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首页> 外文期刊>Human Molecular Genetics >Glycogen-branching enzyme deficiency leads to abnormal cardiac development: novel insights into glycogen storage disease IV.
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Glycogen-branching enzyme deficiency leads to abnormal cardiac development: novel insights into glycogen storage disease IV.

机译：糖原分支酶缺乏症会导致心脏异常发育：对糖原贮积病的新见解IV。

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Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease caused by a deficiency in glycogen-branching enzyme (GBE1) activity that results in the accumulation of amylopectin-like polysaccharide, which presumably leads to osmotic swelling and cell death. This disease is extremely heterogeneous in terms of tissue involvement, age of onset and clinical manifestation. The most severe fetal form presents as hydrops fetalis; however, its pathogenetic mechanisms are largely unknown. In this study, mice carrying a stop codon mutation (E609X) in the Gbe1 gene were generated using a gene-driven mutagenesis approach. Homozygous mutants (Gbe(-/-) mice) recapitulated the clinical features of hydrops fetalis and the embryonic lethality of the severe fetal form of GSD-IV. However, contrary to conventional expectations, little amylopectin accumulation and no cell degeneration were found in Gbe(-/-) embryonic tissues. Glycogen accumulation was reduced in developing hearts of Gbe(-/-)embryos, and abnormal cardiac development, including hypertrabeculation and noncompaction of the ventricular wall, was observed. Further, Gbe1 ablation led to poor ventricular function in late gestation and ultimately caused heart failure, fetal hydrops and embryonic lethality. We also found that the cell-cycle regulators cyclin D1 and c-Myc were highly expressed in cardiomyocytes and likely contributed to cardiomyocyte proliferation and trabeculation/compaction of the ventricular wall. Our results reveal that early molecular events associated with Gbe1 deficiency contribute to abnormal cardiac development and fetal hydrops in the fetal form of GSD-IV.
机译：IV型糖原贮积病（GSD-IV）是由糖原支化酶（GBE1）活性不足引起的常染色体隐性遗传疾病，导致支链淀粉样多糖的积累，可能导致渗透性肿胀和细胞死亡。就组织受累，发病年龄和临床表现而言，这种疾病极为不同。最严重的胎儿形式表现为胎儿水肿。然而，其致病机理在很大程度上尚不清楚。在这项研究中，使用基因驱动诱变方法产生了在Gbe1基因中带有终止密码子突变（E609X）的小鼠。纯合突变体（Gbe（-/-）小鼠）概括了胎儿积水的临床特征和严重的GSD-IV胎儿形式的胚胎致死率。但是，与传统的预期相反，在Gbe（-/-）胚胎组织中几乎没有支链淀粉的积累，也没有发现细胞变性。糖原积累在Gbe（-/-）胚胎发育中的心脏中减少，并且观察到异常的心脏发育，包括过度束缚和心室壁不紧密。此外，Gbe1消融导致妊娠晚期心室功能不佳，并最终导致心力衰竭，胎儿积水和胚胎致死率。我们还发现细胞周期调节剂细胞周期蛋白D1和c-Myc在心肌细胞中高度表达，并可能促进心肌细胞的增殖和心室壁的小梁/紧致。我们的结果表明，与Gbe1缺乏症有关的早期分子事件导致异常的心脏发育和胎儿形式的GSD-IV胎儿积液。

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