A novel mouse model that recapitulates adult-onset glycogenosis type 4
A novel mouse model that recapitulates adult-onset glycogenosis type 4
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DOI：
10.1093/hmg/ddv385
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发表时间：
2015-12-01
影响因子：
3.5
通讯作者：
Craigen, William J.
中科院分区：
文献类型：
--
作者：
Akman, H. Orhan;Emmanuele, Valentina;Craigen, William J.
糖原累积病IV型（GSD IV）是一种罕见的常染色体隐性遗传病，由糖原分支酶（GBE）缺乏引起。这种疾病的诊断标志是一种称为聚葡聚糖（PG）的糖原分支不良形式的积累。该疾病在临床上是异质性的，具有不同的组织受累和发病年龄。酶活性的完全丧失在子宫内或婴儿期是致命的，主要影响肌肉和肝脏。然而，残留的酶活性为5-20%，导致幼年或成年人发病的疾病，主要影响中枢和外周神经系统和肌肉，后者被称为成人葡聚糖体病（APBD）。在这里，我们描述了GSD IV的小鼠模型，反映了这种疾病谱。同源重组被用于敲入在德系犹太血统的APBD患者中发现的最常见的GBE 1突变p.Y329S c.986A > C。该等位基因纯合子小鼠（Gbe 1 ys/ys）表现出与APBD相似的表型，具有广泛的PG蓄积。成年小鼠表现出进行性神经肌肉功能障碍并过早死亡。虽然症状的发作仅限于成年小鼠，但PG在新生小鼠的组织中积累，但最初不存在于大脑皮层和心肌中。因此，PG在大多数组织中耐受性良好，但最终在神经元及其轴突中蓄积会引起神经病，导致后肢痉挛和过早死亡。该小鼠模型模拟了人类成人型分支酶缺乏症的病理学和病理生理学特征。
Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by deficiency of the glycogen-branching enzyme (GBE). The diagnostic hallmark of the disease is the accumulation of a poorly branched form of glycogen known as polyglucosan (PG). The disease is clinically heterogeneous, with variable tissue involvement and age at onset. Complete loss of enzyme activity is lethal in utero or in infancy and affects primarily the muscle and the liver. However, residual enzyme activity as lowas 5-20% leads to juvenile or adult onset of a disorder that primarily affects the central and peripheral nervous system and muscles and in the latter is termed adult polyglucosan body disease (APBD). Here, we describe a mouse model of GSD IV that reflects this spectrum of disease. Homologous recombination was used to knock in the most common GBE1 mutation p.Y329S c.986A > C found in APBD patients of Ashkenazi Jewish decent. Mice homozygous for this allele (Gbe1ys/ys) exhibit a phenotype similar to APBD, with widespread accumulation of PG. Adult mice exhibit progressive neuromuscular dysfunction and die prematurely. While the onset of symptoms is limited to adult mice, PG accumulates in tissues of newborn mice but is initially absent from the cerebral cortex and heart muscle. Thus, PG is well tolerated in most tissues, but the eventual accumulation in neurons and their axons causes neuropathy that leads to hind limb spasticity and premature death. This mouse model mimics the pathology and pathophysiologic features of human adult-onset branching enzyme deficiency.