Browsing by Author "Wallace, Douglas C."

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    Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation
    (National Academy of Science, 2022) Schaefer, Patrick M.; Scherer Alves, Leonardo; Lvova, Maria; Huang, Jessica; Rathi, Komal; Janssen, Kevin; Butic, Arrienne; Yardeni, Tal; Morrow, Ryan; Lott, Marie; Murdock, Deborah; Song, Angela; Keller, Kierstin; Garcia, Benjamin A.; Francomano, Clair A.; Wallace, Douglas C.; Medical and Molecular Genetics, School of Medicine
    Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.
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    ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer
    (bioRxiv, 2024-10-21) Stojanovic, Lora; Abbotts, Rachel; Tripathi, Kaushlendra; Coon, Collin M.; Rajendran, Saranya; Farid, Elnaz Abbasi; Hostetter, Galen; Guarnieri, Joseph W.; Wallace, Douglas C.; Liu, Sheng; Wan, Jun; Calendo, Gennaro; Marker, Rebecca; Gohari, Zahra; Inayatullah, Mohammed M. A.; Tiwari, Vijay K.; Kader, Tanjina; Santagata, Sandro; Drapkin, Ronny; Kommoss, Stefan; Pfisterer, Jacobus; Konecny, Gottfried E.; Coopergard, Ryan; Issa, Jean-Pierre; Winterhoff, Boris J. N.; Topper, Michael J.; Sandusky, George E.; Miller, Kathy D.; Baylin, Stephen B.; Nephew, Kenneth P.; Rassool, Feyruz V.; Medical and Molecular Genetics, School of Medicine
    DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR. In patient OC databases, high ZNFX1 expression levels correlate with advanced stage disease. ZNFX1 expression alone significantly correlates with an increase in overall survival in a phase 3 trial for therapy-resistant OC patients receiving bevacizumab in combination with chemotherapy. In correlative RNA-seq data, inflammasome signaling through ZNFX1 correlates with abnormal vasculogenesis. ZNFX1 controls PMR signaling through the mitochondria and may serve as a biomarker to facilitate offering personalized therapy in OC patients, highlighting the strong translational significance of our findings.