The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy.
The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy.
复制标题
mRNA 中插入 33 个核苷酸导致鞘脂激活蛋白 (SAP-1) 缺陷型异染性脑白质营养不良的机制。
DOI：
10.1007/bf00204185
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发表时间：
1991
期刊：
影响因子：
5.3
通讯作者：
Wenger,DA
中科院分区：
文献类型：
--
作者：
Zhang,XL;Rafi,MA;DeGala,G;Wenger,DA
异染性脑白质营养不良是一种严重的常染色体隐性遗传病，由溶酶体降解缺陷引起的硫苷脂蓄积引起。虽然大多数患者在溶酶体酶芳基硫酸酯酶A中有突变，但一些患者在所需的热稳定鞘脂激活蛋白中有突变，我们称之为SAP-1。一名SAP-1缺乏症患者先前被证明在其mRNA中有33个核苷酸插入。这导致产生具有11个额外氨基酸的成熟SAP-1，其在细胞内加工期间不稳定。在这份手稿中，我们证明了这33个核苷酸存在于一个4kb内含子的中间附近，并且在33个核苷酸插入之前的第二个位置上的一个碱基变化，c到a，加上紧接在这个变化上游的一串嘧啶的存在，产生了一个新的3′剪接点。在33个核苷酸的插入中存在一串嘧啶，在3′端附近有三个cag三核苷酸，导致正常人的选择性剪接，正如本实验室和其他人所发现的那样。插入区之后是一个gt二核苷酸，该二核苷酸被剪接成典型的3′共有序列。单核苷酸的变化，从c到a，通过鉴定近亲父母和一个姐妹的正常和突变序列来证实，以前被鉴定为这种疾病的携带者。
Metachromatic leukodystrophy is a severe autosomal recessive disorder caused by accumulation of sulfatide resulting from deficient lysosomal degradation. While most patients have mutations in the lysosomal enzyme arylsulfatase A, some patients have mutations in a required heat stable sphingolipid activator protein, we call SAP-1. One patient with SAP-1 deficiency was previously demonstrated to have a 33-nucleotide insertion in her mRNA. This resulted in the production of mature SAP-1 with 11 extra amino acids, which was unstable during intracellular processing. In this manuscript we demonstrate that the 33 nucleotides are present near the middle of a 4-kb intron, and that a single base change, c to a, in the second position preceding the 33-nucleotide insertion, coupled with the presence of a string of pyrimidines immediately upstream from this change, creates a new 3′ splice junction. The presence of a string of pyrimidines within the 33-nucleotide insertion, which has three cag trinucleotides near the 3′ end, leads to alternative splicing in normal people as found in this laboratory and by others. The insertion region is followed by a gt dinucleotide that is spliced to a typical 3′ consensus sequence. The single nucleotide change, c to a, was confirmed by identifying normal and mutant sequence in the consanguineous parents and a sister, previously identified as a carrier of this disorder.