A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions
A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions
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DOI：
10.1016/j.ajhg.2009.07.009
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发表时间：
2009-08-14
影响因子：
9.8
通讯作者：
Suomalainen, Anu
中科院分区：
文献类型：
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作者：
Tyynismaa, Henna;Ylikallio, Emil;Suomalainen, Anu
常染色体显性进行性眼外肌麻痹（adPEO）是一种线粒体疾病，其特征是在有丝分裂后组织中积累多个线粒体DNA（mtDNA）缺失。这种疾病是异质性的，有五个已知的核疾病基因编码蛋白质ANTI，Twinkle，POLG，POLG 2和OPA 1。这些蛋白质的缺陷会影响mtDNA的维持，可能导致复制叉停滞，随后形成mtDNA缺失和进行性呼吸链缺陷。在这里，我们提出了一个大的adPEO家庭与多个mtDNA缺失，其疾病是不能解释的突变在任何已知的adPEO基因座。我们将该家系的致病基因定位于染色体8q22.1-q23.3。关键连锁区包含RRM 2B基因，该基因编码核糖核苷酸还原酶p53 R2的小亚基，该亚基先前已被证明对维持mtDNA拷贝数至关重要。RRM 2B的突变筛查显示，在所有受影响的个体中，外显子9（c.979C -> T [p.R327X]）中存在杂合无义突变，而在380条对照染色体中不存在。在另一个adPEO家族中发现了相同的突变。突变的mRNA逃脱无义介导的衰变，并导致在与核糖核苷酸还原酶亚基R1的相互作用所必需的25个高度保守的C-末端氨基酸的截短的蛋白质。我们的结论是RRM 2B的显性负性或功能获得性突变是多个mtDNA缺失和adPEO的原因。
Autosomal-dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder that is characterized by accumulation of multiple mitochondrial DNA (mtDNA) deletions in postmitotic tissues. The disorder is heterogeneous, with five known nuclear disease genes that encode the proteins ANTI, Twinkle, POLG, POLG2, and OPA1. Defects in these proteins affect mtDNA maintenance, probably leading to stalled replication forks, consequent mtDNA deletion formation, and progressive respiratory chain deficiency. Here we present a large adPEO family with Multiple mtDNA deletions, whose disease was not explained by mutations in any of the known adPEO loci. We mapped the disease locus in this family to chromosome 8q22.1-q23.3. The critical linkage region contained the RRM2B gene, which encodes the small subunit of the ribonucleotide reductase p53R2, which has previously been shown to be essential for the maintenance of mtDNA copy number. Mutation screening of RRM2B revealed a heterozygous nonsense mutation in exon 9 (c.979C -> T [p.R327X]) in all affected individuals that was absent in 380 control chromosomes. The same mutation was found to segregate in another adPEO family. The mutant mRNA escaped nonsense-mediated decay and resulted in a protein with truncation of 25 highly conserved C-terminal amino acids essential for the interaction with the ribonucleotide reductase subunit R1. We conclude that dominant-negative or gain-of-function mutations in RRM2B are a cause of multiple mtDNA deletions and adPEO.