دورية أكاديمية
أعرض في EDS

Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes.

التفاصيل البيبلوغرافية
العنوان: Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes.
المؤلفون: Dilliott AA; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.; Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada., Kwon S; The Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Rouleau GA; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.; Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada.; Department of Human Genetics, McGill University, Montreal, Quebec, Canada., Iqbal S; The Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA., Farhan SMK; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.; Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada.; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
المصدر: Brain : a journal of neurology [Brain] 2023 Nov 02; Vol. 146 (11), pp. 4608-4621.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Oxford University Press
Original Publication: London.
مواضيع طبية MeSH: Amyotrophic Lateral Sclerosis*/genetics, Humans ; Transcriptome/genetics ; Proteomics ; Mutation, Missense/genetics ; Genetic Testing
مستخلص: Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants, particularly missense variants, many of which are of unknown clinical significance. Here, we leverage the sequencing efforts of the ALS Knowledge Portal (3864 individuals with ALS and 7839 controls) and Project MinE ALS Sequencing Consortium (4366 individuals with ALS and 1832 controls) to perform proteomic and transcriptomic characterization of missense variants in 24 ALS-associated genes. The two sequencing datasets were interrogated for missense variants in the 24 genes, and variants were annotated with gnomAD minor allele frequencies, ClinVar pathogenicity classifications, protein sequence features including Uniprot functional site annotations, and PhosphoSitePlus post-translational modification site annotations, structural features from AlphaFold predicted monomeric 3D structures, and transcriptomic expression levels from Genotype-Tissue Expression. We then applied missense variant enrichment and gene-burden testing following binning of variation based on the selected proteomic and transcriptomic features to identify those most relevant to pathogenicity in ALS-associated genes. Using predicted human protein structures from AlphaFold, we determined that missense variants carried by individuals with ALS were significantly enriched in β-sheets and α-helices, as well as in core, buried or moderately buried regions. At the same time, we identified that hydrophobic amino acid residues, compositionally biased protein regions and regions of interest are predominantly enriched in missense variants carried by individuals with ALS. Assessment of expression level based on transcriptomics also revealed enrichment of variants of high and medium expression across all tissues and within the brain. We further explored enriched features of interest using burden analyses and identified individual genes were indeed driving certain enrichment signals. A case study is presented for SOD1 to demonstrate proof-of-concept of how enriched features may aid in defining variant pathogenicity. Our results present proteomic and transcriptomic features that are important indicators of missense variant pathogenicity in ALS and are distinct from features associated with neurodevelopmental disorders.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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معلومات مُعتمدة: Canada CIHR
فهرسة مساهمة: Keywords: amyotrophic lateral sclerosis; missense variants; protein features; transcriptomic features; variants of uncertain significance
تواريخ الأحداث: Date Created: 20230703 Date Completed: 20231109 Latest Revision: 20231110
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10629772
DOI: 10.1093/brain/awad224
PMID: 37394881
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2156
DOI:10.1093/brain/awad224