This Article Abstract Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McWhinney, S. R. Articles by Eng, C. Search for Related Content PubMed PubMed Citation Articles by McWhinney, S. R. Articles by Eng, C.

Large Germline Deletions of Mitochondrial Complex II Subunits SDHB and SDHD in Hereditary Paraganglioma

Clinical Cancer Genetics Program (S.R.M., R.T.P., C.E.), Human Cancer Genetics Program (S.R.M., R.T.P., M.M.S., C.E.), Comprehensive Cancer Center, Department of Molecular Genetics (S.R.M., C.E.), and Division of Human Genetics (R.T.P., C.E.), Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210; Department of Pediatrics, Southern Illinois University School of Medicine (S.R.F., M.C.S.), Springfield, Illinois 62794; Departments of Medicine (M.M.S.) and Endocrinology (E.P.D.), Federal University of Minas Gerais, Belo Horizonte, Brazil; Department of Endocrinology (E.P.D.), Hospital Felício Rocho, Belo Horizonte, Brazil; and Cancer Research UK, Human Cancer Genetics Research Group (C.E.), University of Cambridge, Cambridge CB2 1XY, United Kingdom

Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., The Ohio State University Human Cancer Genetics Program, 420 West 12th Avenue, Suite 690 TMRF, Columbus, Ohio 43210. E-mail: eng-1{at}medctr.osu.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
More than 30% of adrenal pheochromocytomas are hereditary. These neuroendocrine tumors are major components of three inherited cancer syndromes: multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and pheochromocytoma/paraganglioma syndrome (PC/PGL). Germline mutations in RET; VHL; and SDHB, SDHC, and SDHD are associated with multiple endocrine neoplasia type 2, VHL, and PC/PGL, respectively. The majority (>70%) of hereditary extraadrenal PCs [catecholamine-secreting paragangliomas (PGL)] are accounted for by germline intragenic mutations in SDHB, SDHC, or SDHD. Therefore, a subset of hereditary PGL is not accounted for. Here we report two unrelated hereditary PGL families, one with a germline whole-gene deletion of SDHD (family 4194), the other a partial deletion of SDHB (family BRZ01). Although they were initially designated mutation negative for all of the PC-associated genes after PCR-based analysis, we suspected that a large deletion or rearrangement might be present. Genotyping around the PC-associated genes demonstrated that both families were consistent with linkage with one of these genes. Using fine structure genotyping and semiquantitative duplex PCR analysis, we identified an approximately 96-kb deletion spanning SDHD in family 4194 and an approximately 1-kb deletion involving the 5' end of SDHB in family BRZ01. Thus, including SDHB and SDHD deletion analysis could increase gene-testing sensitivity for PGL patients, which would aid in genetic counseling and management of patients and families.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ADRENAL PHEOCHROMOCYTOMAS (PC) are major component neoplasias of the heritable syndromes multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau disease (VHL). The causative genes for these syndromes are RET and VHL. In addition, PC/paraganglioma (PGL) syndrome (PC/PGL) is characterized by adrenal PC and/or catecholamine-secreting (often referred to as extraadrenal PC) or biochemically silent PGL. This syndrome is caused by germline mutations in SDHB, SDHC, and SDHD (1, 2, 3, 4, 5, 6, 7).

Germline mutations in SDHB, SDHD, and less commonly SDHC account for up to 70% of familial head and neck PGL (8), perhaps 8% of apparently sporadic head and neck PGL (1) and approximately 9% of apparently sporadic PC (9). There likely exists a fourth paraganglioma locus (PGL2) at 11q13, but the gene has not yet been cloned (8). Succinate dehydrogenase, or mitochondrial complex II, consists of the aforementioned subunits, SDHB, SDHC, and SDHD, along with a fourth subunit, SDHA. This complex is encoded by nuclear genes and plays a role in the Krebs cycle and electron transport chain (10). Germline mutations in each of the components of complex II have been shown to disrupt complex formation and subsequently decrease the enzymatic activity of the remaining complex (11). How this leads to tumorigenesis is currently unknown.

