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目的 本研究拟查明1个中国汉族肥厚型心肌病(HCM)家系的致病突变,并探讨基因型-表型关联。方法 利用二代测序技术,全面筛查家系先证者的28个HCM相关致病基因。通过Sanger测序,在家系中验证和筛查发现的可能致病突变,并对突变携带者进行表型分析。结果 二代测序发现先证者携带MYH7基因Glu931del杂合突变。家系筛查发现4名患者均携带该突变,突变与疾病共分离,该突变为此HCM家系的致病突变,常染色体显性遗传。Glu931del突变位于MYH7基因第23外显子,三个核苷酸缺失(c.2791_2793del GAG),导致其所编码的心脏β-肌球蛋白重链的第931位谷氨酸缺失。MYH7基因第931位谷氨酸残基在不同物种间高度保守。临床表型分析发现,家系中4例患者的左心室最厚厚度在19mm-30mm之间,静息状态均无明显左室流出道梗阻,表现为胸痛、心悸和呼吸困难,并伴黑曚或有晕厥史。该家系另有两例患者在家系筛查前发生猝死,确诊年龄分别为5岁和6岁,死亡年龄均为16岁。该家系随访12年,HCM临床症状进展较快,1例患者左心室最大厚度由7mm发展为30mm,两例患者心功能进展为NYHA分级Ⅲ/Ⅳ级。结论 MYH7基因Glu931del突变导致的HCM表型较严重,易发生猝死和心衰,但也存在较大的表型异质性。二代高通量测序可以用于HCM致病基因的全面筛查。 相似文献
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目的研究汉族人群家族性肥厚型心肌病的致病基因突变位点,分析基因型与临床表型的关系。方法采集1个家族性肥厚型心肌病(HCM)家系成员的血液样本,并收集临床表型资料;对该家系先证者的28个HCM相关致病基因利用高通量测序进行靶向重测序;利用Sanger测序在家系成员中检测发现的致病突变位点;分析致病突变携带者的临床表型特点。结果高通量测序和Sanger测序发现并证实先证者携带β肌球蛋白重链基因(MYH7)Val606Met杂合错义突变,该突变在307名正常对照未检出;其他27个HCM相关致病基因中,未检出致病突变。家系遗传筛查发现3例HCM患者均携带MYH7基因Val606Met错义突变,该突变与HCM共分离。该家系3例HCM患者伴有心悸、胸痛、黑矇、晕厥等症状,先证者已经出现严重的心力衰竭,接受心脏移植后上述症状消失,生活质量明显改善。该家系另有2名成员在调查前发生心源性猝死。结论虽然有报道MYH7基因Val606Met错义突变为良性突变,但在本研究家系中,易导致早发心衰和猝死。因突变引起的终末期心衰接受心脏移植可能为最佳的治疗手段。 相似文献
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先天性心脏病是最常见的出生缺陷性疾病,严重危害婴幼儿健康。心脏发育过程中控制发育的基因突变是先天性心脏病的常见原因。近年来,越来越多的研究表明Islet1基因在心脏早期发育过程中起着至关重要的作用,该基因的突变或多态性可导致先天性心脏病的发生,现就近年来Islet1基因与先天性心脏病关系的研究进展做一综述。 相似文献
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老年学实验用果蝇寿命指标的选择 总被引:1,自引:0,他引:1
许多研究者用果蝇来进行衰老遗传因素、衰老形态学、生理生化学、衰老与环境以及抗衰老药物等方面的研究。果蝇由于遗传因素的差异而寿命亦有不同,为进行寿命实验研究提出适合果蝇品系和易行的果蝇寿命指标,我们对实验室现有从国外引进的12种品系黑腹果蝇观察6种不同寿命指标,并对计算结果进行探讨。 相似文献
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先天性心脏病(以下称先心病)是一类严重危害婴幼儿健康的先天畸形。心脏发育过程中控制发育的基因突变是先心病的常见原因。大量研究表明Nkx2.5作为与发育相关的同源盒基因的一种,在心脏发育过程中起重要的作用,该基因的突变或多态性将影响心脏发育导致先心病。本文系统地阐述了Nkx2.5基因的结构?功能及其与先心病的关系,进而在分子水平上对心脏的发生和先心病发病有更深入的了解。 相似文献
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《心肺血管病杂志》2021,(10)
正在胚胎时期,心脏是第一个形成和发挥作用的器官。先天性心脏病(congenital heart disease,CHD)是指在胚胎时期心脏和大血管发育缺陷或者部分未发育所导致的先天畸形,在我国先天畸形中占首位。流行病学调查显示,我国CHD发病率从1980年至1984年的0.201‰上升到2015年至2019年的4.905‰~([1]),并且在2009年已成为导致婴儿先天畸形死亡的主要原因~([2])。至今为止,CHD致病基因的遗传方式和表型表达均不清楚,随着动物实验和医学遗传学的发展,据估计目前大约有400个基因与CHD的发生有联系~([3])。 相似文献
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《中华心血管病杂志》2022,(7):728-732
心脏受累是许多遗传性神经肌肉疾病常见的骨骼肌外表现, 主要包括心肌病、心力衰竭、心律失常、心脏猝死等表型。由于心脏神经肌肉症状重叠或仅有单一器官临床表型, 导致常误诊为一个疾病。随着分子诊断技术的快速发展, 基因检测有助于诊断或早期发现一些无症状心脏受累患者。该文介绍了5种遗传性神经肌肉疾病的分子遗传机制和心脏受累表型, 并提出了相应的诊断与治疗的个体化管理建议。 相似文献
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《中国循环杂志》2015,(2)
目的:分析肥厚型心肌病(HCM)致病基因型与临床表现的关系及基因筛查在HCM筛查及疾病鉴别诊断中的作用。方法:选择一个HCM家系共14人,多重靶向测序技术对先证者的26个已知最常见的HCM致病基因进行全外显子捕获测序,用Sanger测序对发现的突变进行验证并对其他家系成员及307名健康对照进行该突变位点的筛查,分析其基因型与临床表型的特点。结果:先证者及其子携带MYH7基因c.2146 GA(Gly716Arg)突变,该突变位于MYH7基因19号外显子,导致第716位氨基酸残基由Gly变为Arg,其他25个基因未发现突变。Sanger测序验证后对其他家系成员进行突变筛查,其他家庭成员及对照组未发现该突变,该突变与HCM在该家系中共分离。先证者携带的致病突变为从头突变,并遗传给其子。先证者临床表现为发病早(14岁)、劳力性呼吸困难、胸痛、心悸、心力衰竭,其子出生时即发现心肌肥厚。其父虽然室间隔肥厚(15 mm),但结合其年轻时曾为运动员的经历及遗传筛查的阴性结果,可基本排除其为HCM患者,考虑为生理性肥厚。结论:该家系HCM由MYH7基因从头突变p.Gly716Arg导致,该突变临床发病早,症状较重,预后较差,为恶性突变。基因筛查在HCM家系筛查及疾病鉴别诊断中有重要意义。 相似文献
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目的应用第二代测序方法筛查一早发高血压遗传家系致病基因突变点,并探讨临床意义。方法选择早发特征的一高血压家系,先证者进行Illumina Miseq目标区域捕获测序及生物信息分析,包括对单基因高血压相关的43个致病基因的编码区及侧翼区进行了检测。之后,对最小等位基因频率(MAF)≤1%的突变多态位点进行聚合酶链反应(PCR)并Sanger测序验证,并与高血压表型连锁分析。结果在家系高血压患者中发现钙敏感受体(CaSR)基因外显子7的2156位置鸟嘌呤(G)突变为腺嘌呤(A),导致第719位的氨基酸由色氨酸(Trp)变为终止密码子,为新发的无义突变,呈杂合型(c.G2156A,p.W719X),预测该突变导致所编码的蛋白质发生截短从而丧失其正常功能。而在无高血压病史家系成员中未发现携带此突变点。家系高血压患者临床表型特点有:面部潮红、易激动,头胀晕,发病年龄18~30岁;舒张压高,舒张压对药物反应不佳;血压对天气变化敏感;在应激状态下(如感染)会出现轻度高血钙症;而在无高血压病史家系成员中未发现这些特点,也没有应激性高血钙症表现。结论CaSR基因的c.G2156A(p.W719X)新发的无义突变可能是此早发高血压家系或应激性高血钙症的遗传病因。 相似文献
