Expansion of the Allelic, Locus, and Clinical Heterogeneity of Aminoacyl-tRNA Synthetase-Associated Diseases Implicates Impaired Enzyme Function as the Pathogenic Mechanism

Aminoacyl-tRNA synthetases;Human disease;Charcot-Marie-Tooth disease;Genetics;Science;Cellular & Molec Biology PhD

Griffin, LaurieWeisman, Lois S ;

University of Michigan

关键词: Aminoacyl-tRNA synthetases;    Human disease;    Charcot-Marie-Tooth disease;    Genetics;    Science;    Cellular & Molec Biology PhD;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/143978/lbgriff_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes that charge tRNA with cognate amino acids, a critical step in protein translation. Mutations in multiple ARS family members have been implicated in dominant and recessive diseases, which span a broad spectrum of phenotypes, including multi-organ disease and tissue specific peripheral neuropathy. The allelic heterogeneity at these loci and the mechanism by which these mutations lead to disease are currently unknown. In this work we sought to: (1) expand the locus and allelic heterogeneity for ARS-mediated recessive and dominant disease;(2) functionally characterize the effects of disease-associated mutations on ARS activity; and (3) investigate the mechanism of pathogenesis in ARS-mediated peripheral neuropathy.Our studies have identified and/or characterized 30 mutations at six ARS loci. Importantly, we identified mutations in four ARS loci not previously associated with recessive phenotypes; provided the necessary genetic evidence to implicate histidyl-tRNA synthetase in inherited peripheral neuropathy; expanded the allelic heterogeneity of glycyl-, alanyl-, and tyrosyl-tRNA synthetase mutations in peripheral neuropathy; and excluded one previously disease-associated mutation (S581L glycyl-tRNA synthetase) in disease pathogenesis. Functional studies of ARS mutations demonstrate that impaired function is a common characteristic of disease-associated ARS mutations and that there is a direct correlation between the level of impaired ARS function and the occurrence of dominant or recessive phenotypes. These data indicate that reduced function is a component of pathogenesis in both recessive and dominant ARS-associated disease. To identify the precise loss-of-function mechanism involved in dominant ARS-mediated peripheral neuropathy, we performed studies to assess GARS variants for a dominant-negative effect and for altered protein interactions that may explain protein mislocalization. Initial results indicate differential interactions between wild-type and mutant GARS that have the potential to address both loss- and gain-of-function hypotheses in the field. Together, this dissertation expands the genetic and allelic heterogeneity in dominant and recessive ARS-associated disease, provides insight into the pathomechanism of ARS-mediated peripheral neuropathy, and has the potential to inform future attempts at therapeutic development.