To date, more than 40 germline mutations in SDHB, SDHC, and SDHD have been reported, and all are intragenic mutations with no descriptions of large deletions or rearrangements (1, 3, 7, 12). However, not all familial PC and/or PGL cases have been found to have germline intragenic mutations. Therefore, we sought to address the hypothesis that such families may carry germline large deletions or rearrangements in one of the SDH genes.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Family 4194 (Fam4194)

The proband, III-1, was diagnosed with bilateral carotid PGL, which were biochemically silent, at the age of 28 yr (Fig. 1A). Apart from the proband, there were five other family members affected with biochemically silent PGL (four with carotid PGL and one with PGL at the base of the skull) and eight unaffected individuals (Fig. 1A). The father (II-4) of the proband, who is an obligate carrier of the putative mutation, is currently 56 yr old and has not had PGL. Three of his siblings have had PGL: II-5 (PGL at age 50 yr; possible recurrence or second primary tumor during the late 50s), II-9 (PGL at the base of the skull, diagnosed at age 50 yr; cerebral aneurysm at age 53 yr), and II-11 (carotid PGL at age 20 yr; recurrence at age 43 yr). In addition, the proband’s father has two affected cousins: II-1 (carotid PGL diagnosed in his early 30s) and II-2 (bilateral carotid PGL diagnosed at age 13 yr; subsequently diagnosed with colon cancer at age 48 yr).

View larger version (20K): [in this window] [in a new window]   FIG. 1. Two families affected with PC and/or PGL. Roman numerals denote generation number; Arabic numerals, individual number. *, Family members with DNA available for genetic testing. Numbers below the asterisks indicate affected individual’s ages (yr) at onset of paraganglioma. A, Fam4194. Note predominance of head and neck PGLs. B, Family BRZ01. Note occurrence of adrenal PC and intraabdominal PGL.

The proband, III-3, was diagnosed with a catecholamine-secreting abdominal PGL at the age of 8 yr (Fig. 1B). The mother of the proband, II-2, was diagnosed with a biochemically silent carotid PGL at the age of 38 yr. In addition, the proband’s maternal aunt was diagnosed with a thoracic catecholamine-secreting PGL at the age of 14 yr. We were unable to obtain DNA samples from any unaffected individuals in this family.

Informed consent was obtained in accordance with and approved by the Human Subjects Protection Committee of The Ohio State University.

Analysis of sequence variation of PC-associated genes

Genomic DNA from 14 members of Fam4194, six affected and eight unaffected, as well as three affected individuals from family BRZ01, was extracted from blood leukocytes using standard techniques (QIAGEN, Valencia, CA). Germline mutation analyses for all exons, exon-intron boundaries, and flanking intronic regions were performed for VHL, SDHA, SDHB, SDHC, and SDHD and for MEN 2-associated RET exons 10, 11, and 13–16. PCR was performed using a QIAGEN HotStarTaq kit for 38 cycles with a 55 C annealing temperature for all primers for all genes (for primers, see Supplemental Table 1, published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org/). An aliquot of the PCR product was purified using exonuclease I/shrimp alkaline phosphatase treatment (New England BioLabs, Beverly, MA, and USB Corp., Cleveland, OH). The purified amplicons were directly sequenced using Big-Dye Terminators version 3.1 cycle sequencing kit [Applied Biosystems, Inc., Foster City, CA] and analyzed on an ABI 3730 DNA analyzer.

Genotyping

Four microsatellite markers closely flanking each gene, VHL, SDHB, SDHC, and SDHD, and eight single-nucleotide polymorphism (SNP) loci within SDHA, were chosen with a heterozygosity index greater than 0.6 for linkage analysis (see Supplemental Table 2). To genotype these markers for each of the 14 family members in Fam4194 and the three family members in family BRZ01, PCR using a fluorescently labeled forward primer was performed. Subsequent to PCR, the products were fractionated on an ABI 3700 DNA Analyzer. The output provided either one or two allele size(s) for each marker, and these were then analyzed using the ABI PRISM Genotyper, version 3.7 NT. We used these data to form haplotypes for the region surrounding each gene and analyzed these haplotypes for association or lack thereof with the affected family members.

