THE EFFECT OF A SINGLE-BASE PAIR DELETION (DELTA-T525) AND A C1634T MISSENSE MUTATION (PRO545LEU) ON THE EXPRESSION OF LYSOSOMAL ALPHA-GLUCOSIDASE IN PATIENTS WITH GLYCOGEN-STORAGE-DISEASE TYPE-II
THE EFFECT OF A SINGLE-BASE PAIR DELETION (DELTA-T525) AND A C1634T MISSENSE MUTATION (PRO545LEU) ON THE EXPRESSION OF LYSOSOMAL ALPHA-GLUCOSIDASE IN PATIENTS WITH GLYCOGEN-STORAGE-DISEASE TYPE-II
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DOI：
10.1093/hmg/3.12.2213
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发表时间：
1994-12-01
影响因子：
3.5
通讯作者：
REUSER, AJJ
中科院分区：
文献类型：
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作者：
HERMANS, MMP;DEGRAAFF, E;REUSER, AJJ
II 型糖原累积病（GSDII，庞贝病）是由溶酶体 α-葡萄糖苷酶缺乏症的常染色体隐性遗传引起的。通过序列分析，我们鉴定了两名无关患者的溶酶体α-葡萄糖苷酶基因（GAA）中的突变，他们分别具有一个和两个相同错义突变的拷贝。发现受影响较轻的成年患者是 C1634T 转变的纯合子，导致 pro545 被 leu 取代。受影响更严重的青少年患者具有相同的突变等位基因，并在第二个等位基因中结合了 1 个碱基对缺失 (Delta T525)，导致核苷酸位置 658 - 660 过早终止。这两种突变均被引入野生型 α-葡萄糖苷酶 cDNA 中，并在 COS-1 细胞中表达，以分析其影响。 Delta T525突变完全阻止溶酶体cr-葡萄糖苷酶的形成。 pro545→leu 取代与正常合成相容，但阻碍酶成熟并导致溶酶体 α-葡萄糖苷酶活性净损失 92%。根据等位基因构成，成人 GSDII 患者的残留活性比幼年 GSDII 患者高 2 倍。在另外两名不相关的患者中检测到了 Delta T525 缺失，并且在另外两名 GSDII 白人患者中也发现了 C1634T 转变。
Glycogen storage disease type II (GSDII, Pompe's disease) is caused by an autosomal recessive inheritance of lysosomal alpha-glucosidase deficiency. By sequence analysis we have identified the mutations in the lysosomal alpha-glucosidase gene (GAA) of two unrelated patients, who have one and two copies, respectively, of the same missense mutation. The milder affected adult patient was found to be homozygous for a C1634T transition resulting in the substitution of pro545 by leu. The more severely affected adolescent patient had this same mutant allele combined with a 1 base pair deletion (Delta T525) in the second allele causing premature termination at nucleotide positions 658 - 660. Both these mutations were introduced in wild-type alpha-glucosidase cDNA and expressed in COS-1 cells to analyse their effect. The Delta T525 mutation prohibits the formation of lysosomal cr-glucosidase completely. The pro545-->leu substitution is compatible with normal synthesis but hampers enzyme maturation and results in a 92% net loss of lysosomal alpha-glucosidase activity. The patient with adult GSDII has, in accordance with the allelic constitution, a 2-fold higher residual activity than the patient with juvenile GSDII. The Delta T525 deletion was detected in two other unrelated patients, and also the C1634T transition was encountered in two more Caucasian patients with GSDII.