SUMMARY:
Mutant SerRS proteins are known to impact various molecular and cellular functions.
TITLE:
Heterozygous Seryl-tRNA synthetase 1 variants cause Charcot-Marie-Tooth disease
DESCRIPTION:
OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding Seryl-tRNA synthetase 1 (SerRS) for three families affected with CMT.
CONTENT:
Ann Neurol. 2022 Sep 11. doi: 10.1002/ana.26501. Online ahead of print.
ABSTRACT
OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding Seryl-tRNA synthetase 1 (SerRS) for three families affected with CMT.
METHODS: Whole-exome sequencing was performed in 16 patients and 14 unaffected members of three unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays.
RESULTS: Combined linkage analysis for the three families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the three families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation.
INTERPRETATION: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. This article is protected by copyright. All rights reserved.
PMID:36088542 | DOI:10.1002/ana.26501
SOURCE:
Annals of neurology
TAGS:
Mutant SerRS
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2022-09-11T07:23:42Z
DATE – DOI: 2022-09-11T07:23:42Z
DATE – PUBMED: 2022 Sep 11
DATE OUTPUT MATCHED: True
DATE – ADDED:
Sun, 11 Sep 2022 06:00:00 -0400
DATE – RETRIEVED:
09/11/22 07:01AM
2022-09-11T07:01:41-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:36088542,doi:10.1002/ana.26501
PUBMED ID:
pubmed:36088542
DOI:
10.1002/ana.26501
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36088542/
LINK – DOI:
https://doi.org/10.1002/ana.26501
LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/ana.26501
REFERENCES:
CMT Treatment Report, Urgent Research, 2022-09-11T07:01:41-04:00, https://www.cmttreatmentreport.com.