Mapping of the disease locus and identification of ADAMTS10 as a candidate gene in a canine model of primary open angle glaucoma.
Mapping of the disease locus and identification of ADAMTS10 as a candidate gene in a canine model of primary open angle glaucoma.
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DOI：
10.1371/journal.pgen.1001306
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发表时间：
2011-02
期刊：
影响因子：
4.5
通讯作者：
Kuchtey RW
中科院分区：
文献类型：
--
作者：
Kuchtey J;Olson LM;Rinkoski T;Mackay EO;Iverson TM;Gelatt KN;Haines JL;Kuchtey RW
原发性开角型青光眼（POAG）是世界范围内导致失明的主要原因，眼压升高是一个重要的危险因素。房水通过小梁网流出的阻力增加导致眼内压升高，但具体机制尚不清楚。在这项研究中，我们使用全基因组 SNP 芯片将一群患有遗传性 POAG 的比格犬中的疾病基因定位到犬 20 号染色体上的单个 4 Mb 基因座内。比格犬 POAG 基因座与之前在人类 19 号染色体上定位的人类眼压数量性状基因座同线。整个犬 POAG 基因座的序列捕获和下一代测序揭示了总共 2,692 个 SNP 与疾病分离。在疾病分离 SNP 中，54 个位于外显子内，其中 8 个导致氨基酸替换。最强的候选变体导致金属蛋白酶 ADAMTS10 的高度保守区域中甘氨酸被精氨酸取代。蛋白质印迹显示 ADAMTS10 蛋白优先在小梁网中表达，支持该变体对房水流出具有特异性的作用。 POAG 比格犬中发现的 ADAMTS10 中的 Gly661Arg 变体表明，细胞外基质加工的改变和/或微纤维结构或功能的缺陷可能与眼内压升高有关，为未来的研究和治疗策略提供了特定的生化目标。原发性开角型青光眼 (POAG) 是影响数千万人视力丧失和失明的主要原因。高眼压是该病的强烈危险因素，也是唯一有效的治疗目标。高眼压是由于房水通过小梁网（一种由交替的细胞层和结缔组织组成的特殊过滤组织）流出的阻力增加所致，但阻力增加的具体原因尚不清楚。本研究中使用的人类 POAG 动物模型是一群比格犬，它们携带以高眼压为主要表现的遗传性疾病。我们发现 ADAMTS10 中的一个变体属于有助于细胞外基质形成的基因家族，并且其本身可能参与弹性微纤维结构的形成。我们发现 ADAMTS10 蛋白在小梁网中的表达水平特别高。在受 POAG 影响的小猎犬中发现的 ADAMTS10 候选变异表明，结缔组织和/或弹性微纤维缺陷的处理改变可能与眼压升高有关，为未来的研究和治疗策略提供了特定的生化目标。
Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide, with elevated intraocular pressure as an important risk factor. Increased resistance to outflow of aqueous humor through the trabecular meshwork causes elevated intraocular pressure, but the specific mechanisms are unknown. In this study, we used genome-wide SNP arrays to map the disease gene in a colony of Beagle dogs with inherited POAG to within a single 4 Mb locus on canine chromosome 20. The Beagle POAG locus is syntenic to a previously mapped human quantitative trait locus for intraocular pressure on human chromosome 19. Sequence capture and next-generation sequencing of the entire canine POAG locus revealed a total of 2,692 SNPs segregating with disease. Of the disease-segregating SNPs, 54 were within exons, 8 of which result in amino acid substitutions. The strongest candidate variant causes a glycine to arginine substitution in a highly conserved region of the metalloproteinase ADAMTS10. Western blotting revealed ADAMTS10 protein is preferentially expressed in the trabecular meshwork, supporting an effect of the variant specific to aqueous humor outflow. The Gly661Arg variant in ADAMTS10 found in the POAG Beagles suggests that altered processing of extracellular matrix and/or defects in microfibril structure or function may be involved in raising intraocular pressure, offering specific biochemical targets for future research and treatment strategies. Primary open angle glaucoma (POAG) is a leading cause of vision loss and blindness affecting tens of millions of people. Ocular hypertension is a strong risk factor for the disease and the only effective target of treatment. Ocular hypertension results from increased resistance to outflow of aqueous humor through the trabecular meshwork, a specialized filtration tissue consisting of alternating layers of cells and connective tissue, but the specific reasons for the increased resistance are not known. The animal model for human POAG used in this study was a colony of Beagle dogs that carry an inherited form of the disease in which ocular hypertension is the primary manifestation. We have found a variant in ADAMTS10 that belongs to a family of genes that contribute to formation of extracellular matrix and may itself be involved in formation of elastic microfiber structures. We found that the ADAMTS10 protein is expressed at particularly high levels in the trabecular meshwork. The candidate variant in ADAMTS10 found in the POAG–affected Beagles suggests that altered processing of connective tissue and/or elastic microfiber defects may be involved in raising eye pressure, offering specific biochemical targets for future research and treatment strategies.
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影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
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影响因子：
3.4
作者：
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影响因子：
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影响因子：
3.4
作者：
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影响因子：
12.3
作者：
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通讯作者：
Salzberg SL