PXD023842

PXD023842 is an original dataset announced via ProteomeXchange.

Title	Clinical and molecular characteristics indicate mitochondrial dysfunction in Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation
Description	Introduction Aminoacyl tRNA-synthetases are ubiquitously expressed enzymes that attach amino acids to their cognate tRNA molecule. Mutations in several of the aminoacyl tRNA-syntheases are described to cause peripheral neuropathy, i.e. AARS1, GARS1, HARS1, YARS1 and WARS1. The Alanyl-tRNA Synthetase (AARS) is encoded by the AARS1. Bi-allelic mutations have been described responsible for epileptic encephalopathy with persistent myelination defect, while mutation in a single allele cause Charcot-Marie-Tooth disease type 2 (CMT2). Do date it is uncertain how a single AARS1 mutation cause tissue specific neuropathy. Methods The AARS1 was sequenced by next-generation sequencing in probands. Family members were examined by Sanger sequencing. Blood samples from affected and healthy controls were used for quantitative RNA analysis, biochemical analysis of alanine, and proteomics. Results Three Norwegian CMT2 families carried the same novel heterozygous AARS1 variant (NM_001605.2:c.976C>T p.(Arg326Trp)). The three families consisted of in total 17 genetically examined family members, of which 11 individuals carried the AARS1 variant and six unaffected individuals did not carry the variant. All individuals carrying the AARS1 variant presented with a mild to moderately severe CMT2 phenotype with adult onset, except a man age 91 years (reported by his son). Label-free quantitative proteomic analysis of four affected individuals pointed towards an effect on the immune system, comprising proteins known to represent components of systemic response to chronic injury and inflammation. Interestingly, a wide-spread impact on mitochondrial dysfunction was identified. Specifically, the oxidative phosphorylation complexes I, IV and V were highly downregulated. Conclusion Three Norwegian CMT2 families with an AARS1 variant, suggests mitochondrial dysfunction in AARS1 neuropathy.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:41:35.351.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tuula Nyman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-26 23:15:21	ID requested
1	2022-10-13 17:23:31	announced
⏵ 2	2023-11-14 07:41:37	announced	2023-11-14: Updated project metadata.

H, ø, yer H, Busk Ø L, Esbensen QY, R, ø, sby O, Hilmarsen HT, Russell MB, Nyman TA, Braathen GJ, Nilsen HL, Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation. BMC Neurol, 22(1):299(2022) [pubmed]

submitter keyword: proteomics,CMT2, mitochondrial dysfunction, peripheral neuropathy, AARS1

Tuula Nyman
contact affiliation	Head of Proteomics
contact email	tuula.nyman@medisin.uio.no
lab head
Tuula Nyman
contact affiliation	University of Oslo
contact email	tuula.nyman@medisin.uio.no
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023842
     1. Label: PRIDE project
     2. Name: Clinical and molecular characteristics indicate mitochondrial dysfunction in Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation