A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses.
A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses.
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DOI：
10.1186/s13395-018-0155-0
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发表时间：
2018-03-06
期刊：
影响因子：
4.9
通讯作者：
Valberg SJ
中科院分区：
文献类型：
--
作者：
Finno CJ;Gianino G;Perumbakkam S;Williams ZJ;Bordbari MH;Gardner KL;Burns E;Peng S;Durward-Akhurst SA;Valberg SJ
免疫介导的肌炎（IMM）的原因尚不清楚，其特征是夸特马（QH）复发性、快速发作的肌肉萎缩。IMM的组织病理学标志是肌纤维的淋巴细胞浸润。本研究的目的是确定与马IMM相关的推定的功能变体。使用马SNP 50和SNP 70基因分型阵列对来自相同环境的36个IMM QH和54个品种匹配的未受影响的QH进行全基因组关联（GWA）研究。混合模型分析确定了chr 11上约2.87 Mb区域内的9个SNP，它们与IMM表型显著相关（Punadjusted < 1.4 × 10− 6）。该区域内的相关单倍型包括38个注释基因，包括4个肌球蛋白基因（MYH 1、MYH 2、MYH 3和MYH 13）。四个IMM和四个未受影响的QH的全基因组测序鉴定了MYH 1编码肌球蛋白重链2X中的一个分离的非同义E321 G突变。另外35匹IMM和22匹未受影响的QH的基因分型证实了相关性（P = 2.9 × 10− 5），来自21个非QH品种的175匹马中不存在推定的突变。淋巴细胞浸润发生在2X型肌纤维和2X纤维的比例下降，在炎症的存在。蛋白质建模和接触/稳定性分析确定了14个受突变影响的残基，这些突变显著降低了稳定性。我们的结论是MYH 1的突变与QH相关品种的IMM表型易感性高度相关。这是MYH 1突变的首次报道，也是骨骼肌肌球蛋白突变与自身免疫性疾病之间的首次联系。本文的在线版本（10.1186/s13395-018-0155-0）包含补充材料，可供授权用户使用。
The cause of immune-mediated myositis (IMM), characterized by recurrent, rapid-onset muscle atrophy in Quarter Horses (QH), is unknown. The histopathologic hallmark of IMM is lymphocytic infiltration of myofibers. The purpose of this study was to identify putative functional variants associated with equine IMM. A genome-wide association (GWA) study was performed on 36 IMM QHs and 54 breed matched unaffected QHs from the same environment using the Equine SNP50 and SNP70 genotyping arrays. A mixed model analysis identified nine SNPs within a ~ 2.87 Mb region on chr11 that were significantly (Punadjusted < 1.4 × 10− 6) associated with the IMM phenotype. Associated haplotypes within this region encompassed 38 annotated genes, including four myosin genes (MYH1, MYH2, MYH3, and MYH13). Whole genome sequencing of four IMM and four unaffected QHs identified a single segregating nonsynonymous E321G mutation in MYH1 encoding myosin heavy chain 2X. Genotyping of additional 35 IMM and 22 unaffected QHs confirmed an association (P = 2.9 × 10− 5), and the putative mutation was absent in 175 horses from 21 non-QH breeds. Lymphocytic infiltrates occurred in type 2X myofibers and the proportion of 2X fibers was decreased in the presence of inflammation. Protein modeling and contact/stability analysis identified 14 residues affected by the mutation which significantly decreased stability. We conclude that a mutation in MYH1 is highly associated with susceptibility to the IMM phenotype in QH-related breeds. This is the first report of a mutation in MYH1 and the first link between a skeletal muscle myosin mutation and autoimmune disease. The online version of this article (10.1186/s13395-018-0155-0) contains supplementary material, which is available to authorized users.
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影响因子：
2.4
作者：
Bordbari MH;Penedo MCT;Aleman M;Valberg SJ;Mickelson J;Finno CJ
通讯作者：
Finno CJ
影响因子：
3.7
作者：
Massey J;Rothwell S;Rusbridge C;Tauro A;Addicott D;Chinoy H;Cooper RG;Ollier WE;Kennedy LJ
通讯作者：
Kennedy LJ
组织分辨的基因结构完善了马转录组。
影响因子：
4.4
作者：
Mansour TA;Scott EY;Finno CJ;Bellone RR;Mienaltowski MJ;Penedo MC;Ross PJ;Valberg SJ;Murray JD;Brown CT
通讯作者：
Brown CT
影响因子：
2.6
作者：
Durward-Akhurst SA;Finno CJ;Barnes N;Shivers J;Guo LT;Shelton GD;Valberg SJ
通讯作者：
Valberg SJ
影响因子：
3
作者：
Eyal, E;Najmanovich, R;Sobolev, V
通讯作者：
Sobolev, V