Publications by authors named "Elizabeth A Burke"

3 Publications

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A novel frameshift mutation in SOX10 causes Waardenburg syndrome with peripheral demyelinating neuropathy, visual impairment and the absence of Hirschsprung disease.

Am J Med Genet A 2020 05 9;182(5):1278-1283. Epub 2020 Mar 9.

NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

Waardenburg syndrome (WS) is a group of genetic disorders associated with varying components of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and eyes. There exist four different WS subtypes, each defined by the absence or presence of additional features. One of the genes associated with WS is SOX10, a key transcription factor for the development of neural crest-derived lineages. Here we report a 12-year-old boy with a novel de novo SOX10 frameshift mutation and unique combination of clinical features including primary peripheral demyelinating neuropathy, hearing loss and visual impairment but absence of Hirschsprung disease and the typical pigmentary changes of hair or skin. This expands the spectrum of currently recognized phenotypes associated with WS and illustrates the phenotypic heterogeneity of SOX10-associated WS.
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May 2020

HO oxidation of cysteine residues in c-Jun N-terminal kinase 2 (JNK2) contributes to redox regulation in human articular chondrocytes.

J Biol Chem 2018 10 6;293(42):16376-16389. Epub 2018 Sep 6.

Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina 27599

Reactive oxygen species (ROS), in particular HO, regulate intracellular signaling through reversible oxidation of reactive protein thiols present in a number of kinases and phosphatases. HO has been shown to regulate mitogen-activated protein kinase (MAPK) signaling depending on the cellular context. We report here that in human articular chondrocytes, the MAPK family member c-Jun N-terminal kinase 2 (JNK2) is activated by fibronectin fragments and low physiological levels of HO and inhibited by oxidation due to elevated levels of HO The kinase activity of affinity-purified, phosphorylated JNK2 from cultured chondrocytes was reversibly inhibited by 5-20 μm HO Using dimedone-based chemical probes that react specifically with sulfenylated cysteines (RSOH), we identified Cys-222 in JNK2, a residue not conserved in JNK1 or JNK3, as a redox-reactive site. MS analysis of human recombinant JNK2 also detected further oxidation at Cys-222 and other cysteines to sulfinic (RSOH) or sulfonic (RSOH) acid. HO treatment of JNK2 resulted in detectable levels of peptides containing intramolecular disulfides between Cys-222 and either Cys-213 or Cys-177, without evidence of dimer formation. Substitution of Cys-222 to alanine rendered JNK2 insensitive to HO inhibition, unlike C177A and C213A variants. Two other JNK2 variants, C116A and C163A, were also resistant to oxidative inhibition. Cumulatively, these findings indicate differential regulation of JNK2 signaling dependent on HO levels and point to key cysteine residues regulating JNK2 activity. As levels of intracellular HO rise, a switch occurs from activation to inhibition of JNK2 activity, linking JNK2 regulation to the redox status of the cell.
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October 2018

Cysteine-Mediated Redox Regulation of Cell Signaling in Chondrocytes Stimulated With Fibronectin Fragments.

Arthritis Rheumatol 2016 Jan;68(1):117-26

University of North Carolina School of Medicine, Chapel Hill.

Objective: Oxidative posttranslational modifications of intracellular proteins can potentially regulate signaling pathways relevant to cartilage destruction in arthritis. In this study, oxidation of cysteine residues to form sulfenic acid (S-sulfenylation) was examined in osteoarthritic (OA) chondrocytes and investigated in normal chondrocytes as a mechanism by which fragments of fibronectin (FN-f) stimulate chondrocyte catabolic signaling.

Methods: Chondrocytes isolated from OA and normal human articular cartilage were analyzed using analogs of dimedone that specifically and irreversibly react with protein S-sulfenylated cysteines. Global S-sulfenylation was measured in cell lysates with and without FN-f stimulation by immunoblotting and in fixed cells by confocal microscopy. S-sulfenylation in specific proteins was identified by mass spectroscopy and confirmed by immunoblotting. Src activity was measured in live cells using a fluorescence resonance energy transfer biosensor.

Results: Proteins in chondrocytes isolated from OA cartilage were found to have elevated basal levels of S-sulfenylation relative to those of chondrocytes from normal cartilage. Treatment of normal chondrocytes with FN-f induced increased levels of S-sulfenylation in multiple proteins, including the tyrosine kinase Src. FN-f treatment also increased the levels of Src activity. Pretreatment with dimedone to alter S-sulfenylation function or with Src kinase inhibitors inhibited FN-f-induced production of matrix metalloproteinase 13.

Conclusion: These results demonstrate for the first time the presence of oxidative posttranslational modification of proteins in human articular chondrocytes by S-sulfenylation. Due to the ability to regulate the activity of a number of cell signaling pathways, including catabolic mediators induced by fibronectin fragments, S-sulfenylation may contribute to cartilage destruction in OA and warrants further investigation.
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January 2016