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The mutation status of cancer driver genes may correlate with different degrees of malignancy of cancers. The doubling time and multidrug resistance are 2 phenotypes that reflect the degree of malignancy of cancer cells. Because most of cancer driver genes are hard to target, identification of their synthetic lethal partners might be a viable approach to treatment of the cancers with the relevant mutations.The genome-wide screening for synthetic lethal partners is costly and labor intensive. Thus, a computational approach facilitating identification of candidate genes for a focus synthetic lethal RNAi screening will accelerate novel anticancer drug discovery.We used several publicly available cancer cell lines and tumor tissue genomic data in this study.We compared the doubling time and multidrug resistance between the NCI-60 cell lines with mutations in some cancer driver genes and those without the mutations. We identified some candidate synthetic lethal genes to the cancer driver genes APC, KRAS, BRAF, PIK3CA, and TP53 by comparison of their gene phenotype values in cancer cell lines with the relevant mutations and wild-type background. Further, we experimentally validated some of the synthetic lethal relationships we predicted.We reported that mutations in some cancer driver genes mutations in some cancer driver genes such as APC, KRAS, or PIK3CA might correlate with cancer proliferation or drug resistance. We identified 40, 21, 5, 43, and 18 potential synthetic lethal genes to APC, KRAS, BRAF, PIK3CA, and TP53, respectively. We found that some of the potential synthetic lethal genes show significantly higher expression in the cancers with mutations of their synthetic lethal partners and the wild-type counterparts. Further, our experiments confirmed several synthetic lethal relationships that are novel findings by our methods.We experimentally validated a part of the synthetic lethal relationships we predicted. We plan to perform further experiments to validate the other synthetic lethal relationships predicted by this study.Our computational methods achieve to identify candidate synthetic lethal partners to cancer driver genes for further experimental screening with multiple lines of evidences, and therefore contribute to development of anticancer drugs. 相似文献
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Jan J. Molenaar Marli E. Ebus Dirk Geerts Jan Koster Fieke Lamers Linda J. Valentijn Ellen M. Westerhout Rogier Versteeg Huib N. Caron 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(31):12968-12973
Two genes have a synthetically lethal relationship when the silencing or inhibiting of 1 gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetically lethal to neuroblastoma cells with MYCN amplification and over-expression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification, and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by 3 RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53, and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetically lethal relationship between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. 相似文献
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Chitin synthase III: synthetic lethal mutants and "stress related" chitin synthesis that bypasses the CSD3/CHS6 localization pathway.
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B C Osmond C A Specht P W Robbins 《Proceedings of the National Academy of Sciences of the United States of America》1999,96(20):11206-11210
