Accumulation of Laforin and Other Related Proteins in Canine Lafora Disease With EPM2B Repeat Expansion
Accumulation of Laforin and Other Related Proteins in Canine Lafora Disease With EPM2B Repeat Expansion
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DOI：
10.1177/0300985818758471
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发表时间：
2018-07-01
影响因子：
2.4
通讯作者：
Uchida, Kazuyuki
中科院分区：
文献类型：
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作者：
Chambers, James K.;Thongtharb, Atigan;Uchida, Kazuyuki
犬拉福拉病（LD）是一种常染色体隐性遗传病，主要累及小型硬毛腊肠犬，引起非致死性结构性癫痫。EPM 2B基因的重复扩增导致调节糖原代谢的泛素连接酶malin的功能受损。结构异常的糖原主要在中枢神经系统中积累和形成葡聚糖体。作者对4例LD病例进行了全面的临床、遗传和病理学研究，这些LD病例影响了EPM 2B重复扩增的小型硬毛腊肠犬，并伴有葡聚糖体的全身分布以及laforin和其他功能相关蛋白在葡聚糖体中的蓄积。肌阵挛发作在7-9岁时首次出现，犬在14-16岁时死亡。钙结合蛋白免疫组化显示葡聚糖小体位于浦肯野细胞胞体和树突状突起内。聚葡聚糖体也对laforin、hsp 70、α/β-突触核蛋白、泛素、LC 3和p62呈阳性。Laforin阳性葡聚糖体位于神经胶质细胞阳性神经元中，但不在GFAP阳性星形胶质细胞中。在非神经组织中，高碘酸希夫（PAS）阳性的葡聚糖体观察到心脏，骨骼肌，肝脏，顶泌汗腺，平滑肌层的膀胱。在骨骼肌中，仅在1型纤维中观察到聚葡聚糖体，而在2型纤维中未观察到。结果表明，尽管EPM 2B基因的重复扩增是犬特有的，但犬LD中葡聚糖体的免疫组织化学性质与人LD相当。然而，重要的表型变异存在于2个物种之间，包括受影响的骨骼肌纤维类型。
Canine Lafora disease (LD) is an autosomal recessive genetic disorder causing nonfatal structural epilepsy, mainly affecting miniature wirehaired dachshunds. Repeat expansion in the EPM2B gene causes a functional impairment of the ubiquitin ligase malin which regulates glycogen metabolism. Abnormally structured glycogen accumulates and develop polyglucosan bodies predominantly in the central nervous system. The authors performed a comprehensive clinical, genetic, and pathological study of 4 LD cases affecting miniature wirehaired dachshund dogs with EPM2B repeat expansions, with systemic distribution of polyglucosan bodies and accumulation of laforin and other functionally associated proteins in the polyglucosan bodies. Myoclonic seizures first appeared at 7-9 years of age, and the dogs died at 14-16 years of age. Immunohistochemistry for calbindin revealed that the polyglucosan bodies were located in the cell bodies and dendritic processes of Purkinje cells. Polyglucosan bodies were also positive for laforin, hsp70, alpha/beta-synuclein, ubiquitin, LC3, and p62. Laforin-positive polyglucosan bodies were located in neurofilament-positive neurons but not in GFAP-positive astrocytes. In nonneural tissues, periodic acid-Schiff (PAS)-positive polyglucosan bodies were observed in the heart, skeletal muscle, liver, apocrine sweat gland, and smooth muscle layer of the urinary bladder. In the skeletal muscle, polyglucosan bodies were observed only in type 1 fibers and not in type 2 fibers. The results indicate that although the repeat expansion of the EPM2B gene is specific to dogs, the immunohistochemical properties of polyglucosan body in canine LD are comparable to human LD. However, important phenotypic variations exist between the 2 species including the affected skeletal muscle fiber type.