The molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma corporis diffusum with glycopeptiduria.
The molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma corporis diffusum with glycopeptiduria.
复制标题
α-N-乙酰氨基半乳糖苷酶基因的分子损伤导致弥漫性体血管角化瘤伴糖肽尿。
DOI：
10.1172/jci117404
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Desnick,RJ
中科院分区：
文献类型：
--
作者：
Wang,AM;Kanzaki,T;Desnick,RJ
弥漫性身体血管角化瘤合并糖肽尿症是一种先天性糖蛋白尿症，是由人α-N-乙酰氨基半乳糖酶（E.C.）活性缺乏引起的。3.2.1.49; alpha-GalNAc）。第一个病人，这种常染色体隐性遗传病，一个46岁的近亲日本妇女，提出了弥漫性血管角化瘤，轻度智力障碍，周围神经轴索变性。在患有由α-GalNAc基因中的错义突变（指定为E325 K）引起的神经轴突营养不良的争斗发作形式的近亲兄弟中也已经报道了α-GalNAc活性缺陷。为了鉴定引起表型上不同的成人发作性疾病的突变，对来自受影响的纯合子的DNA和RNA进行Southern和北方杂交分析，其揭示了大体上正常的α-GalNAc基因结构和正常的转录物大小和缺失。α-GalNAc转录物的逆转录、扩增和测序鉴定了核苷酸（nt）985处的单个C至T转变，其预测了α-GalNAc多肽的残基329（指定为R329 W）中的精氨酸至色氨酸取代。通过PCR扩增的来自家族成员的基因组DNA与等位基因特异性寡核苷酸的杂交证实了这种碱基取代。含有R329 W突变的α-GalNAc构建体的瞬时表达导致免疫反应性多肽的表达，所述免疫反应性多肽没有可检测的α-GalNAc活性。瞬时表达和放射性标记的正常E325 K的生物合成和稳定性的比较（发作）和R329 W COS-1细胞中的（成年发病）α-GalNAc多肽表明两种突变前体都被加工成成熟形式;然而，E325 K突变体多肽比R329 W亚基降解更快，从而为婴儿和成人发病表型的明显不同提供了基础。图像
Angiokeratoma corporis diffusum with glycopeptiduria is a recently recognized inborn error of glycoprotein catabolism resulting from the deficient activity of human alpha-N-acetylgalactosaminidase (E.C. 3.2.1.49; alpha-GalNAc). The first patient with this autosomal recessive disorder, a 46-yr-old consanguineous Japanese woman, presented with diffuse angiokeratoma, mild intellectual impairment, and peripheral neuroaxonal degeneration. Deficient alpha-GalNAc activity also has been reported in consanguineous brothers with an infantile-onset form of neuroaxonal dystrophy resulting from a missense mutation (designated E325K) in the alpha-GalNAc gene. To identify the mutation causing the phenotypically distinct adult-onset disorder, Southern and Northern hybridization analyses of DNA and RNA from the affected homozygote were performed which revealed a grossly normal alpha-GalNAc gene structure and normal transcript size and abundancy. Reverse transcription, amplification, and sequencing of the alpha-GalNAc transcript identified a single C to T transition at nucleotide (nt) 985 that predicted an arginine to tryptophan substitution in residue 329 (designated R329W) of the alpha-GalNAc polypeptide. This base substitution was confirmed by hybridization of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Transient expression of an alpha-GalNAc construct containing the R329W mutation resulted in the expression of an immunoreactive polypeptide which had no detectable alpha-GalNAc activity. Comparison of the biosynthesis and stabilities of the transiently expressed and radiolabeled normal, E325K (infantile-onset) and R329W (adult-onset) alpha-GalNAc polypeptides in COS-1 cells indicated that both the mutant precursors were processed to the mature form; however, the E325K mutant polypeptide was more rapidly degraded than the R329W subunit, thereby providing a basis for the distinctly different infantile- and adult-onset phenotypes.Images