A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations

Rebecca Meyer-Schuman; Sheila Marte; Tyler J Smith; Shawna M E Feely; Marina Kennerson; Garth Nicholson; Mike E Shy; Kristin S Koutmou; Anthony Antonellis

doi:10.1093/hmg/ddad054

Back

A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations

Journal article

Open access

Peer reviewed

A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations

Rebecca Meyer-Schuman, Sheila Marte, Tyler J Smith, Shawna M E Feely, Marina Kennerson, Garth Nicholson, Mike E Shy, Kristin S Koutmou and Anthony Antonellis

Human molecular genetics, Vol.32(13), pp.2177-2191

06/19/2023

DOI: 10.1093/hmg/ddad054

PMCID: PMC10281750

PMID: 37010095

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281750View

Published (Version of record) Open Access

Abstract

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that ligate tRNA molecules to cognate amino acids. Heterozygosity for missense variants or small in-frame deletions in six ARS genes causes dominant axonal peripheral neuropathy. These pathogenic variants reduce enzyme activity without significantly decreasing protein levels and reside in genes encoding homo-dimeric enzymes. These observations raise the possibility that neuropathy-associated ARS variants exert a dominant-negative effect, reducing overall ARS activity below a threshold required for peripheral nerve function. To test such variants for dominant-negative properties, we developed a humanized yeast assay to co-express pathogenic human alanyl-tRNA synthetase (AARS1) mutations with wild-type human AARS1. We show that multiple loss-of-function AARS1 mutations impair yeast growth through an interaction with wild-type AARS1, but that reducing this interaction rescues yeast growth. This suggests that neuropathy-associated AARS1 variants exert a dominant-negative effect, which supports a common, loss-of-function mechanism for ARS-mediated dominant peripheral neuropathy.

Mutation

Alanine-tRNA Ligase - genetics

Amino Acyl-tRNA Synthetases - genetics

Humans

Peripheral Nerves - metabolism

Peripheral Nervous System Diseases - pathology

Details

Title: Subtitle: A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations
Creators: Rebecca Meyer-Schuman - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Sheila Marte - University of Michigan
Tyler J Smith - University of Michigan
Shawna M E Feely - University of Iowa
Marina Kennerson - Molecular Medicine Laboratory, Concord General Repatriation Hospital, Sydney, NSW 2139, Australia
Garth Nicholson - Molecular Medicine Laboratory, Concord General Repatriation Hospital, Sydney, NSW 2139, Australia
Mike E Shy - University of Iowa, Iowa Neuroscience Institute
Kristin S Koutmou - University of Michigan
Anthony Antonellis - Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.32(13), pp.2177-2191
DOI: 10.1093/hmg/ddad054
PMID: 37010095
PMCID: PMC10281750
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: R35 GM128836 / NIGMS NIH HHS T32 GM007544 / NIGMS NIH HHS F31 NS108510 / NINDS NIH HHS R35 GM136441 / NIGMS NIH HHS
Language: English
Date published: 06/19/2023
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984473217602771

Metrics

21 Record Views

8 Times Cited - Web of Science