{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:14:06Z","timestamp":1791288846425,"version":"4.3.0"},"reference-count":55,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5454","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2000,2,4]]},"abstract":"<jats:p>\n                    Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the\n                    <jats:italic>PGL1<\/jats:italic>\n                    gene, described here, revealed germ line mutations in the\n                    <jats:italic>SDHD<\/jats:italic>\n                    gene on chromosome 11q23.\n                    <jats:italic>SDHD<\/jats:italic>\n                    encodes a mitochondrial respiratory chain protein\u2014the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.\n                  <\/jats:p>","DOI":"10.1126\/science.287.5454.848","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T05:35:26Z","timestamp":1027748126000},"page":"848-851","source":"Crossref","is-referenced-by-count":1438,"title":["Mutations in\n                    <i>SDHD<\/i>\n                    , a Mitochondrial Complex II Gene, in Hereditary Paraganglioma"],"prefix":"10.1126","volume":"287","author":[{"given":"Bora E.","family":"Baysal","sequence":"first","affiliation":[{"name":"Department of Psychiatry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Ferrell","sequence":"additional","affiliation":[{"name":"Department of Human Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan E.","family":"Willett-Brozick","sequence":"additional","affiliation":[{"name":"Department of Psychiatry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Department of Human Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Myssiorek","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communicative Disorders, Long Island Jewish Medical Center, New Hyde Park, New York, NY 11040, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Bosch","sequence":"additional","affiliation":[{"name":"Department of Human Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andel van der","family":"Mey","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter E. M.","family":"Taschner","sequence":"additional","affiliation":[{"name":"Department of Human Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy S.","family":"Rubinstein","sequence":"additional","affiliation":[{"name":"Pittsburgh Cancer Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene N.","family":"Myers","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The University of Pittsburgh Medical Center, Pittsburgh, PA 15213\u20132593, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Charles W.","family":"Richard","sequence":"additional","affiliation":[{"name":"Wyeth-Ayerst Research, Genetics Institute, 35 Cambridgepark Drive, Cambridge, MA 02140, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cees J.","family":"Cornelisse","sequence":"additional","affiliation":[{"name":"Department of Pathology, Leiden University Medical Center, 2300 RA, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Devilee","sequence":"additional","affiliation":[{"name":"Department of Human Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Devlin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0034-5687(99)00024-9","volume":"115","author":"Zhu H.","year":"1999","unstructured":"Zhu H., Bunn H. 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The activated HIF-1 stimulates the synthesis of erythropoietin (Epo) which increases red blood cell mass; of vascular endothelial growth factor which stimulates new blood vessel growth; and of tyrosine hydroxylase which is involved in the control of ventilation by the CB (1 2)."},{"key":"e_1_3_1_5_2","first-page":"636","volume":"100","author":"Arias-Stella J.","year":"1976","unstructured":"Arias-Stella J., Bustos F., Arch. Pathol. Lab. Med. 100, 636 (1976);","journal-title":"Arch. Pathol. Lab. Med."},{"key":"e_1_3_1_5_3","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S0046-8177(76)80052-4","volume":"7","author":"Arias-Stella J.","year":"1976","unstructured":"Arias-Stella J., Valcarcel J., Hum. Pathol. 7, 361 (1976);","journal-title":"Hum. Pathol."},{"key":"e_1_3_1_5_4","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/path.1711040404","volume":"104","author":"Edwards C.","year":"1971","unstructured":"Edwards C., et al., J. 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D., Cornelisse C. J., Schmidt P. H., van de Kamp J. J., Lancet 2, 1291 (1989).","journal-title":"Lancet"},{"key":"e_1_3_1_11_2","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1093\/hmg\/7.10.1599","volume":"7","author":"Morison I. M.","year":"1998","unstructured":"Morison I. M., Reeve A. E., Hum. Mol. Genet. 