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【bio-news】《细胞》：华中科大发现心房颤动和猝
据了解，心血管疾病目前是发达国家所有疾病中的头号杀手。心房颤动是临床最常见的持续心律失常。据统计，人群患病率接近百分之零点七七，在美国影响三百万人，中国患者高达一千三百万，危害极大，大大提高患者死亡率和脑中风的发生率。
张贤钦等对一有五代成员的大型房颤疾病家系进行遗传分析后证实，这个名为NUP155的基因产生的一种突变会导致房颤和猝死。该家族拥有七个心脏病患者，其中五人不到两岁发生猝死。家族中，患者体内NUP155基因存在突变，而健康成员携带的是该基因的正常版本。
他们发现，NUP155是一个编码核孔复合物组分的基因，其主要功能是控制遗传物质mRNA由细胞核到细胞质的转运，以便翻译成为蛋白质。NUP155也控制一些重要蛋白质由细胞质到细胞核的转运。所以，NUP155是一处于比较上游的位置调控基因，能够对其他很多基因和蛋白质的表达进行调控，从而造成了房颤发生，通常威胁到青壮年人群的健康。NUP155基因的一些细微改变，也有可能增加常见的散发性房颤发生的危险性。
王擎系华中科技大学生命学院院长和该校人类基因组研究中心主任，同时兼任美国克利夫兰临床医院心血管遗传中心主任。他们表示，发现一个新的导致房颤和猝死的分子靶点和一个全新的分子通路，将推动未来对房颤和猝死进行分子诊断的实现，创立基因诊断试剂盒，预防房颤和猝死。同时，这一新发现为开发治疗房颤和猝死等心脏病提供了新的策略和靶点。
全文链接： http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4V46YNT-J&_user=10&_coverDate=12%2F12%2F2008&_rdoc=1&_fmt=high&_orig=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=232682f146bbd5be5e68ad69d9b89ab7 Summary
Atrial fibrillation (AF) is the most common form of sustained clinical arrhythmia. We previously mapped an AF locus to chromosome 5p13 in an AF family with sudden death in early childhood. Here we show that the specific AF gene underlying this linkage is NUP155, which encodes a member of the nucleoporins, the components of the nuclear pore complex (NPC). We have identified a homozygous mutation, R391H, in NUP155 that cosegregates with AF, affects nuclear localization of NUP155, and reduces nuclear envelope permeability. Homozygous NUP155−/− knockout mice die before E8.5, but heterozygous NUP155+/− mice show the AF phenotype. The R391H mutation and reduction of NUP155 are associated with inhibition of both export of Hsp70 mRNA and nuclear import of Hsp70 protein. These human and mouse studies indicate that loss of NUP155 function causes AF by altering mRNA and protein transport and link the NPC to cardiovascular disease.
Author Keywords: CELLBIO; HUMDISEASE; PROTEINS
Article Outline
Introduction
Results
Genetic Linkage of Autosomal Recessive AF to Chromosome 5p13 in the Expanded arAF1 Family and Fine Mapping
A Missense Mutation in NUP155 Cosegregates with AF in the arAF1 Family
Mutation R391H Affects Nuclear Envelope Localization of NUP155 Protein and Nuclear Envelope Permeability
Heterozygous NUP155+/− Knockout Mice Are Associated with AF
Mutant NUP155 Reduces Atrial Action Potential Duration and Inhibits Export of Hsp70 mRNA and Nuclear Import of Hsp70 Protein
Discussion
Experimental Procedures
Study Subjects and Linkage Analysis
Mutational Analysis
Cell Culture and Immunostaining
Quantitative RT-PCR Analysis
Western Blot Analysis
Generation of NUP155 Knockout Mice
Isolation of Mouse Atrial Myocytes, Measurements of Action Potential Duration, and Immunocytochemistry
Mouse ECG Recordings
Nuclear Envelope Permeability Assays
Assays for Export of Hsp70 mRNA and Nuclear Import of Hsp70 Protein
Statistical Analysis
Acknowledgements
Supplemental Data
References
Figure 1. Genotyping and Linkage Analysis of an AF Family, arAF1
(A) Genotyping results are shown for an affected member (boxed VI:3), a newly born male in the arAF1 family, together with the results for other family members reported previously (Oberti et al., 2004). The new affected male patient, VI:3, was genotyped with five linked markers at the arAF1 locus, including D5S493, D5S426, D5S455, D5S1998, and D5S1964. Affected individuals are shown as filled squares (males) and circles (females); normal individuals are indicated by empty symbols; obligate heterozygous carriers are shown with dots in symbols; deceased family members are shown with slashes (/); the proband is indicated by an arrow.
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作者:admin@医学,生命科学 2011-03-24 13:59
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