Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts
Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts
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DOI：
10.1038/sj.ejhg.5201242
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发表时间：
2004-09-01
影响因子：
5.2
通讯作者：
Pelin, K
中科院分区：
文献类型：
--
作者：
Donner, K;Sandbacka, M;Pelin, K
巨大的星云蛋白是横纹肌肌节细丝的基本结构成分。星云蛋白与肌动蛋白结合，其大小与肌动蛋白细丝长度相关，提示在肌原纤维形成过程中，星云蛋白可能决定了细丝的长度。我们已经描述了星云蛋白基因3‘末端(NEB)的基因组结构，并在常染色体隐性遗传性线虫肌病患者中鉴定了18种不同的NEB突变。在这里，我们介绍了整个星云蛋白基因的基因组组织，并鉴定了许多选择性剪接的mRNAs。该基因由183个外显子组成，跨越249kb的基因组序列。翻译起始密码子位于外显子3，终止密码子和3‘非编码区位于外显子183。有四个区域具有选择性剪接的外显子，即外显子63-66，82-105,143-144和166-177，导致许多不同的转录本。选择性剪接的外显子143-144产生了两个不同的转录本，在不同的肌肉类型和不同发育阶段的肌肉之间不同。选择性剪接的外显子166-177仅在成人胫前肌中就表达至少20种不同的转录本。初步结果显示，在剩下的两个选择性剪接区中都有几个转录本。NEB的广泛选择性剪接可能解释了为什么具有纯合子截断突变的线虫肌病患者表现出与预期相反的星云蛋白羧基末端的表达。使用替代转录本也可以解释为什么在有两个截断突变的患者中，严重的表型很少见。
The giant nebulin protein is a fundamental structural component of the thin filaments of the striated muscle sarcomere. Nebulin binds to actin and the size of nebulin correlates with actin filament length, suggesting that nebulin may determine the length of the thin filaments during myofibrillogenesis. We have previously described the genomic organization of the 3' end of the nebulin gene (NEB), and identified 18 different NEB mutations in patients with autosomal recessive nemaline myopathy. Here we present the genomic organization of the entire nebulin gene, and the identification of numerous alternatively spliced mRNAs. The gene comprises 183 exons spanning 249 kb of the genomic sequence. The translation initiation codon is in exon 3, and the stop codon and the 3' UTR are in exon 183. There are four regions with alternatively spliced exons, that is, exons 63-66, 82-105, 143-144 and 166-177, giving rise to a number of different transcripts. The alternatively spliced exons 143-144 give rise to two different transcripts varying between muscle types and between muscles of different developmental stages. The alternatively spliced exons 166-177 express at least 20 different transcripts in adult human tibialis anterior muscle alone. Preliminary results show several transcripts in both of the two remaining alternatively spliced regions. Extensive alternative splicing of NEB may explain why nemaline myopathy patients with homozygous truncating mutations show expression of the carboxy-terminus of the nebulin protein contrary to expectations. The use of alternative transcripts might also explain why severe phenotypes are rare among patients with two truncating mutations.