7, 1599 (1998).","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_1_12_2","unstructured":"B. E. Baysal et al. in preparation."},{"key":"e_1_3_1_13_2","unstructured":"The polymerase chain reaction (PCR) primer sequences for the two new CA repeat polymorphisms that flank the 400-kb critical interval size were as follows: STRP1 (D11S5011) 5\u2032-TTGGCATCAATGGAAAGCACT-3\u2032 and 5\u2032-TTGGGAATCTTTTGCCTGGAA-3\u2032; STRP2 (D11S5019) 5\u2032-CATTTGTCCAGTTACCCGTA-3\u2032 and 5\u2032-TATTGACTAATGGACACTGGAA-3\u2032. STRP1 has five alleles in the 187- to 195-bp range. STRP2 has four alleles in the 168- to 174-bp range. Both STRP were amplified with standard PCR conditions (20) and analyzed as described (7)."},{"key":"e_1_3_1_14_2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1006\/geno.1997.4880","volume":"44","author":"Baysal B. E.","year":"1997","unstructured":"Baysal B. E., et al., Genomics 44, 214 (1997);","journal-title":"Genomics"},{"key":"e_1_3_1_14_3","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5389.744"},{"key":"e_1_3_1_15_2","unstructured":"The complete sequence of EST229158 is available at the Genome Database ()."},{"key":"e_1_3_1_16_2","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1159\/000134700","volume":"79","author":"Hirawake H.","year":"1997","unstructured":"Hirawake H., Taniwaki M., Tamura A., Kojima S., Kita K., Cytogenet. Cell Genet. 79, 132 (1997).","journal-title":"Cytogenet. 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Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_1_21_2","unstructured":"The primers for exon amplifications were as follows: 1F 5\u2032-TGACCTTGAGCCCTCAGGAACG-3\u2032 and 1R 5\u2032-TCAGGGTGGGAAGACCCCT-3\u2032; 2F 5\u2032-GATCATCCTAATGACTCTTTCC-3\u2032 and 2R 5\u2032-AGCAGCAGCGATGGAGAGAA-3\u2032; 3F 5\u2032-CTTTTATGAATCTGGTCCTTTTTG-3\u2032 and 3R 5\u2032-CAACTATATTTGGAATTGCTATAC-3\u2032; 4F 5\u2032-TGATGTTATGATTTTTTCTTTTTCT-3\u2032 and 4R 5\u2032-CAATTCTTCAAAGTATGAAGTCA-3\u2032. Primers 1F and 4R are located in 5\u2032 and 3\u2032 untranslated regions in exons 1 and 4 respectively. The other primers were designed from intronic sequences. The amplicon sizes for exons 1 2 3 and 4 are 98 bp 168 bp 200 bp and 224 bp respectively. PCR amplifications of 50 to 100 ng of genomic DNA were performed in Techne PHC3 thermal cyclers using AmpliTaq Gold DNA polymerase (Perkin Elmer Cetus). Amplification conditions were as follows: initial denaturation at 94\u00b0C for 10 min then 35 cycles of 45 s of denaturation at 94\u00b0C 45 s of annealing at 55\u00b0C and 45 s of extension at 72\u00b0C and completed with a final extension at 72\u00b0C for 10 min. The amplicons were first visualized in a 1% ethidium bromide\u2013stained agarose gel. SSCP analysis was performed with genomic DNA as described ["},{"key":"e_1_3_1_21_3","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0378-1119(98)00350-3","volume":"217","author":"Baysal B. E.","year":"1998","unstructured":"Baysal B. E., Farr J., Goss J., Devlin B., Richard C. W., Gene 217, 107 (1998);","journal-title":"Gene"},{"key":"e_1_3_1_21_4","unstructured":"]. Aberrant amplicons were sequenced in an ABI377 fluorescent sequencer. The segregation of mutations in PGL families and screening in normal control chromosomes were performed by restriction enzyme analyses of mutant amplicons. The mutations in PGL families result in loss of the recognition site for the following restriction enzymes: family 3 Nla III; family 5 and family 7 Msp I; family 8 Mbo II; family 11 Ava II. The Dutch founder mutation results in gain of an Rsa I site."},{"key":"e_1_3_1_22_2","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1086\/301951","volume":"63","author":"van Schothorst E. M.","year":"1998","unstructured":"van Schothorst E. M., et al., Am. J. Hum. Genet. 63, 468 (1998).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_23_2","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1074\/jbc.271.1.521","volume":"271","author":"Nakamura K.","year":"1996","unstructured":"Nakamura K., et al., J. Biol. Chem. 271, 521 (1996);","journal-title":"J. Biol. Chem."},{"key":"e_1_3_1_23_3","doi-asserted-by":"crossref","first-page":"4148","DOI":"10.1021\/bi9716635","volume":"37","author":"Vibat C. R.","year":"1998","unstructured":"Vibat C. R., Cecchini G., Nakamura K., Kita K., Gennis R. B., Biochemistry 37, 4148 (1998);","journal-title":"Biochemistry"},{"key":"e_1_3_1_23_4","doi-asserted-by":"crossref","first-page":"8717","DOI":"10.1074\/jbc.274.13.8717","volume":"274","author":"Shenoy S. K.","year":"1999","unstructured":"Shenoy S. K., Yu L., Yu C., J. Biol. Chem. 274, 8717 (1999).