Semiquantitative duplex PCR analysis

To look at the gene dosage of each SDHD exon in Fam4194, as well as each SDHB exon in family BRZ01, compared with a control gene GAPDH, a duplex PCR was performed individually with each exon and GAPDH. PCR was performed using QIAGEN Multiplex HotStarTaq Mix. For all exons in both SDHB and SDHD, the optimal ratio of GAPDH:SDHB/SDHD genomic DNA was determined (Supplemental Table 3). The SDHD/GAPDH and SDHB/GAPDH amplicons were quantified by spot densitometry on the Alpha Innotech Corp. ChemiImager Fluorescence and Low Light Imaging System (Alpha Innotech Corp., San Leandro, CA), with ChemiImager 4000 version 4.04 software.

Fine mapping of putative SDHD deletion

Markers surrounding SDHD were selected by using National Center for Biotechnology Information (NCBI) MapViewer (http://www.ncbi.nlm.nih.gov/mapview/) to fill in the regions between the markers used for linkage and SDHD (Fig. 2A). Whenever possible, markers with a heterozygosity index of greater than 0.6 were used (34% of markers). Published primers on the NCBI UniSTS web site (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unists) were ordered for each marker with a fluorescent tag added to the forward primer to enable use for genotyping on the ABI 3700 DNA Analyzer.

View larger version (24K): [in this window] [in a new window]   FIG. 2. Physical map showing SDHD and SDHB and flanking genomic regions involved in the respective deletions. A, 11q23 region including SDHD. B, 1p36 region including SDHB.

SDHD expression analysis using quantitative RT-PCR

Quantitative RT-PCR using SYBR-green dye was used to compare the expression level of SDHD transcript with an internal control (GAPDH) in the germline of two affected individuals (II-2 and III-1) and one unaffected individual (II-3) from Fam4194 (Fig. 1A). RNA was not available from members of family BRZ01, and thus expression analysis was not possible. QIAGEN SYBR-Green HotStarTaq Master Mix was combined with a forward and reverse primer that spanned the exon/exon boundary of exons 1 and 2 of SDHD. This eliminated any possibility of amplifying from (low level) genomic DNA contamination, if present at all. The PCR was performed on the ABI PRISM 7700 Sequence Detection System. The data were analyzed using the ABI PRISM 7700 Sequence Detection software version 1.6 and evaluated for an increased cycle threshold. An increased GAPDH:SDHD ratio was indicative of decreased expression of our gene transcript of interest with respect to the control gene transcript (GAPDH). All samples were run in duplicate for both SDHD and GAPDH primer sets.

Fine mapping of putative SDHB deletion

We performed sequential semiquantitative duplex PCR using amplicons flanking SDHB exon 1 combined with GAPDH to determine the deleted region in family BRZ01. Details are outlined above (Semiquantitative Duplex PCR Analysis section). These amplicons included one for exon 2, multiple amplicons in intron 1 (IVS1A and IVS1B), and amplicons in the 5' untranslated region (UTR) of SDHB (5'UTRa and 5'UTRb) (see Fig. 2B).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Germline SDHD deletion in Fam4194

The proband of Fam4194 (Fig. 1A, individual III-1) was initially analyzed for sequence variations and germline mutations in the PC-susceptibility genes, RET, VHL, SDHB, SDHC, and SDHD, as well as SDHA. Mutations and sequence variants were not detected, with the exception of a common SNP in exon 7 of SDHA found in Fam4194 that is seen frequently in the general population as well.

We used four markers to genotype the regions flanking each of the genes VHL, SDHB, SDHC, and SDHD in addition to eight SNP loci commonly found within the SDHA exons. Haplotypes were formed from genotypes flanking each gene and inspected for association ("consistent with linkage") or lack of association (linkage excluded) between the affected individuals and a particular haplotype. We were able to exclude linkage to VHL, SDHA, SDHB, and SDHC in Fam4194 (data not shown). However, a specific haplotype around SDHD was found to be shared by all of the affected individuals in Fam4194 but was not found in any of the unaffected individuals. Because we showed that Fam4194 had SDHD marker haplotypes consistent with linkage, we resequenced the four SDHD exons and confirmed the absence of coding or splice-site variants. Therefore, we further explored SDHD as a potential locus for large deletion or rearrangement.

