Muscular dystrophy-dystroglycanopathy in a family of Labrador retrievers with a LARGE1 mutation.
Muscular dystrophy-dystroglycanopathy in a family of Labrador retrievers with a LARGE1 mutation.
复制标题
DOI：
10.1016/j.nmd.2021.07.016
复制
发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Mickelson JR
中科院分区：
文献类型：
--
作者：
Shelton GD;Minor KM;Guo LT;Friedenberg SG;Cullen JN;Hord JM;Venzke D;Anderson ME;Devereaux M;Prouty SJ;Handelman C;Campbell KP;Mickelson JR
α-肌营养不良聚糖 (αDG) 是一种高度糖基化的细胞表面蛋白，在肌肉细胞与细胞外基质相互作用中发挥重要作用。 αDG 与细胞外配体的相互作用依赖于合成和延伸杂多糖基质聚糖的 LARGE1 糖基转移酶的活性。 αDG 糖基化和基质聚糖形成异常是肌营养不良症（一组先天性肌营养不良症）的致病机制。对相关 6 周大拉布拉多猎犬幼犬的肌肉活检进行了评估，这些幼犬的吸乳能力较差，与正常同窝同伴相比身材较小，呈弓形腿姿势，肌酸激酶活性显着升高。肌肉冷冻切片鉴定出具有明显退化和再生、多灶性单核细胞浸润和肌内膜纤维化的营养不良表型。家庭成员的单核苷酸多态性 (SNP) 阵列基因分型数据确定了 4 个病例相对于 8 个对照的三个纯合性区域。对其中一个病例的全基因组序列数据的分析发现，LARGE1 基因中存在终止密码子突变，该突变截断了 40% 的蛋白质。免疫荧光染色和蛋白质印迹证明受影响狗的骨骼肌和心脏中不存在基质聚糖。与对照相比，未检测到较大的酶活性。这是关于狗的肌聚糖病的第一份报告。
Alpha-dystroglycan (αDG) is a highly glycosylated cell surface protein with a significant role in cell-to-extracellular matrix interactions in muscle. αDG interaction with extracellular ligands relies on the activity of the LARGE1 glycosyltransferase that synthesizes and extends the heteropolysaccharide matriglycan. Abnormalities in αDG glycosylation and formation of matriglycan are the pathogenic mechanisms for the dystroglycanopathies, a group of congenital muscular dystrophies. Muscle biopsies were evaluated from related 6-week-old Labrador retriever puppies with poor suckling, small stature compared to normal litter mates, bow-legged stance and markedly elevated creatine kinase activities. A dystrophic phenotype with marked degeneration and regeneration, multifocal mononuclear cell infiltration and endomysial fibrosis was identified on muscle cryosections. Single nucleotide polymorphism (SNP) array genotyping data on the family members identified three regions of homozygosity in 4 cases relative to 8 controls. Analysis of whole genome sequence data from one of the cases identified a stop codon mutation in the LARGE1 gene that truncates 40% of the protein. Immunofluorescent staining and western blotting demonstrated the absence of matriglycan in skeletal muscle and heart from affected dogs. Compared to control, LARGE enzyme activity was not detected. This is the first report of a dystroglycanopathy in dogs.
登录
查看更多内容
影响因子：
3.5
作者：
Barraza-Flores, Pamela;Fontelonga, Tatiana M.;Burkin, Dean J.
通讯作者：
Burkin, Dean J.
影响因子：
4.3
作者：
Inamori K;Hara Y;Willer T;Anderson ME;Zhu Z;Yoshida-Moriguchi T;Campbell KP
通讯作者：
Campbell KP
影响因子：
2.4
作者：
Jagannathan, V;Droegemueller, C.;Wade, Claire
通讯作者：
Wade, Claire
影响因子：
3.4
作者：
Libell EM;Richardson JA;Lutz KL;Ng BY;Mockler SRH;Laubscher KM;Stephan CM;Zimmerman BM;Edens ER;Reinking BE;Mathews KD
通讯作者：
Mathews KD
影响因子：
64.8
作者：
Michele, DE;Barresi, R;Campbell, KP
通讯作者：
Campbell, KP