Fig. 1: Dysregulated immune signalling in fibroblasts of patients with MIRAS to viral PAMP mimetics.
From: Ancestral allele of DNA polymerase gamma modifies antiviral tolerance
a, The genotype–phenotype association of MIRAS POLG1 variant (rs113994097). Significance (P values) and disease categories are shown. The triangles indicate diseases or traits: upward-pointing triangles show a positive association, and vice versa. The dotted line shows the cut-off for significance. Analysis was performed using SAIGE mixed model logistic regression. Data are from ref. 6. b, POLG1 protein levels in patients with MIRAS (patient) and control fibroblasts. Western blot and quantification. The loading control was HSP60. Fibroblasts are from six patients and six control individuals, all female. c, Schematic of antiviral innate immune signalling responses to viral PAMPs. d, IFN-I signalling pathway genes induced by viral PAMP mimetics (dsRNA/poly(I:C) or dsDNA) in patient and control fibroblasts (as in b). Quantitative PCR (qPCR) analysis of cDNA. The reference gene was ACTB. Top, box plot. Bottom, heat map showing the average gene expression per condition. e, IFN-I signalling pathway protein induction by viral PAMP mimetic (dsRNA (poly(I:C)) or dsDNA) in patient and control (C) fibroblasts. Representative western blot analysis of four female control individuals and patients. The loading control was HSP60. Quantification is shown in Extended Data Fig. 2b. f, Paracrine immune signalling of fibroblasts in response to treatment with viral PAMP mimetic. Representative western blot of four female control individuals and patients (Pt). The loading control was HSP60. Quantification is shown in Extended Data Fig. 2e. g, mtDNA and mtRNA release into cytosolic extracts of fibroblasts (as in b; Extended Data Fig. 3e,f) after viral PAMP mimetic exposure for 7 h. Cytosolic versus whole-cell MT-CYB and MT-CO1 DNA or cDNA was analysed using qPCR. h,i, Immune signalling (h) and necroptosis activation (i) in fibroblasts (as in b) after prolonged viral PAMP mimetic treatment. Quantification of the western blot is shown for the indicated treatment times (Extended Data Fig. 3g,i). The loading control was β-actin. For b, d, g, h and i, the box plots show minimum to maximum values (whiskers), 25th to 75th percentiles (box limits) and median (centre line). Statistical analysis was performed using two-tailed unpaired Student’s t-tests. See also Extended Data Figs. 1–3 and Supplementary Table 1.
