Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene
Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene
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DOI：
10.1172/jci118517
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发表时间：
1996-02-15
影响因子：
15.9
通讯作者：
Chen, YT
中科院分区：
文献类型：
--
作者：
Bao, Y;Kishnani, P;Chen, YT
糖原累积病IV型（GSD-IV）是一种由糖原分支酶（GBE）活性缺陷引起的常染色体隐性遗传病。最典型和最常见的形式是进行性肝硬化和衰竭，导致肝移植或5岁时死亡。然而，肝脏疾病并不总是渐进的。此外，还报道了该疾病的神经肌肉类型。GSD-TV的分子基础尚不清楚，临床变异性也没有已知的原因。我们研究了GBE基因在患者的各种介绍GSD-IV。在2例典型表现的患者中发现了GBE基因的3个点突变：R515 C、F257 L和R524 X。瞬时表达实验表明，这些突变失活GBE活性。两个点突变，L224 P和Y329 S，在两个独立的等位基因的患者与非进行性肝形式检测。L224 P导致CBE活性完全丧失，而Y329 S导致GBE活性丧失约50%。Y329 S等位基因也在另一名非进展性GSD-IV患者中检测到，但在35名无关对照或更严重形式的GSD-IV患者中未检测到。一个210-bp的GBE cDNA的核苷酸873至1082的缺失，检测到在致命的新生儿神经肌肉介绍的患者。这种缺失代表一个完整外显子的丢失，是由aa）的3'受体剪接位点突变标签引起的。删除消除了GBE活性。我们的研究表明，三种不同形式的GSD-IV是由同一GBE基因突变引起的。数据还表明，在Y329 S等位基因中GBE活性的显著保留可能是轻度疾病的原因。基因型/表型相关性的进一步研究可能会产生有用的信息，在预测临床结果。
Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease resulting from deficient glycogen-branching enzyme (GBE) activity. The classic and most common form is progressive liver cirrhosis and failure Leading to either liver transplantation or death by 5 yr of age. However, the liver disease is not always progressive. In addition, a neuromuscular type of the disease has been reported. The molecular basis of GSD-TV is not known, nor is there a known reason for the clinical variability. We studied the GBE gene in patients with various presentations of GSD-IV. Three point mutations in the GBE gene were found in two patients with the classical presentation: R515C, F257L, and R524X. Transient expression experiments showed that these mutations inactivated GBE activity. Two point mutations, L224P and Y329S, were detected in two separate alleles of a patient with the nonprogressive hepatic form. The L224P resulted in complete loss of CBE activity, whereas the Y329S resulted in loss of similar to 50% of GBE activity, The Y329S allele was also detected in another patient with the nonprogressive form of GSD-IV but not in 35 unrelated controls or in patients with the more severe forms of GSD-IV. A 210-bp deletion from nucleotide 873 to 1082 of the GBE cDNA was detected in a patient with the fatal neonatal neuromuscular presentation. This deletion, representing the loss of one full exon, was caused by a 3' acceptor splicing site mutation tag to aa). The deletion abolished GBE activity. Our studies indicate that the three different forms of GSD-IV were caused by mutations in the same GBE gene. The data also suggest that the significant retention of GBE activity in the Y329S allele may be a reason for the mild disease. Further study of genotype/phenotype correlations may yield useful information in predicting the clinical outcomes.