutation. Intriguingly a silent SNP (c.204C > T) in SDHD was significantly more common in HNPGL cases (6/34) than in controls (1/100, P = 0.0011). Combining our results with those from two other large studies in which both SDHB and SDHD have been analysed, SDHB mutations were most commonly associated with phaeochromocytoma susceptibility and SDHD with the development of HNPGL (P = 0.025). However, germline SDHB and SDHD mutations demonstrate considerable phenotypic variability and genotype-phenotype correlations are complex. CONCLUSION: The significantly lower frequency (P = 0.028) of germline SDH subunit mutations in familial PC only cases compared to those with familial PC and HNPGL suggests that further PC susceptibility gene(s) remain to be identified.en
dc.language.isoenen
dc.subjectAdrenal Gland Canceren
dc.subjectHead and Neck Canceren
dc.subjectCancer Proteinsen
dc.subject.meshAdolescent-
dc.subject.meshAdrenal Gland Neoplasms-
dc.subject.meshAdult-
dc.subject.meshChild-
dc.subject.meshDNA Mutational Analysis-
dc.subject.meshGenetic Predisposition to Disease-
dc.subject.meshGerm-Line Mutation-
dc.subject.meshHead and Neck Neoplasms-
dc.subject.meshHumans-
dc.subject.meshIron-Sulfur Proteins-
dc.subject.meshMembrane Proteins-
dc.subject.meshMiddle Aged-
dc.subject.meshNeoplasm Proteins-
dc.subject.meshParaganglioma-
dc.subject.meshPheochromocytoma-
dc.subject.meshProtein Subunits-
dc.subject.meshSuccinate Dehydrogenase-
dc.titleGenetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility.en
dc.typeArticleen
dc.contributor.departmentSection of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham, UK.en
dc.identifier.journalClinical Endocrinologyen

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