To test the hypothesis that a large deletion or rearrangement in or involving SDHD that is not detectable by standard PCR-based methods was responsible for Fam4194, we performed semiquantitative duplex PCR and spot densitometry. We found that the ratio of each SDHD exon to the control GAPDH in the affected individuals was decreased when compared with the unaffected individuals (Fig. 3).

View larger version (53K): [in this window] [in a new window]   FIG. 3. SDHD deletion in Fam4194 revealed by semiquantitative duplex PCR with spot densitometry and quantitative RT-PCR. Comparison of SDHD exons 1–4 to GAPDH control using semiquantitative duplex genomic PCR. SDHD exons are the higher molecular weight band and GAPDH the lower. All bands were quantified using spot densitometry.

To define both the 5' and 3' breakpoints of the SDHD deletion in Fam4194, we performed fine structure genotyping using denser markers flanking SDHD (Fig. 2A). When a marker was found to be heterozygous, that region could definitely be assigned a not-deleted status. When a marker was found to be homozygous (or hemizygous), then that region was circumstantially assigned possible-deletion status for further analysis (see below). Using this strategy of sequential genotyping and status assignment, we were able to define the largest possible region of deletion spanning a 178-kb genomic distance, flanked by markers D11S4192 5' of SDHD and by D11S5019 3' of SDHD (Fig. 2A). D11S4192 is 143 kb upstream of the A in the ATG of SDHD, whereas D11S5019 is 24 kb downstream of the stop codon of SDHD (Fig. 2A).

Because the only two markers between D11S4192 and SDHD on the 5' end, RH104183 and D11S2329E, were homozygous for both affected and unaffected family members, we did further analysis to determine whether this region was hemizygous or truly homozygous in the affected individuals. Semiquantitative duplex PCR was performed, and the ratio of each marker to GAPDH was determined. The data indicated that the 63 kb between and including these two markers was indeed deleted in the affected individuals, and we could therefore conclude that the 5' breakpoint was in an 80-kb region between D11S4192 and RH104183 (Fig. 2A, hatched box). We then continued fine mapping of the 5' breakpoint in this region and performed semiquantitative duplex PCR to compare the dosage of genomic DNA in that region with that in our control gene, GAPDH. To do this, we used amplicons at every 10 kb along this 63-kb interval. We also used this strategy in the 24 kb at the 3' end of SDHD, between the stop codon and D11S5019 to fine map the 3' breakpoint of the deletion. After narrowing the region of the breakpoint sites on both the 5' and 3' ends of SDHD, we determined that the maximum deleted region was approximately 96 kb, including the entire SDHD gene.

Germline partial SDHB deletion in family BRZ01

The proband of family BRZ01 (Fig. 1B, individual III-3) was initially analyzed for sequence variations and germline mutations in the PC-susceptibility genes, RET, VHL, SDHA, SDHB, SDHC, and SDHD. We found that the sequences of all genes were normal with the exception of a common SNP found in exon 1 of SDHB (18 A/C), at which the three affected individuals were homozygous for the polymorphism.

Using the same methods used in Fam4194, four markers in the regions flanking VHL, SDHB, SDHC, and SDHD were genotyped in addition to the eight SNP loci in SDHA. Again, we formed haplotypes from genotypes for each gene and looked for either an association or lack of association with the affected individuals. We were initially able to exclude linkage to VHL, SDHA, and SDHD. A haplotype flanking SDHC was found to be associated with the three affected individuals, but SDHC gene deletion was then excluded using semiquantitative PCR (data not shown). In addition, a haplotype block spanning SDHB was found to be shared by the three affected individuals in family BRZ01. We resequenced SDHB and, again, showed that the only sequence variation in this gene was an exon 1 SNP (18 C>A) for which all affected individuals were homozygous for the polymorphic allele (i.e., 18 AA or 18 A–). This variation lends circumstantial evidence for a putative exon 1 deletion in that all previous individuals and controls with this polymorphism have always been heterozygous at this site (i.e., 18 AC). Thus, we explored SDHB as a putative locus for large deletion or rearrangements that were undetectable by PCR-based methods.

