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      Novel recessive mutations in COQ4 cause severe infantile cardiomyopathy and encephalopathy associated with CoQ 10 deficiency

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          Abstract

          Coenzyme Q 10 (CoQ 10) or ubiquinone is one of the two electron carriers in the mitochondrial respiratory chain which has an essential role in the process of oxidative phosphorylation. Defects in CoQ 10 synthesis are usually associated with the impaired function of CoQ 10–dependent complexes I, II and III. The recessively transmitted CoQ 10 deficiency has been associated with a number of phenotypically and genetically heterogeneous groups of disorders manifesting at variable age of onset. The infantile, multisystemic presentation is usually caused by mutations in genes directly involved in CoQ 10 biosynthesis. To date, mutations in COQ1 ( PDSS1 and PDSS2), COQ2, COQ4, COQ6, COQ7, COQ8A/ ADCK3, COQ8B/ADCK4, and COQ9 genes have been identified in patients with primary form of CoQ 10 deficiency. Here we report novel mutations in the COQ4 gene, which were identified in an infant with profound mitochondrial disease presenting with perinatal seizures, hypertrophic cardiomyopathy and severe muscle CoQ 10 deficiency.

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          Most cited references30

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          COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.

          Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of end-stage renal failure. Identification of single-gene causes of SRNS has generated some insights into its pathogenesis; however, additional genes and disease mechanisms remain obscure, and SRNS continues to be treatment refractory. Here we have identified 6 different mutations in coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping. Each mutation was linked to early-onset SRNS with sensorineural deafness. The deleterious effects of these human COQ6 mutations were validated by their lack of complementation in coq6-deficient yeast. Furthermore, knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q10 treatment. In rats, COQ6 was located within cell processes and the Golgi apparatus of renal glomerular podocytes and in stria vascularis cells of the inner ear, consistent with an oto-renal disease phenotype. These data suggest that coenzyme Q10-related forms of SRNS and hearing loss can be molecularly identified and potentially treated.
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            COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement.

            Primary coenzyme Q(10) (CoQ(10)) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ(10) synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [II+III] and decreased CoQ(10) concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.
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              Metabolism and function of coenzyme Q.

              Coenzyme Q (CoQ) is present in all cells and membranes and in addition to be a member of the mitochondrial respiratory chain it has also several other functions of great importance for the cellular metabolism. This review summarizes the findings available to day concerning CoQ distribution, biosynthesis, regulatory modifications and its participation in cellular metabolism. There are a number of indications that this lipid is not always functioning by its direct presence at the site of action but also using e.g. receptor expression modifications, signal transduction mechanisms and action through its metabolites. The biosynthesis of CoQ is studied in great detail in bacteria and yeast but only to a limited extent in animal tissues and therefore the informations available is restricted. However, it is known that the CoQ is compartmentalized in the cell with multiple sites of biosynthesis, breakdown and regulation which is the basis of functional specialization. Some regulatory mechanisms concerning amount and biosynthesis are established and nuclear transcription factors are partly identified in this process. Using appropriate ligands of nuclear receptors the biosynthetic rate can be increased in experimental system which raises the possibility of drug-induced upregulation of the lipid in deficiency. During aging and pathophysiological conditions the tissue concentration of CoQ is modified which influences cellular functions. In this case the extent of disturbances is dependent on the localization and the modified distribution of the lipid at cellular and membrane levels.
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                Author and article information

                Contributors
                Journal
                Mol Genet Metab Rep
                Mol Genet Metab Rep
                Molecular Genetics and Metabolism Reports
                Elsevier
                2214-4269
                11 May 2017
                September 2017
                11 May 2017
                : 12
                : 23-27
                Affiliations
                [a ]Division of Clinical and Biochemical Genetics, The Hospital for Sick Children, Canada
                [b ]Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada
                [c ]Division of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Medical Center, United States
                [d ]Department of Neurology, Columbia University Medical Center, United States
                Author notes
                [* ]Corresponding author at: 630 West 168th Street, P&S 17-401, New York, NY 10032, United States.630 West 168th Street, P&S 17-401New YorkNY10032United States abn2@ 123456cumc.columbia.edu
                Article
                S2214-4269(17)30036-8
                10.1016/j.ymgmr.2017.05.001
                5432661
                28540186
                ef942d23-bc6a-450f-afa8-cbf5bf785aff
                © 2017 Published by Elsevier Inc.

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

                History
                : 29 March 2017
                : 5 May 2017
                : 5 May 2017
                Categories
                Case Report

                coq10 deficiency,coq4,infantile cardiomyopathy,encephalomyopathy,whole exome sequencing

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