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_1_24_2","unstructured":"The single-step method of RNA extraction ["},{"key":"e_1_3_1_24_3","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","volume":"162","author":"Chomczynski P.","year":"1987","unstructured":"Chomczynski P., Sacchi N., Anal. Biochem. 162, 156 (1987);","journal-title":"Anal. Biochem."},{"key":"e_1_3_1_24_4","unstructured":"] was used according to a commercial protocol (RNAzol B Tel-Test Friendswood TX). Complementary DNA synthesis was performed using SUPERSCRIPT II (Life Technologies) and oligo(dT) primers; the recommended conditions were used. Reverse transcriptase\u2013PCR (RT-PCR) of cDNA templates was performed by 30 to 35 cycles of amplification with primers 1F and 4R (amplicon size 533 bp). PCR products were precipitated with isopropanol washed with 70% ethanol and resuspended in tris-EDTA buffer. A synonymous single nucleotide polymorphism (SNP)\u2014(C\/T) in codon 68 in exon 3\u2014was identified by SSCP and sequence analysis in family 8 and in several normal control samples. This SNP detected by Spe I restriction enzyme digestion was used for allelic expression analysis."},{"key":"e_1_3_1_25_2","doi-asserted-by":"crossref","first-page":"A271","DOI":"10.1086\/302481","volume":"65","author":"Farr J. E.","year":"1999","unstructured":"Farr J. E., et al., Am. J. Hum. Genet. 65, A271 (1999).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_26_2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/ng0997-12","volume":"17","author":"Vu T. H.","year":"1997","unstructured":"Vu T. H., Hoffman A. R., Nature Genet. 17, 12 (1997).","journal-title":"Nature Genet."},{"key":"e_1_3_1_27_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/gcc.2870110202","volume":"11","author":"Devilee P.","year":"1994","unstructured":"Devilee P., et al., Genes Chromosomes Cancer 11, 71 (1994);","journal-title":"Genes Chromosomes Cancer"},{"key":"e_1_3_1_27_3","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/S0046-8177(98)90411-7","volume":"29","author":"van Schothorst E. M.","year":"1998","unstructured":"van Schothorst E. M., et al., Hum. Pathol. 29, 1045 (1998).","journal-title":"Hum. Pathol."},{"key":"e_1_3_1_28_2","unstructured":"P. Devilee et al. data not shown."},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/20459"},{"key":"e_1_3_1_30_2","unstructured":"P. Vaupel O. Thews D. K. Kelleher M. Hoeckel Strahlenther. Onkol. 174 Suppl. 4 6 (1998)."},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/379088a0"},{"key":"e_1_3_1_32_2","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1002\/(SICI)1096-9896(199901)187:1<28::AID-PATH166>3.0.CO;2-R","volume":"187","author":"Koreth J.","year":"1999","unstructured":"Koreth J., Bakkenist C. J., McGee J. O., J. Pathol. 187, 28 (1999).","journal-title":"J. Pathol."},{"key":"e_1_3_1_32_3","unstructured":"and references therein."},{"key":"e_1_3_1_33_2","unstructured":"Abbreviations for the amino acid residues are as follows: A Ala; C Cys; D Asp; E Glu; F Phe; G Gly; H His; I Ile; K Lys; L Leu; M Met; N Asn; P Pro; Q Gln; R Arg; S Ser; T Thr; V Val; W Trp; Y Tyr."},{"key":"e_1_3_1_34_2","unstructured":"We thank the families participating in this study; R. Carrau J. Johnson A. Petropoulos S. Farb L. Coia K. Grant J. Nasser J. Green J. Kohn D. Saphier L. Pratt W. Chase J. Oosterwijk M. Godfrey S. Kirkpatrick P. Heutink S. Saha and J. Jansen for referring patients; C. Melvin-Drovdlic for help in family counseling; J. Goss U. Surti S. Gollin and N. Kuipers-Dijkshoorn for technical help; and G. J. B. van Ommen and D. Kupfer for administrative and financial support. Supported by grants from the University of Pittsburgh Medical Center (Competitive Medical Research Fund to B.E.B.) the American Cancer Society (VM-180) and the National Institute of Mental Health (MH57881) to B.D. and the Dutch Cancer Society (KWF98-1721 to A.B. and P.E.M.T.)."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.287.5454.848","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T04:55:35Z","timestamp":1705121735000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.287.5454.848"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,2,4]]},"references-count":55,"journal-issue":{"issue":"5454","published-print":{"date-parts":[[2000,2,4]]}},"alternative-id":["10.1126\/science.287.5454.848"],"URL":"https:\/\/doi.org\/10.1126\/science.287.5454.848","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,2,4]]}}}