美國猶他州猶他大學(xué)生物化學(xué)院,，醫(yī)學(xué)院內(nèi)科學(xué),，以及哈佛大學(xué)醫(yī)學(xué)院細胞生物學(xué)系的科學(xué)家發(fā)現(xiàn)一個全新的抑癌基因SDH5，相關(guān)論文發(fā)表在Science在線版上,。
最新發(fā)現(xiàn)的抑癌基因命名為SDH5,。這個基因編碼一個細胞呼吸所必須的線粒體蛋白。導(dǎo)致Sdh5蛋白失活的基因點突變會引發(fā)一種叫做副神經(jīng)節(jié)瘤的少見的頭頸部腫瘤,。此前,，沒有關(guān)于Sdh5蛋白功能的研究，郝淮湘博士等人基于兩個主要原因開始了對這個蛋白的研究,。第一,，Sdh5蛋白的氨基酸序列很保守，表明這個蛋白很可能有重要的生物功能,。第二,，線粒體蛋白質(zhì)組學(xué)研究將Sdh5定位于線粒體,，而線粒體功能障礙和很多人類疾病包括癌癥都相關(guān)。
研究人員先用模式生物酵母研究了酵母Sdh5蛋白的功能,。在酵母中,，Sdh5和琥珀酸脫氫酶（succinate dehydrogenase，SDH）的催化亞基Sdh1相互作用,，負責(zé)黃素腺嘌呤二核苷酸（FAD)與Sdh1的共價結(jié)合(Flavination),。琥珀酸脫氫酶既是三羧酸循環(huán)又是電子傳遞鏈的組成部分（又稱為復(fù)合體Ⅱ），由四個亞基組成 （Sdh1-4）,。 Sdh1的核黃素輔基對琥珀酸脫氫酶復(fù)合體的活力,，組裝和穩(wěn)定性起重要作用。 因此,，SDH5基因缺陷的酵母細胞完全沒有琥珀酸脫氫酶活力,，也不能進行細胞呼吸。
正如預(yù)期一樣,，氨基酸序列高度相似的人的Sdh5蛋白具有相同的功能,。之前的遺傳學(xué)研究表明，總共四種遺傳型副神經(jīng)節(jié)瘤中的三種（PGL1,，PGL3,PGL4）分別與編碼琥珀酸脫氫酶亞基的SDHD,， SDHC和SDHB基因的突變有關(guān)。PGL2型副神經(jīng)節(jié)瘤的致病基因還沒有被確定,，但已經(jīng)被定位到11q13.1這個染色體區(qū)域,， 而SDH5基因正處于這個區(qū)域。
通過與荷蘭的人類遺傳學(xué)家合作,，對一個PGL2型副神經(jīng)節(jié)瘤的患病家系成員的SDH5基因進行了測序,，果然發(fā)現(xiàn)了一個與疾病共分離的單核苷酸突變。在這個家系中的45位突變攜帶者中,，33人患有副神經(jīng)節(jié)瘤,，證明SDH5就是PGL2致病基因。這個點突變將位于最保守區(qū)域的第78位甘氨酸變?yōu)榫彼幔℅78R）,，導(dǎo)致Sdh5蛋白失去功能,，因此腫瘤組織中的琥珀酸脫氫酶無法獲得必須的核黃素輔基。
通過整合多個學(xué)科的手段（生物信息學(xué),，酵母遺傳學(xué),， 生物化學(xué)，人類遺傳學(xué)和分子生物學(xué)）,，郝淮湘博士從一個功能未知的蛋白入手,，發(fā)現(xiàn)了一個疾病基因并闡明了其分子功能和致病機理。擴展了對琥珀酸脫氫酶/復(fù)合體Ⅱ的了解。其他電子傳遞鏈復(fù)合體需要多個輔助蛋白來實現(xiàn)復(fù)合體的輔基修飾和組裝,，但復(fù)合體Ⅱ的輔助蛋白一直沒有被發(fā)現(xiàn),，Sdh5和不久之前發(fā)現(xiàn)的SDHAF1（Nat Genet. 2009 May 24.）表明類似機制的存在。此外,，郝淮湘博士的發(fā)現(xiàn)為線粒體代謝和癌癥的關(guān)聯(lián)提供了又一例證,。
最后，遺傳檢測SDHB,， SDHC和SDHD基因突變是副神經(jīng)節(jié)瘤診斷的重要組成部分,，SDH5應(yīng)該被加入這個檢測以使其完整。其他由琥珀酸脫氫酶缺陷導(dǎo)致的疾病比如胃腸道間質(zhì)瘤 （GIST）的臨床診斷也應(yīng)該考慮SDH5,。（生物谷Bioon.com）
生物谷推薦原始出處：
Science July 23, 2009 DOI: 10.1126/science.1175689
SDH5, a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma
Huai-Xiang Hao 1, Oleh Khalimonchuk 2, Margit Schraders 3, Noah Dephoure 4, Jean-Pierre Bayley 5, Henricus Kunst 6, Peter Devilee 7, Cor W. R. J. Cremers 6, Joshua D. Schiffman 8, Brandon G. Bentz 9, Steven P. Gygi 4, Dennis R. Winge 2, Hannie Kremer 3, Jared Rutter 1*
1 Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
2 Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
3 Department of Otorhinolaryngology, Donders Centre for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, Netherlands.; Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, Netherlands.
4 Department of Cell Biology, Harvard University Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
5 Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZA, Netherlands.
6 Department of Otorhinolaryngology, Donders Centre for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, Netherlands.
7 Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZA, Netherlands.; Department of Pathology, Leiden University Medical Centre, Leiden 2333 ZA, Netherlands.
8 Department of Oncological Sciences and Huntsman Cancer Institute University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
9 Department of Surgery, Division of Otolaryngology–Head and Neck Surgery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Mammalian mitochondria contain about 1100 proteins, nearly 300 of which are uncharacterized. Given the well-established role of mitochondrial defects in human disease, functional characterization of these proteins may shed new light on disease mechanisms. Starting with yeast as a model system, we investigated an uncharacterized but highly conserved mitochondrial protein (named here Sdh5). Both yeast and human Sdh5 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both respiratory complex II and the TCA cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin-adenine dinucleotide cofactor). Germline loss-of-function mutations in the human SDH5 gene, located on chromosome 11q13.1, segregate with disease in a family with hereditary paraganglioma (PGL), a neuroendocrine tumor previously linked to mutations in genes encoding SDH subunits. Thus, a mitochondrial proteomics analysis in yeast has led to the discovery of a human tumor susceptibility gene.
