Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle
Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle
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DOI：
10.1172/jci118799
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发表时间：
1996-07-15
影响因子：
15.9
通讯作者：
Chen, YT
中科院分区：
文献类型：
--
作者：
Shen, JJ;Bao, Y;Chen, YT
糖原累积病III型（GSD-III）是一种由糖原脱支酶（GDE）活性缺陷引起的常染色体隐性遗传病。大多数GSD-III患者在肝脏和肌肉中都缺乏GDE（IIIa型），和一些GSD-III患者有GDE缺乏肝脏，但保留在肌肉在本研究中，通过单链构象多态性（SSCP）、DNA测序、限制性内切酶分析和家族研究分析了3名GSD-IIIb患者的GDE基因，揭示了它们中的每一个都是两种不同突变的复合杂合子。所有三名患者的第一个突变等位基因均涉及GDE蛋白第6位氨基酸密码子第3外显子的突变。两个在GDE cDNA的核苷酸17和18处具有AG缺失（17 delAG），这导致随后的氨基酸序列的改变和截短的蛋白质（25 X）;另一个在cDNA的核苷酸16处具有C到T的转变，这将谷氨酰胺密码子改变为终止密码子（Q6 X）。在另外10例GSD-IIIb患者中，也有8例发现了17 delAG突变。在其余两名GSD-IIIb患者中发现了Q6 X突变。在31例GSD-IIIa患者、2例GSD-IIId患者和28例无关的正常对照中均未发现这两种突变。在3例GSD-IIIb患者中，第二种突变等位基因分别为R864 X、R1228 X和W 680 X，R864 X和R1228 X并非GSD-IIIb的唯一基因，因为它们也见于GSD-IIIa患者（在白人患者中的频率分别为10.3%和5.2%）。我们的数据表明，IIIa和IIIb在相同的GDE基因突变，并建立了第一次的GSD-III，在肝脏和肌肉中差异表达的分子基础，第三外显子突变与GSD-IIIb的显着和特定的关联可能提供洞察控制GDE基因的组织特异性表达的机制。外显子3突变的鉴定也具有临床意义，因为它区分了GSD-IIIb和IIIa，因此允许从血液样本而不是更具侵入性的肌肉活检进行诊断。
Glycogen storage disease type III (GSD-III), an autosomal recessive disease, is caused by deficient glycogen debranching enzyme (GDE) activity. Most GSD-III patients are GDE deficient in both liver and muscle (type IIIa), and some GSD-III patients have GDE absent in liver but retained in muscle (type IIIb), The molecular basis for this enzymatic variability is largely unknown, In the present study, the analysis of the GDE gene in three GSD-IIIb patients by single-strand conformation polymorphism (SSCP), DNA sequencing, restriction analysis, and family studies, revealed each of them as being a compound heterozygote for two different mutations. The first mutant alleles in all three patients involved mutations in exon 3 at amino acid codon 6 of the GDE protein. Two had an AG deletion at nucleotides 17 and 18 of the GDE cDNA (17delAG) which resulted in change of subsequent amino acid sequence and a truncated protein (25X); the other had a C to T transition at nucleotide 16 of the cDNA which changed a Glutamine codon to a stop codon (Q6X). The 17delAG mutation was also found in 8 of the 10 additional GSD-IIIb patients. The Q6X mutation was found in one of the remaining two GSD-IIIb patients. These two mutations were not found in any of the 31 GSD-IIIa patients, 2 GSD-IIId patients, nor 28 unrelated normal controls, The second mutant alleles in each of the three GSD-IIIb patients were R864X, R1228X, and W680X, The R864X and R1228X were not unique for GSD-IIIb as they were also found in GSD-IIIa patients (frequency of 10.3% and 5.2% in Caucasian patients, respectively). Our data demonstrated that both IIIa and IIIb had mutations in the same GDE gene and established for the first time the molecular basis of GSD-III that differentially expressed in liver and muscle, The striking and specific association of exon 3 mutations with GSD-IIIb may provide insight into mechanisms controlling tissue-specific expression of the GDE gene. The identification of exon 3 mutations has clinical significance as well because it distinguished GSD-IIIb from IIIa hence permitting diagnosis from a blood sample rather than a more invasive muscle biopsy.