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      Genetic disorders coupled to ROS deficiency

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          Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. Disturbances such as continuously elevated ROS levels will result in oxidative stress and development of disease, but likewise, insufficient ROS production will be detrimental to health. Reduced or even complete loss of ROS generation originates mainly from inactivating variants in genes encoding for NADPH oxidase complexes. In particular, deficiency in phagocyte Nox2 oxidase function due to genetic variants ( CYBB, CYBA, NCF1, NCF2, NCF4) has been recognized as a direct cause of chronic granulomatous disease (CGD), an inherited immune disorder. More recently, additional diseases have been linked to functionally altered variants in genes encoding for other NADPH oxidases, such as for DUOX2/ DUOXA2 in congenital hypothyroidism, or for the Nox2 complex, NOX1 and DUOX2 as risk factors for inflammatory bowel disease. A comprehensive overview of novel developments in terms of Nox/Duox-deficiency disorders is presented, combined with insights gained from structure–function studies that will aid in predicting functional defects of clinical variants.

          Graphical abstract


          • Deficiency in reactive oxygen species is often caused by NADPH oxidase variants.

          • Overview of chronic granulomatous disease and alterations in the Nox2 complex.

          • CGD iPS cells as promising novel tools.

          • Risk for inflammatory bowel disease by Nox2 complex, Nox1 and Duox2 mutations.

          • Loss-of-function variants in DUOX2 and DUOXA2 trigger congenital hypothyroidism.

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          Inflammatory bowel disease.

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            Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression.

            Superoxide dismutases are an ubiquitous family of enzymes that function to efficiently catalyze the dismutation of superoxide anions. Three unique and highly compartmentalized mammalian superoxide dismutases have been biochemically and molecularly characterized to date. SOD1, or CuZn-SOD (EC, was the first enzyme to be characterized and is a copper and zinc-containing homodimer that is found almost exclusively in intracellular cytoplasmic spaces. SOD2, or Mn-SOD (EC, exists as a tetramer and is initially synthesized containing a leader peptide, which targets this manganese-containing enzyme exclusively to the mitochondrial spaces. SOD3, or EC-SOD (EC, is the most recently characterized SOD, exists as a copper and zinc-containing tetramer, and is synthesized containing a signal peptide that directs this enzyme exclusively to extracellular spaces. What role(s) these SODs play in both normal and disease states is only slowly beginning to be understood. A molecular understanding of each of these genes has proven useful toward the deciphering of their biological roles. For example, a variety of single amino acid mutations in SOD1 have been linked to familial amyotrophic lateral sclerosis. Knocking out the SOD2 gene in mice results in a lethal cardiomyopathy. A single amino acid mutation in human SOD3 is associated with 10 to 30-fold increases in serum SOD3 levels. As more information is obtained, further insights will be gained.
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              Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system.

              The NADPH oxidase (Nox) enzymes are critical mediators of cardiovascular physiology and pathophysiology. These proteins are expressed in virtually all cardiovascular cells, and regulate such diverse functions as differentiation, proliferation, apoptosis, senescence, inflammatory responses and oxygen sensing. They target a number of important signaling molecules, including kinases, phosphatases, transcription factors, ion channels, and proteins that regulate the cytoskeleton. Nox enzymes have been implicated in many different cardiovascular pathologies: atherosclerosis, hypertension, cardiac hypertrophy and remodeling, angiogenesis and collateral formation, stroke, and heart failure. In this review, we discuss in detail the biochemistry of Nox enzymes expressed in the cardiovascular system (Nox1, 2, 4, and 5), their roles in cardiovascular cell biology, and their contributions to disease development.

                Author and article information

                Redox Biol
                Redox Biol
                Redox Biology
                17 July 2015
                December 2015
                17 July 2015
                : 6
                : 135-156
                [a ]Conway Institute, University College Dublin, Dublin, Ireland
                [b ]Université Grenoble Alpes, TIMC-IMAG Pôle Biologie, CHU de Grenoble, Grenoble, France
                [c ]CGD Diagnosis and Research Centre, Pôle Biologie, CHU de Grenoble, Grenoble, France
                Author notes
                [* ]Correspondence to: Conway Institute, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland. ulla.knaus@ 123456ucd.ie
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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