Childhood-onset hypomyelinating leukodystrophy and the multi-tRNA synthetase complex

儿童期发病的低髓鞘性脑白质营养不良和多 tRNA 合成酶复合物

基本信息

  • 批准号:
    10582441
  • 负责人:
  • 金额:
    $ 62.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-15 至 2027-11-30
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Child-onset hypomyelinating leukodystrophy (HLD) is a genetically heterogeneous group of neurodegenerative diseases characterized by reduced cerebral myelin formation. Clinical features include cognitive as well as motor impairment appearing in childhood. There are no curative treatments. Our collaborator, Dr. Grace Yoon, evaluated two siblings presenting with severe neurological deficit and a shared phenotype consisting of global developmental delay and intellectual disability, prenatal onset undergrowth and microcephaly, rotatory nystagmus, ataxia and progressive gait disturbance/spasticity, and hypomyelination on brain MRI. Whole exome sequencing revealed homozygosity of a c.4444C>A mutation in the EPRS1 gene. The mutation is in the coding sequence (cds) of the gene causing a Pro-to-Thr point mutation at aa position 1482. The EPRS1 gene encodes the bifunctional, glutamyl-prolyl tRNA synthetase (EPRS1) that resides in the cytoplasmic multi- tRNA synthetase complex (MSC). The P1482T mutation is located near the C-terminus of the protein in a region of the Pro synthetase outside the catalytic or anti-codon recognition domains. The specific activity of recombinant P1482T mutant EPRS1 is indistinguishable from wild-type. In contrast, EPRS1 protein expression in immortalized lymphoblastoid cell lines (LCL) from affected siblings is about 20% of that in unaffected controls. EPRS1 mRNA levels are identical in siblings and controls indicating post-transcriptional regulation. Our preliminary studies show a dual mechanism determining diminished EPRS1 level in affected LCLs, namely, decreased nuclear export of mutant mRNA, followed by decreased cytoplasmic translation. We show that decreased EPRS1 expression causes release of other MSC constituents. Remarkably, suppression of several other MSC components causally implicated in HLD also induce MSC constituent release, suggesting a common etiology of an entire class of HLDs. We hypothesize that inefficient nuclear export and translation of c.4444C>A EPRS1 mRNA reduces MSC-bound EPRS1, causing release of MSC constituents and driving the HLD phenotype. Likewise, defects in genes encoding other MSC constituents share a common pathway and etiology of HLD. We will test this hypothesis by pursuing these Specific Aims: In Aim 1 we will elucidate molecular mechanisms underlying reduced expression of EPRS1P1482T variant, focusing on the role of m6A methylation. Aim 2 determines the HLD-related phenotype of our newly generated, genetically-modified Eprs1P1482T mice. In Aim 3 we will investigate effect of deficiency of MSC constituents on MSC integrity and adverse consequences in myelinating oligodendrocytes. A CNS-specific transcriptomic analysis will be done by single-nucleus RNA-sequencing. Completion of these studies will elucidate a unique mechanism of gene dysregulation that induces HLD, and will provide a unique mouse model of HLD that will permit detailed in vivo analysis of the cellular defects in HLD. Importantly, these results suggest the possibility of specific, RNA-based therapeutic intervention to rescue translation of the variant EPRS1 mRNA and rescue the neurologic defect.
项目总结/文摘

项目成果

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Ranjan Dutta其他文献

Ranjan Dutta的其他文献

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{{ truncateString('Ranjan Dutta', 18)}}的其他基金

Molecular correlates of sub-regional thalamic degeneration in multiple sclerosis
多发性硬化症亚区域丘脑变性的分子相关性
  • 批准号:
    10449474
  • 财政年份:
    2022
  • 资助金额:
    $ 62.66万
  • 项目类别:
Understanding role of circadian disruption in pathogenesis of MS
了解昼夜节律紊乱在多发性硬化症发病机制中的作用
  • 批准号:
    10442857
  • 财政年份:
    2022
  • 资助金额:
    $ 62.66万
  • 项目类别:
Molecular correlates of sub-regional thalamic degeneration in multiple sclerosis
多发性硬化症亚区域丘脑变性的分子相关性
  • 批准号:
    10553206
  • 财政年份:
    2022
  • 资助金额:
    $ 62.66万
  • 项目类别:
Understanding role of circadian disruption in pathogenesis of MS
了解昼夜节律紊乱在多发性硬化症发病机制中的作用
  • 批准号:
    10574570
  • 财政年份:
    2022
  • 资助金额:
    $ 62.66万
  • 项目类别:
MicroRNAs as critical regulators of remyelination in Multiple Sclerosis
MicroRNA 作为多发性硬化症髓鞘再生的关键调节因子
  • 批准号:
    9272452
  • 财政年份:
    2016
  • 资助金额:
    $ 62.66万
  • 项目类别:

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