Multi-OMICS analyses unveil STAT1 as a potential modifier gene in mevalonate kinase deficiency

Annals of the Rheumatic Diseases
Raphael CarapitoSeiamak Bahram

Abstract

The objective of the present study was to explain why two siblings carrying both the same homozygous pathogenic mutation for the autoinflammatory disease hyper IgD syndrome, show opposite phenotypes, that is, the first being asymptomatic, the second presenting all classical characteristics of the disease. Where single omics (mainly exome) analysis fails to identify culprit genes/mutations in human complex diseases, multiomics analyses may provide solutions, although this has been seldom used in a clinical setting. Here we combine exome, transcriptome and proteome analyses to decipher at a molecular level, the phenotypic differences between the two siblings. This multiomics approach led to the identification of a single gene-STAT1-which harboured a rare missense variant and showed a significant overexpression of both mRNA and protein in the symptomatic versus the asymptomatic sister. This variant was shown to be of gain of function nature, involved in an increased activation of the Janus kinase/signal transducer and activator of transcription signalling (JAK/STAT) pathway, known to play a critical role in inflammatory diseases and for which specific biotherapies presently exist. Pathway analyses based on information from differe...Continue Reading

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Citations

Apr 30, 2020·Orphanet Journal of Rare Diseases·Katie KerrAmy Jayne McKnight
Jul 16, 2019·The Journal of Pediatrics·Lisa J Martin, D Woodrow Benson
Aug 4, 2020·Journal of Translational Autoimmunity·Achille MarinoRolando Cimaz
Apr 17, 2021·Expert Review of Proteomics·Daniela BraconiAnnalisa Santucci
May 1, 2021·Journal of Clinical Medicine·Guilaine BoursierIsabelle Touitou
Jul 3, 2021·International Journal of Molecular Sciences·Giulia Di DonatoFrancesco Chiarelli
Oct 15, 2021·Médecine sciences : M/S·Laurent MesserJean Sibilia

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Methods Mentioned

BETA
exome sequencing
density gradient centrifugation
RNA-Seq
exome
RNAseq
Assay
ELISA

Software Mentioned

limma
R
Proteome
IPA
GraphPad
Scaffold
Bioconductor R package DESeq
Lifescope
Mascot
GATK

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