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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome
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Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome

机译:线粒体组氨酸tRNA合成酶HARS2的突变导致Perrault综合征的卵巢发育不全和感觉神经性听力丧失

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摘要

Perrault syndrome is a genetically heterogeneous recessive disorder characterized by ovarian dysgenesis and sensorineural hearing loss. In a nonconsanguineous family with five affected siblings, linkage analysis and genomic sequencing revealed the genetic basis of Perrault syndrome to be compound heterozygosity for mutations in the mitochondrial histidyl tRNA synthetase HARS2 at two highly conserved amino acids, L200V and V368L. The nucleotide substitution creating HARS2 p.L200V also created an alternate splice leading to deletion of 12 codons from the HARS2 message. Affected family members thus carried three mutant HARS2 transcripts. Aminoacy-lation activity of HARS2 p.V368L and HARS2 p.L200V was reduced and the deletion mutant was not stably expressed in mammalian mitochondria. In yeast, lethality of deletion of the single essential histydyl tRNA synthetase HTS1 was fully rescued by wild-type HTS1 and by HTS1 p.L198V (orthologous to HARS2 p.L200V), partially rescued by HTS1 p.V381L (orthologous to HARS2 p.V368L), and not rescued by the deletion mutant. In Caenorhabditis elegans, reduced expression by RNAi of the single essential histydyl tRNA synthetase bars-1 severely compromised fertility. Together, these data suggest that Perrault syndrome in this family was caused by reduction of HARS2 activity. These results implicate aberrations of mitochondrial translation in mammalian gonadal dysgenesis. More generally, the relationship between HARS2 and Perrault syndrome illustrates how causality may be demonstrated for extremely rare inherited mutations in essential, highly conserved genes.
机译:Perrault综合征是一种遗传异质性隐性疾病,其特征是卵巢发育不全和感觉神经性听力丧失。在一个有五个受影响兄弟姐妹的非近亲家庭中,连锁分析和基因组测序揭示了Perrault综合征的遗传基础是线粒体组氨酸tRNA合成酶HARS2中两个高度保守的氨基酸L200V和V368L突变的复合杂合性。产生HARS2 p.L200V的核苷酸取代还产生了一个替代剪接,导致HARS2信息中缺失了12个密码子。因此,受影响的家庭成员携带了三个突变的HARS2转录本。 HARS2 p.V368L和HARS2 p.L200V的氨基化活性降低,缺失突变体在哺乳动物线粒体中不稳定表达。在酵母中,野生型HTS1和HTS1 p.L198V(与HARS2 p.L200V同源)可完全挽救单个必不可少的组氨酸tRNA合成酶HTS1的致死性,而HTS1 p.V381L(与HARS2 p同源)可部分挽救致命的缺失。 V368L),并且不能通过缺失突变体挽救。在秀丽隐杆线虫中,RNAi对单个必需的组氨酸tRNA合成酶bars-1的表达降低严重影响了生育能力。总之,这些数据表明该家族中的Perrault综合征是由HARS2活性降低引起的。这些结果暗示了哺乳动物性腺发育不全中线粒体翻译的异常。更笼统地说,HARS2和Perrault综合征之间的关系说明了如何证明基本,高度保守基因中极为罕见的遗传突变的因果关系。

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    Departments of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195,Departments of Genome Sciences, University of Washington, Seattle, WA 98195;

    Departments of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195,Departments of Genome Sciences, University of Washington, Seattle, WA 98195;

    Departments of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195,Departments of Genome Sciences, University of Washington, Seattle, WA 98195;

    Departments of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195,Departments of Genome Sciences, University of Washington, Seattle, WA 98195;

    Departments of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195,Departments of Genome Sciences, University of Washington, Seattle, WA 98195;

    Department of Pediatrics (Medical Genetics), University of Utah, Salt Lake City, UT 84132;

    Departments of Biological Structure, University of Washington, Seattle, WA 98195;

    Departments of Biochemistry, University of Washington, Seattle, WA 98195;

    Departments of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195,Departments of Genome Sciences, University of Washington, Seattle, WA 98195;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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