Bao Y, Kishnani P, Wu J Y, Chen Y T
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Clin Invest. 1996 Feb 15;97(4):941-8. doi: 10.1172/JCI118517.
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-IV 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 GBE activity, whereas the Y329S resulted in loss of approximately 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 (ag 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.
IV型糖原贮积病（GSD-IV）是一种常染色体隐性疾病，由糖原分支酶（GBE）活性不足引起。其典型且最常见的形式是进行性肝硬化和肝功能衰竭，导致在5岁前要么进行肝移植，要么死亡。然而，肝脏疾病并不总是进行性的。此外，还报道了该疾病的一种神经肌肉类型。GSD-IV的分子基础尚不清楚，临床变异性的原因也未知。我们研究了具有不同GSD-IV表现的患者的GBE基因。在两名具有典型表现的患者中发现了GBE基因的三个点突变：R515C、F257L和R524X。瞬时表达实验表明这些突变使GBE活性失活。在一名具有非进行性肝脏形式的患者的两个单独等位基因中检测到两个点突变，L224P和Y329S。L224P导致GBE活性完全丧失，而Y329S导致GBE活性丧失约50%。在另一名非进行性GSD-IV形式的患者中也检测到了Y329S等位基因，但在35名无关对照或更严重形式的GSD-IV患者中未检测到。在一名具有致命性新生儿神经肌肉表现的患者中检测到GBE cDNA从核苷酸873至1082的210 bp缺失。这种缺失代表一个完整外显子的丢失，是由一个3'受体剪接位点突变（ag变为aa）引起的。该缺失使GBE活性丧失。我们的研究表明，GSD-IV的三种不同形式是由同一GBE基因中的突变引起的。数据还表明，Y329S等位基因中GBE活性的显著保留可能是疾病较轻的一个原因。对基因型/表型相关性的进一步研究可能会在预测临床结果方面产生有用信息。