We screened Saccharomyces strains for mutants that are synthetically lethal with deletion of the major chitin synthase gene CHS3. In addition to finding, not surprisingly, that mutations in major cell wall-related genes such as FKS1 (glucan synthase) and mutations in any of the Golgi glycosylation complex genes (MNN9 family) are lethal in combination with chs3Delta, we found that a mutation in Srv2p, a bifunctional regulatory gene, is notably lethal in the chs3 deletion. In extending studies of fks1-chitin synthase 3 interactions, we made the surprising discovery that deletion of CSD3/CHS6, a gene normally required for Chs3p delivery and activity in vivo, was not lethal with fks1 and, in fact, that lack of Csd3p/Chs6p did not decrease the high level of stress-related chitin made in the fks1 mutant. This finding suggests that "stress response" chitin synthesis proceeds through an alternate Chs3p targeting pathway. 相似文献
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n-3脂肪酸是指第一个双键位于分子甲基端第三个碳原子上的多不饱和脂肪酸(n-3PUFA),主要包括α-亚麻酸(ALA)、二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)。它们在深海鱼(如鲑鱼、鳟鱼和金枪鱼)和鱼油中含量丰富。近年来研究表明,摄取n-3脂肪酸对心血管疾病具有保护作用。大量的流行病学研究、动物研究和临床实验证明摄入鱼类或其他来源的长链n-3PUFA(EPA和DHA)有抗动脉粥样硬化的作用。Harris等提出,红细胞膜EPA和DHA在总脂肪酸中.... 相似文献
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Alec C. Kimmelman Aram F. Hezel Andrew J. Aguirre Hongwu Zheng Ji-hye Paik Haoqiang Ying Gerald C. Chu Jean X. Zhang Ergun Sahin Giminna Yeo Aditya Ponugoti Roustem Nabioullin Scott Deroo Shenghong Yang Xiaoxu Wang John P. McGrath Marina Protopopova Elena Ivanova Jianhua Zhang Bin Feng Ming S. Tsao Mark Redston Alexei Protopopov Yonghong Xiao P. Andrew Futreal William C. Hahn David S. Klimstra Lynda Chin Ronald A. DePinho 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(49):19372-19377
Pancreas ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically presents as advanced, unresectable disease. This invasive tendency, coupled with intrinsic resistance to standard therapies and genome instability, are major contributors to poor long-term survival. The genetic elements governing the invasive propensity of PDAC have not been well elucidated. Here, in the course of validating resident genes in highly recurrent and focal amplifications in PDAC, we have identified Rio Kinase 3 (RIOK3) as an amplified gene that alters cytoskeletal architecture as well as promotes pancreatic ductal cell migration and invasion. We determined that RIOK3 promotes its invasive activities through activation of the small G protein, Rac. This genomic and functional link to Rac signaling prompted a genome wide survey of other components of the Rho family network, revealing p21 Activated Kinase 4 (PAK4) as another amplified gene in PDAC tumors and cell lines. Like RIOK3, PAK4 promotes pancreas ductal cell motility and invasion. Together, the genomic and functional profiles establish the Rho family GTP-binding proteins as integral to the hallmark invasive nature of this lethal disease. 相似文献
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柞蚕蛹虫草对黑腹果蝇寿命的影响 总被引:8,自引:0,他引:8
目的 探讨柞蚕蛹虫草对黑腹果蝇寿命、吃食次数、性功能及繁殖能力的影响。方法 对果蝇寿命的影响 :采用乙醚麻醉法 ,收集 1 0h内羽化出的成虫 ,选择个体大小相近的雌雄果蝇 ,在不同浓度的培养基中饲养 ,每天定时 3次统计果蝇死亡数 ,直到全部死亡。对果蝇吃食次数的影响 :待麻醉雌雄果蝇全部苏醒 1 0 min后开始给予不同浓度的食物 ,每隔 5 min计数正在吃食果蝇只数 ,连续观察 4 h。对果蝇性功能的影响 :用 Miauel和 Economos方法。对果蝇繁殖力的影响 :将果蝇随机分组并按雌雄 (1 .5∶ 1 )比例分别饲养在不同浓度培养基中进行繁殖 ,计算子代果蝇 (幼虫 蛹 )数量。结果 柞蚕桶虫草可延长果蝇平均寿命和最高寿命 ,并能增加果蝇吃食次数、交配次数和繁殖能力。结论 柞蚕蛹虫草具有明显延缓衰老的作用。 相似文献
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Partial rescue of a lethal phenotype of fragile bones in transgenic mice with a chimeric antisense gene directed against a mutated collagen gene. 总被引:2,自引:0,他引:2
