Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:35971119", "kind": "science-record", "revision": 3, "content_hash": "sha256:06170938269ddc6a5272c1d09bbc20f9a2be26c84ccad468f5f036d0ff4933ef", "created_at": "2026-11-01T18:15:06Z", "updated_at": "2026-11-01T21:28:38Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation.", "doi": "10.1186/s12883-022-02828-6", "pmid": "35971119", "authors": ["Helle Høyer", "Øyvind L Busk", "Q Ying Esbensen", "Oddveig Røsby", "Hilde T Hilmarsen", "Michael B Russell", "Tuula A Nyman", "Geir J Braathen", "Hilde L Nilsen"], "journal": "BMC neurology", "year": 2022, "abstract": "BACKGROUND: Aminoacyl tRNA-synthetases are ubiquitously-expressed enzymes that attach amino acids to their cognate tRNA molecules. Mutations in several genes encoding aminoacyl tRNA-synthetases, have been associated with peripheral neuropathy, i.e. AARS1, GARS1, HARS1, YARS1 and WARS1. The pathogenic mechanism underlying AARS1-related neuropathy is not known.\nMETHODS: From 2012 onward, all probands presenting at Telemark Hospital (Skien, Norway) with peripheral neuropathy were screened for variants in AARS1 using an \"in-house\" next-generation sequencing panel. DNA from patient's family members was examined by Sanger sequencing. Blood from affected family members and healthy controls were used for quantification of AARS1 mRNA and alanine. Proteomic analyses were conducted in peripheral blood mononuclear cells (PBMC) from four affected family members and five healthy controls.\nRESULTS: Seventeen individuals in two Norwegian families affected by Charcot-Marie-Tooth disease (CMT) were characterized in this study. The heterozygous NM_001605.2:c.976C > T p.(Arg326Trp) AARS1 mutation was identified in ten affected family members. All living carriers had a mild to severe length-dependent sensorimotor neuropathy. Three deceased obligate carriers aged 74-98 were reported to be unaffected, but were not examined in the clinic. Proteomic studies in PBMC from four affected individuals suggest an effect on the immune system mediated by components of a systemic response to chronic injury and inflammation. Furthermore, altered expression of proteins linked to mitochondrial function/dysfunction was observed. Proteomic data are available via ProteomeXchange using identifier PXD023842.\nCONCLUSION: This study describes clinical and neurophysiological features linked to the p.(Arg326Trp) variant of AARS1 in CMT-affected members of two Norwegian families. Proteomic analyses based on of PBMC from four CMT-affected individuals suggest that involvement of inflammation and mitochondrial dysfunction might contribute to AARS1 variant-associated peripheral neuropathy.", "claims": [{"id": "claim-method", "statement": "Analysis of the proteome of four affected individuals compared to five healthy controls revealed a statistically significant difference for 457 proteins (t-test, q < 0.05 and p < 0.05) of which 247 were upregulated and 210 were downregulated (Fig. 3B and Additional file 2).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35971119", "locator": "sections[16] \"Proteomics results\" paragraph 3", "quote": "Analysis of the proteome of four affected individuals compared to five healthy controls revealed a statistically significant difference for 457 proteins (t-test, q < 0.05 and p < 0.05) of which 247 were upregulated and 210 were downregulated (Fig. 3B and Additional file 2)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets used and analysed during the current study are available in the Additional files or from the corresponding author on reasonable request. The AARS1 and ATL1 variants have been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), accession number SCV001571642 and SCV001571643 respectively. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (https://www.ebi.ac.uk/pride/) with the dataset identifier PXD023842 [56].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35971119", "locator": "sections[27] \"Availability of data and materials\" paragraph 2", "quote": "The datasets used and analysed during the current study are available in the Additional files or from the corresponding author on reasonable request. The AARS1 and ATL1 variants have been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), accession number SCV001571642 and SCV001571643 respectively. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (https://www.ebi.ac.uk/pride/) with the dataset identifier PXD023842 [56]."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Proteome analysis of PBMCs from four affected individuals and five healthy controls revealed a statistically significant difference for 457 proteins, of which 247 were upregulated and 210 were downregulated.", "kind": "quantitative", "target": {"value": 0.05, "unit": "p-value", "tolerance": null, "source": "Analysis of the proteome of four affected individuals compared to five healthy controls revealed a statistically significant difference for 457 proteins (t-test, q < 0.05 and p < 0.05) of which 247 were upregulated and 210 were downregulated (Fig. 3B and Additional file 2)."}, "evidence": [{"asset": "source:pmid:35971119", "locator": "sections[16] \"Proteomics results\" paragraph 3", "quote": "Analysis of the proteome of four affected individuals compared to five healthy controls revealed a statistically significant difference for 457 proteins (t-test, q < 0.05 and p < 0.05) of which 247 were upregulated and 210 were downregulated (Fig. 3B and Additional file 2)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Proteome analysis of PBMCs from four affected individuals and five healthy controls revealed a statistically significant difference for 457 proteins, of which 247 were upregulated and 210 were downregulated.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:35971119"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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