Using semiquantitative duplex PCR with spot densitometry to address our hypothesis, we found that the ratio of SDHB exon 1 to GAPDH was significantly decreased when compared with that of five different normal controls (Fig 4). We were able to determine the boundaries of the SDHB deletion in family BRZ01 by performing sequential semiquantitative duplex PCR using amplicons for all SDHB exons as well as amplicons designed within the 5' UTR. We determined that all or part of exon 1 was deleted and that exon 2 was not deleted (Fig. 4). The breakpoint at the 5' end of the deletion was determined to be within the 5' UTR by using semiquantitative duplex PCR with GAPDH. We found that the total deleted region was a maximum of approximately 1 kb of genomic DNA, including the 204 bp of SDHB exon 1 (Fig. 2B).

View larger version (60K): [in this window] [in a new window]   FIG. 4. Partial deletion of SDHB exon (ex) 1 revealed by semiquantitative genomic-based PCR with GAPDH as the control gene and spot densitometry of a boxed region within each band, which is consistent throughout all samples. C1–C5 denote five different normal controls. Note that exon 2 is not deleted by duplex semiquantitative PCR analysis.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Functional confirmation of the presence of the deletion in Fam4194 was possible by demonstration of decreased expression of SDHD in the germline of those with the deletion. Interestingly, the proband had a 4-fold decrease in expression of the SDHD transcript, whereas her affected relative (II-2) had only a 2-fold decrease in SDHD expression. This expressional difference between these two affected individuals may be explained by other factors interacting with SDHD and/or other subunits of complex II. We suspect that expression analysis of SDHB in the affected individuals would similarly result in significantly decreased transcript when compared with normal controls. However, we were unable to pursue this hypothesis because of the unavailability of RNA from these patients.

We also performed in silico scanning for known genes within the putative deletion intervals. TIMM8B is located just upstream of SDHD in the opposite orientation [http://www.ensembl.org/Homo_sapiens (15)] and may be within the deletion interval. TIMM8B, a homolog of TIMM8A, and germline mutations of TIMM8A, on Xq22, are associated with deafness-dystonia-optic atrophy syndrome (16). TIMM8B has not been shown to be associated with disease as yet, but one anecdotal report lists a family with carotid paragangliomas who also had tinnitus and deafness (15). It is equally plausible, if not more so, that the deafness and tinnitus are most likely due to the carotid body/skull base paragangliomas, especially in the context of the fact that this was a Dutch family with a founder mutation known to be intragenic. All of our affected individuals are not afflicted with sensorineural hearing loss or tinnitus, indicating that this phenotype does not result from heterozygous deletion of this gene.

Our observations suggest that large germline deletions in the SDH genes, at least SDHB and SDHD, are another genetic mechanism that are etiologic for familial PC/PGL. Therefore, deletion analysis of these genes should be offered to families or individuals at risk for hereditary PC/PGL if standard PCR-based mutation analysis is apparently negative. If linkage-type genotyping analysis is not available clinically or not possible in the context of PCR-based mutation-"negative" PC/PGL, deletion analysis could begin with SDHD in families or individuals with prominent head and neck PGLs. Similarly, SDHB deletion analysis should be considered first if adrenal PCs predominate. This type of stepped strategy, PCR-based mutation analysis followed by deletion analysis, should increase the sensitivity of gene testing and hence facilitate clinical management for PC/PGL patients as well as their families.

	Footnotes

 
This work was supported by U.S. Public Health Service Grants R01HD39058 (to C.E.) and P30CA16058 (to The Ohio State University Comprehensive Cancer Center).

C.E. is a Doris Duke Distinguished Clinical Scientist.

Abbreviations: Fam4194, Family 4194; MEN 2, multiple endocrine neoplasia type 2; PC, pheochromocytoma; PC/PGL, PC/PGL syndrome; PGL, paraganglioma; SNP, single-nucleotide polymorphism; UTR, untranslated region; VHL, von Hippel-Lindau disease.

Received April 24, 2004.