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J S Khillan S W Li D J Prockop 《Proceedings of the National Academy of Sciences of the United States of America》1994,91(14):6298-6302
Previously, transgenic mice were prepared that developed a lethal phenotype of fragile bones because they expressed an internally deleted mini-gene for the pro alpha 1(I) chain of human type I procollagen. The shortened pro alpha 1(I) chains synthesized from the human transgene bound to and produced degradation of normal pro alpha 1(I) chains synthesized from the normal mouse alleles. Here we assembled an antisense gene that was similar to the internally deleted COL1A1 minigene but the 3' half of the gene was inverted so as to code for an antisense RNA. Transgenic mice expressing the antisense gene had a normal phenotype, apparently because the antisense gene contained human sequences instead of mouse sequences. Two lines of mice expressing the antisense gene were bred to two lines of transgenic mice expressing the mini-gene. In mice that inherited both genes, the incidence of the lethal fragile bone phenotype was reduced from 92% to 27%. The effects of the antisense gene were directly demonstrated by an increase in the ratio of normal mouse pro alpha 1(I) chains to human mini-pro alpha 1(I) chains in tissues from mice that inherited both genes and had a normal phenotype. The results raise the possibility that chimeric gene constructs that contain intron sequences and in which only the second half of a gene is inverted may be particularly effective as antisense genes. 相似文献
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Colonization of America by Drosophila subobscura: heterotic effect of chromosomal arrangements revealed by the persistence of lethal genes
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Mestres F Balanyà J Arenas C Solé E Serra L 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(16):9167-9170
About 20 years ago Drosophila subobscura, a native Palearctic species, colonized both North and South America. In Palearctic populations lethal genes are not associated in general with particular chromosomal arrangements. In colonizing populations they are not randomly distributed and usually are associated to a different degree with chromosomal arrangements caused by the founder event. The persistence of two lethal genes in the colonizing populations, one completely associated with the O(5) inversion and the other partially associated with the O(3+4+7) arrangement, has been analyzed. In all populations studied (five North American and six South American) the observed frequency of the lethal gene completely associated with the O(5) inversion is higher than expected, the difference being statistically significant in all South American and one North American populations. The observed frequency of the lethal gene partially associated with the O(3+4+7) arrangement is also significantly higher than expected. Taking into account that the O(5) inversion exhibits significant latitudinal clines both in North and South America, an overdominant model favoring the heterokaryotypes seems to be in operation. From this model, a polynomial expression has been developed that allows us to estimate the relative fitness and the coefficient of selection against all karyotypes not carrying the O(5) inversion. The relative fitness of the O(5) heterokaryotypes is higher in South American than in North American populations. Furthermore, the observed frequencies of the lethal genes studied are in general very close to those of the equilibrium. This case is an outstanding demonstration in nature of an heterotic effect of chromosomal segments associated with lethal genes on a large geographic scale. 相似文献