Mutation spectrum and splicing variants in the OPA1 gene
Mutation spectrum and splicing variants in the OPA1 gene
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DOI：
10.1007/s00439-001-0633-y
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发表时间：
2001-12-01
期刊：
影响因子：
5.3
通讯作者：
Hamel, CP
中科院分区：
文献类型：
--
作者：
Delettre, C;Griffoin, JM;Hamel, CP
I型视神经萎缩（OPA 1，MIM 165500）是一种显性遗传性视神经病变，其特征是低视力，在许多情况下导致法律的失明。我们最近与其他人一起证明，编码动力蛋白相关线粒体蛋白的OPA 1基因突变是视神经萎缩的主要形式。在这里，我们报告，OPA 1有八个mRNA异构体作为外显子4和两个新的外显子命名为4 b和5 b的选择性剪接的结果。此外，我们通过对30个OPA 1外显子（包括外显子4 b和5 b）进行直接测序，筛选了19例显性视神经萎缩的无关患者，发现其中17例（89%）发生突变，其中8例为新突变。这些突变中的大多数是截短的（65%），位于外显子8至28，但其中一些是主要在GT3结构域（外显子8至15）中发现的氨基酸变化。我们推测OPA 1的至少两种修饰可能导致显性视神经萎缩，即GT3活性的改变和与其他蛋白质相互作用的最后7个C-末端氨基酸的丢失。
Optic atrophy type I (OPA1, MIM 165500) is a dominantly inherited optic neuropathy that features low visual acuity leading in many cases to legal blindness. We have recently shown, with others, that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein, underlie the dominant form of optic atrophy. Here we report that OPA1 has eight mRNA isoforms as a result of the alternative splicing of exon 4 and two novel exons named 4b and 5b. In addition, we screened a cohort of 19 unrelated patients with dominant optic atrophy by direct sequencing of the 30 OPA1 exons (including exons 4b and 5b) and found mutations in 17 (89%) of them of which 8 were novel. A majority of these mutations were truncative (65%) and located in exons 8 to 28, but a number of them were amino acid changes predominantly found in the GTPase domain (exons 8 to 15). We hypothesize that at least two modifications of OPA1 may lead to dominant optic atrophy, that is alteration in GTPase activity and loss of the last seven C-terminal amino acids that putatively interact with other proteins.