Accepted July 22, 2004.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Maher ER, Eng C 2002 The pressure rises: update on the genetics of phaeochromocytoma. Hum Mol Genet 11:2347–2354[Abstract/Free Full Text]
2. Eng C, Kiuru M, Fernandez MJ, Aaltonen LA 2003 A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 3:193–202[CrossRef][Medline]
3. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard 3rd CW, Cornelisse CJ, Devilee P, Devlin B 2000 Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–851[Abstract/Free Full Text]
4. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER 2001 Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69:49–54[CrossRef][Medline]
5. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Mulligan LM 1996 The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276:1575–1579[Abstract/Free Full Text]
6. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L 1993 Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320[Abstract/Free Full Text]
7. Niemann S, Muller U 2000 Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26:268–270[CrossRef][Medline]
8. Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery 3rd WH, Myers EN, Ferrell RE, Rubinstein WS 2002 Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 39:178–183[Abstract/Free Full Text]
9. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C; Freiburg-Warsaw-Columbus Pheochromocytoma Study Group 2002 Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466[Abstract/Free Full Text]
10. Baysal BE, Rubinstein WS, Taschner PE 2001 Phenotypic dichotomy in mitochondrial complex II genetic disorders. J Mol Med 79:495–503[CrossRef][Medline]
11. Douwes Dekker PB, Hogendoorn PC, Kuipers-Dijkshoorn N, Prins FA, van Duinen SG, Taschner PE, van der Mey AG, Cornelisse CJ 2003 SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology. J Pathol 201:480–486[CrossRef][Medline]
12. Baysal BE 2002 Hereditary paraganglioma targets diverse paraganglia. J Med Genet 39:617–622[Abstract/Free Full Text]
13. Renard L, Godfraind C, Boon LM, Vikkula M 2003 A novel mutation in the SDHD gene in a family with inherited paragangliomas—implications of genetic diagnosis for follow up and treatment. Head Neck 25:146–151[CrossRef][Medline]
14. Vanharanta S, Buchta M, McWhinney SR, Virta SK, Peczkowska M, Morrison CD, Lehtonen R, Januszewicz A, Jarvinen H, Juhola M, Mecklin JP, Pukkala E, Herva R, Kiuru M, Nupponen NN, Aaltonen LA, Neumann HP, Eng C 2004 Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 74:153–159[CrossRef][Medline]
15. Badenhop RF, Cherian S, Lord RS, Baysal BE, Taschner PE, Schofield PR 2001 Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. Genes Chromosomes Cancer 31:255–263[CrossRef][Medline]
16. Roesch K, Curran SP, Tranebjaerg L, Koehler CM 2002 Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Hum Mol Genet 11:477–486[Abstract/Free Full Text]

This article has been cited by other articles:

				H. J L M Timmers, A.-P. Gimenez-Roqueplo, M. Mannelli, and K. Pacak Clinical aspects of SDHx-related pheochromocytoma and paraganglioma Endocr. Relat. Cancer, June 1, 2009; 16(2): 391 - 400. [Abstract] [Full Text] [PDF]

				H. P.H. Neumann, Z. Erlic, C. C. Boedeker, L. A. Rybicki, M. Robledo, M. Hermsen, F. Schiavi, M. Falcioni, P. Kwok, C. Bauters, et al. Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out Cancer Res., April 15, 2009; 69(8): 3650 - 3656. [Abstract] [Full Text] [PDF]

				B E Baysal Clinical and molecular progress in hereditary paraganglioma J. Med. Genet., November 1, 2008; 45(11): 689 - 694. [Abstract] [Full Text] [PDF]

				F. Weber and C. Eng Update on the Molecular Diagnosis of Endocrine Tumors: Toward -omics-Based Personalized Healthcare? J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1097 - 1104. [Abstract] [Full Text] [PDF]

				A Cascon, I Landa, E Lopez-Jimenez, A Diez-Hernandez, M Buchta, C Montero-Conde, S Leskela, L J Leandro-Garcia, R Leton, C Rodriguez-Antona, et al. Molecular characterisation of a common SDHB deletion in paraganglioma patients J. Med. Genet., April 1, 2008; 45(4): 233 - 238. [Abstract] [Full Text] [PDF]

				R. D. Guzy, B. Sharma, E. Bell, N. S. Chandel, and P. T. Schumacker Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis Mol. Cell. Biol., January 15, 2008; 28(2): 718 - 731. [Abstract] [Full Text] [PDF]

