A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia.
A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia.
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DOI：
10.1371/journal.pone.0000436
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发表时间：
2007-05-09
期刊：
影响因子：
3.7
通讯作者：
Baysal, Bora E.
中科院分区：
文献类型：
--
作者：
Baysal, Bora E.
正常哺乳动物核基因中的体细胞胞苷突变发生在B淋巴细胞中的抗体多样化期间，并通过RNA编辑在肠细胞中产生载脂蛋白B的同种型。在这里，我描述了琥珀酸脱氢酶（SDH;线粒体复合物II）亚单位B基因（SDHB）是体细胞突变的胞苷残基在正常外周血单核细胞（PBMC）和T细胞急性白血病。SDHB、SDHC或SDHD基因中的生殖系突变导致遗传性副神经节瘤（PGL）肿瘤，其显示由氧剥夺（缺氧）诱导的稳态机制的组成性激活。为了确定在SDHB mRNA中鉴定的突变的发生率，测试了180个样品。SDHB终止密码子突变c.136C>T（R46 X）存在于从PBMC获得的mRNA的显著部分（平均值= 5.8%，范围=小于1至30%，n =52）中。 相反，R46 X突变以非常低的水平存在于PBMC的基因组DNA中。PBMC细胞类型亚群的检查鉴定单核细胞和自然杀伤（NK）细胞为突变体转录物的主要来源，尽管较少的贡献也来自B和T淋巴细胞。在来源于单核细胞、NK、T和B细胞的白血病细胞系中的转录物序列分析表明，靶向SDHB的突变机制在T细胞急性白血病中是可操作的。因此，在20个原发性儿童T细胞急性淋巴细胞白血病（T-ALL）骨髓样本中的5个中检测到实质水平（超过3%）的突变SDHB转录物，但在20个B-ALL样本中没有检测到突变SDHB转录物。此外，在衍生自T-ALL的Jurkat和TALL-104细胞系中鉴定出不同的杂合SDHB错义DNA突变。在正常血细胞中SDHB基因中鉴定出一个复发性失活终止密码子突变，表明SDHB是胞苷脱氨酶的靶点。SDHB突变可能在正常人PBMCs和白血病T细胞对缺氧的预适应中发挥作用。
Somatic cytidine mutations in normal mammalian nuclear genes occur during antibody diversification in B lymphocytes and generate an isoform of apolipoprotein B in intestinal cells by RNA editing. Here, I describe that succinate dehydrogenase (SDH; mitochondrial complex II) subunit B gene (SDHB) is somatically mutated at a cytidine residue in normal peripheral blood mononuclear cells (PBMCs) and T-cell acute leukemia. Germ line mutations in the SDHB, SDHC or SDHD genes cause hereditary paraganglioma (PGL) tumors which show constitutive activation of homeostatic mechanisms induced by oxygen deprivation (hypoxia). To determine the prevalence of a mutation identified in the SDHB mRNA, 180 samples are tested. An SDHB stop-codon mutation c.136C>T (R46X) is present in a significant fraction (average = 5.8%, range = less than 1 to 30%, n = 52) of the mRNAs obtained from PBMCs. In contrast, the R46X mutation is present in the genomic DNA of PBMCs at very low levels. Examination of the PBMC cell-type subsets identifies monocytes and natural killer (NK) cells as primary sources of the mutant transcript, although lesser contributions also come from B and T lymphocytes. Transcript sequence analyses in leukemic cell lines derived from monocyte, NK, T and B cells indicate that the mutational mechanism targeting SDHB is operational in T-cell acute leukemia. Accordingly, substantial levels (more than 3%) of the mutant SDHB transcripts are detected in five of 20 primary childhood T-cell acute lymphoblastic leukemia (T-ALL) bone marrow samples, but in none of 20 B-ALL samples. In addition, distinct heterozygous SDHB missense DNA mutations are identified in Jurkat and TALL-104 cell lines which are derived from T-ALLs. The identification of a recurrent, inactivating stop-codon mutation in the SDHB gene in normal blood cells suggests that SDHB is targeted by a cytidine deaminase enzyme. The SDHB mutations in normal PBMCs and leukemic T cells might play a role in cellular pre-adaptation to hypoxia.
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SDH 突变数据库：涉及嗜铬细胞瘤、副神经节瘤和线粒体复合物 II 缺陷的琥珀酸脱氢酶序列变异的在线资源。
影响因子：
--
作者：
Bayley, JP;Devilee, P;Taschner, PEM
通讯作者：
Taschner, PEM
影响因子：
5.3
作者：
Astrom, K;Cohen, JE;Baysal, BE
通讯作者：
Baysal, BE
影响因子：
15.3
作者：
Neuberger, Michael S.;Rada, Cristina
通讯作者：
Rada, Cristina
HIF1Alpha调节环将缺氧和线粒体信号联系起来。
影响因子：
4.5
作者：
Dahia, PLM;Ross, KN;Wright, ME;Hayashida, CY;Santagata, S;Barontini, M;Kung, AL;Sanso, G;Powers, JF;Tischler, AS;Hodin, R;Heitritter, S;Moore, F;Dluhy, R;Sosa, JA;Ocal, IT;Benn, DE;Marsh, DJ;Robinson, BG;Schneider, K;Garber, J;Arum, SM;Korbonits, M;Grossman, A;Pigny, P;Toledo, SPA;Nosé, V;Li, C;Stiles, CD
通讯作者：
Stiles, CD
影响因子：
4
作者：
Baysal, BE;Willett-Brozick, JE;Rubinstein, WS
通讯作者：
Rubinstein, WS