Fabry disease: novel alpha-galactosidase A 3'-terminal mutations result in multiple transcripts due to aberrant 3'-end formation.
Fabry disease: novel alpha-galactosidase A 3'-terminal mutations result in multiple transcripts due to aberrant 3'-end formation.
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法布里病：新型 α-半乳糖苷酶 A 3 末端突变由于 3 末端形成异常而导致多个转录物。
DOI：
10.1086/376608
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发表时间：
2003
影响因子：
9.8
通讯作者：
Desnick,RobertJ
中科院分区：
文献类型：
--
作者：
Yasuda,Makiko;Shabbeer,Junaid;Osawa,Makiko;Desnick,RobertJ
编码溶酶体外切糖水解酶α-半乳糖苷酶A（α-GalA）的基因突变可引起法布里病，这是一种X连锁隐性遗传性鞘糖脂代谢缺陷。人α-GalA基因是哺乳动物中罕见的3′端非翻译区（UTR）缺失、编码区含有多聚腺苷酸化信号的基因。我们在经典法布里病的无关男性中发现了两个新的移码突变，1277 delAA（del 2）和1284 delACTT（del 4）。这两个突变都发生在编码区的3′端，并消除了终止密码子，del 2也改变了多聚腺苷酸化信号。采用3′端快速扩增cDNA末端（RACE）和聚合酶链反应（PCR）对突变进行鉴定，并对扩增产物进行亚克隆和测序。这两种突变都产生了3′端序列长度不同的多个转录本，有些延长了约100 kb。突变体转录本分类如下：I型转录本的末端符合读框的胸苷在聚腺苷酸化时产生终止密码子，II型转录本的下游终止密码子位于延长的α-GalA序列内，III型转录本的3′端缺乏终止密码子，III型转录本的数量最多。为了确定III型转录物是否被最近描述的缺乏终止密码子的信使的胞质信使RNA降解途径降解，进行了北方印迹分析。然而，在正常和患者淋巴母细胞中发现类似水平的细胞核和细胞质α-GalA mRNA，这表明mRNA降解不是由任一突变引起的。有代表性的转录本类型的表达揭示了细胞内定位和/或蛋白质稳定性和催化活性的差异，大多数突变蛋白质是无功能的。这些3′突变的特征鉴定了一种引起经典法布里病的新分子机制。
Mutations in the gene that encodes the lysosomal exoglycohydrolase, α-galactosidase A (α-GalA), cause Fabry disease, an X-linked recessive inborn error of glycosphingolipid catabolism. Human α-GalA is one of the rare mammalian genes that has its polyadenylation signal in the coding sequence and lacks a 3′ untranslated region (UTR). We identified two novel frameshift mutations, 1277delAA (del2) and 1284delACTT (del4), in unrelated men with classical Fabry disease. Both mutations occurred in the 3′ terminus of the coding region and obliterated the termination codon, and del2 also altered the polyadenylation signal. To characterize these mutations, 3′ rapid amplification of cDNA ends (RACE) and polymerase chain reactions (PCR) were performed, and the amplicons were subcloned and sequenced. Both mutations generated multiple transcripts with various lengths of 3′ terminal sequences, some elongating ∼1 kb. Mutant transcripts were classified as follows: type I transcripts had terminal in-frame thymidines that created termination codons when polyadenylated, type II had downstream termination codons within the elongated α-GalA sequence, and type III, the most abundant, lacked termination codons at their 3′ ends. To determine if the type III transcripts were degraded by the recently described cytosolic messenger RNA degradation pathway for messages lacking termination codons, northern blot analysis was performed. However, the finding of similar levels of nuclear and cytoplasmic α-GalA mRNA in normal and patient lymphoblasts suggested that mRNA degradation did not result from either mutation. Expression of representative transcript types revealed differences in intracellular localization and/or protein stability and catalytic activity, with most mutant proteins being nonfunctional. Characterization of these 3′ mutations identified a novel molecular mechanism causing classical Fabry disease.
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影响因子：
14.9
作者：
CHEN, F;MACDONALD, CC;WILUSZ, J
通讯作者：
WILUSZ, J
影响因子：
4.1
作者：
Ioannou, YA;Zeidner, KM;Desnick, RJ
通讯作者：
Desnick, RJ
mRNA 的质量控制
DOI：
--
发表时间：
2001
期刊：
影响因子：
--
作者：
浩史 早川;Hayakawa Hiroshi
通讯作者：
Hayakawa Hiroshi
DOI：
10.1073/pnas.83.13.4859
发表时间：
1986-07-01
影响因子：
11.1
作者：
BISHOP, DF;CALHOUN, DH;DESNICK, RJ
通讯作者：
DESNICK, RJ
人亚精胺合酶基因：结构和染色体定位。
影响因子：
3.1
作者：
S. Myöhänen;L. Kauppinen;J. Wahlfors;L. Alhonen;J. Jänne
通讯作者：
J. Jänne