				L. Amar, E. Baudin, N. Burnichon, S. Peyrard, S. Silvera, J. Bertherat, X. Bertagna, M. Schlumberger, X. Jeunemaitre, A.-P. Gimenez-Roqueplo, et al. Succinate Dehydrogenase B Gene Mutations Predict Survival in Patients with Malignant Pheochromocytomas or Paragangliomas J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3822 - 3828. [Abstract] [Full Text] [PDF]

				L. Matyakhina, T. A. Bei, S. R. McWhinney, B. Pasini, S. Cameron, B. Gunawan, S. G. Stergiopoulos, S. Boikos, M. Muchow, A. Dutra, et al. Genetics of Carney Triad: Recurrent Losses at Chromosome 1 but Lack of Germline Mutations in Genes Associated with Paragangliomas and Gastrointestinal Stromal Tumors J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2938 - 2943. [Abstract] [Full Text] [PDF]

				E. Korpershoek, B.-J. Petri, F. H van Nederveen, W. N M Dinjens, A. A Verhofstad, W. W de Herder, S. Schmid, A. Perren, P. Komminoth, and R. R de Krijger Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma Endocr. Relat. Cancer, June 1, 2007; 14(2): 453 - 462. [Abstract] [Full Text] [PDF]

				H. J. L. M. Timmers, A. Kozupa, G. Eisenhofer, M. Raygada, K. T. Adams, D. Solis, J. W. M. Lenders, and K. Pacak Clinical Presentations, Biochemical Phenotypes, and Genotype-Phenotype Correlations in Patients with Succinate Dehydrogenase Subunit B-Associated Pheochromocytomas and Paragangliomas J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 779 - 786. [Abstract] [Full Text] [PDF]

				F. M. Brouwers, G. Eisenhofer, J. J. Tao, J. A. Kant, K. T. Adams, W. M. Linehan, and K. Pacak High Frequency of SDHB Germline Mutations in Patients with Malignant Catecholamine-Producing Paragangliomas: Implications for Genetic Testing J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4505 - 4509. [Abstract] [Full Text] [PDF]

				B. Bausch, A.-C. Koschker, M. Fassnacht, J. Stoevesandt, M. M. Hoffmann, C. Eng, B. Allolio, and H. P. H. Neumann Comprehensive Mutation Scanning of NF1 in Apparently Sporadic Cases of Pheochromocytoma J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3478 - 3481. [Abstract] [Full Text] [PDF]

				E. R. Maher Genetics of phaeochromocytoma Br. Med. Bull., June 1, 2006; 79-80(1): 141 - 151. [Abstract] [Full Text] [PDF]

				W. F. Young Jr and A. L. Abboud Paraganglioma--all in the family. J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 790 - 792. [Full Text] [PDF]

				M Montani, A M Schmitt, S Schmid, T Locher, P Saremaslani, P U Heitz, P Komminoth, and A Perren No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma Endocr. Relat. Cancer, December 1, 2005; 12(4): 1011 - 1016. [Abstract] [Full Text] [PDF]

				L. Amar, J. Bertherat, E. Baudin, C. Ajzenberg, B. Bressac-de Paillerets, O. Chabre, B. Chamontin, B. Delemer, S. Giraud, A. Murat, et al. Genetic Testing in Pheochromocytoma or Functional Paraganglioma J. Clin. Oncol., December 1, 2005; 23(34): 8812 - 8818. [Abstract] [Full Text] [PDF]

				M Takahashi, X J Yang, S McWhinney, N Sano, C Eng, S Kagawa, B T Teh, and H-O Kanayama cDNA microarray analysis assists in diagnosis of malignant intrarenal pheochromocytoma originally masquerading as a renal cell carcinoma J. Med. Genet., August 1, 2005; 42(8): e48 - e48. [Abstract] [Full Text] [PDF]

				L Simi, R Sestini, P Ferruzzi, M S Gagliano, F Gensini, M Mascalchi, L Guerrini, C Pratesi, P Pinzani, G Nesi, et al. Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X J. Med. Genet., August 1, 2005; 42(8): e52 - e52. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McWhinney, S. R. Articles by Eng, C. Search for Related Content PubMed PubMed Citation Articles by McWhinney, S. R. Articles by Eng, C.