Contribution of dysferlin deficiency to skeletal muscle pathology in asymptomatic and severe dystroglycanopathy models: generation of a new model for Fukuyama congenital muscular dystrophy.
Contribution of dysferlin deficiency to skeletal muscle pathology in asymptomatic and severe dystroglycanopathy models: generation of a new model for Fukuyama congenital muscular dystrophy.
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DOI：
10.1371/journal.pone.0106721
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Toda T
中科院分区：
文献类型：
--
作者：
Kanagawa M;Lu Z;Ito C;Matsuda C;Miyake K;Toda T
肌营养不良聚糖糖基化缺陷与一组肌营养不良症相关，称为肌营养不良聚糖病，包括福山先天性肌营养不良症（FCMD）。人们普遍认为，肌营养不良蛋白聚糖的异常糖基化导致致病性膜脆性。我们先前产生了在fuklymphocyte中携带创始人retrotranslymphocyte插入的敲入小鼠，fuklymphocyte是负责FCMD的基因，但这些小鼠没有发展成肌营养不良症，这阻碍了探索治疗策略。我们假设dysferlin的功能可能有助于基因敲入小鼠的肌细胞活力;然而，糖基化异常和dysferlin缺陷之间的病理相互作用仍未被探索。为了研究dysferlin缺陷对肌营养不良聚糖病病理学的贡献，我们将dysferlin缺陷型dysferlin sjl/sjl小鼠与fukutin-knock-in fukulum Hp/−和Large-deficient Large myd/myd小鼠杂交，这两种小鼠是表型不同的肌营养不良聚糖病模型。fukerlin Hp/−小鼠未显示营养不良表型;然而，与（dysferlin sjl/sjl：fukerlin Hp/+）小鼠相比，（dysferlin sjl/sjl：fukerlin Hp/−）小鼠显示恶化的表型。这些数据表明，在无症状的fukaHP/−小鼠中功能性dysferlin的缺乏触发了疾病表现并加剧了营养不良表型。使用Large和dysferlin的双突变小鼠进行的一系列病理学分析表明，当营养不良性病理严重时，dysferlin的保护作用似乎减弱，并且也可能取决于dysferlin蛋白的量。总之，我们的研究结果表明，dysferlin对fukerine Hp/− FCMD小鼠模型具有保护作用，而（dysferlin sjl/sjl：fukerine Hp/−）小鼠将可用作最近提出的FCMD反义寡核苷酸治疗的新模型。
Defects in dystroglycan glycosylation are associated with a group of muscular dystrophies, termed dystroglycanopathies, that include Fukuyama congenital muscular dystrophy (FCMD). It is widely believed that abnormal glycosylation of dystroglycan leads to disease-causing membrane fragility. We previously generated knock-in mice carrying a founder retrotransposal insertion in fukutin, the gene responsible for FCMD, but these mice did not develop muscular dystrophy, which hindered exploring therapeutic strategies. We hypothesized that dysferlin functions may contribute to muscle cell viability in the knock-in mice; however, pathological interactions between glycosylation abnormalities and dysferlin defects remain unexplored. To investigate contributions of dysferlin deficiency to the pathology of dystroglycanopathy, we have crossed dysferlin-deficient dysferlin sjl/sjl mice to the fukutin-knock-in fukutin Hp/− and Large-deficient Large myd/myd mice, which are phenotypically distinct models of dystroglycanopathy. The fukutin Hp/− mice do not show a dystrophic phenotype; however, (dysferlin sjl/sjl: fukutin Hp/−) mice showed a deteriorated phenotype compared with (dysferlin sjl/sjl: fukutin Hp/+) mice. These data indicate that the absence of functional dysferlin in the asymptomatic fukutin Hp/− mice triggers disease manifestation and aggravates the dystrophic phenotype. A series of pathological analyses using double mutant mice for Large and dysferlin indicate that the protective effects of dysferlin appear diminished when the dystrophic pathology is severe and also may depend on the amount of dysferlin proteins. Together, our results show that dysferlin exerts protective effects on the fukutin Hp/− FCMD mouse model, and the (dysferlin sjl/sjl: fukutin Hp/−) mice will be useful as a novel model for a recently proposed antisense oligonucleotide therapy for FCMD.
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DOI：
10.1126/science.1233675
发表时间：
2013-04-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jae LT;Raaben M;Riemersma M;van Beusekom E;Blomen VA;Velds A;Kerkhoven RM;Carette JE;Topaloglu H;Meinecke P;Wessels MW;Lefeber DJ;Whelan SP;van Bokhoven H;Brummelkamp TR
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Brummelkamp TR
DOI：
10.1073/pnas.1307960110
发表时间：
2013-12-17
影响因子：
11.1
作者：
Kerr, Jaclyn P.;Ziman, Andrew P.;Bloch, Robert J.
通讯作者：
Bloch, Robert J.
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Klinge, Lars;Harris, John;Bushby, Kate
通讯作者：
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通讯作者：
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作者：
Stevens, Elizabeth;Carss, Keren J.;Muntoni, Francesco
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