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      Clinical and molecular characterization of three patients with Hepatocerebral form of mitochondrial DNA depletion syndrome: a case series

      case-report

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          Abstract

          Background

          Mitochondrial DNA depletion syndromes (MDS) are clinically and phenotypically heterogeneous disorders resulting from nuclear gene mutations. The affected individuals represent a notable reduction in mitochondrial DNA (mtDNA) content, which leads to malfunction of the components of the respiratory chain. MDS is classified according to the type of affected tissue; the most common type is hepatocerebral form, which is attributed to mutations in nuclear genes such as DGUOK and MPV17. These two genes encode mitochondrial proteins and play major roles in mtDNA synthesis.

          Case presentation

          In this investigation patients in three families affected by hepatocerebral form of MDS who were initially diagnosed with tyrosinemia underwent full clinical evaluation. Furthermore, the causative mutations were identified using next generation sequencing and were subsequently validated using sanger sequencing. The effect of the mutations on the gene expression was also studied using real-time PCR. A pathogenic heterozygous frameshift deletion mutation in DGUOK gene was identified in parents of two affected patients (c.706–707 + 2 del: p.k236 fs) presenting with jaundice, impaired fetal growth, low-birth weight, and failure to thrive who died at the age of 3 and 6 months in family I. Moreover, a novel splice site mutation in MPV17 gene (c.461 + 1G > C) was identified in a patient with jaundice, muscle weakness, and failure to thrive who died due to hepatic failure at the age of 4 months. A 5-month-old infant presenting with jaundice, dark urine, poor sucking, and feeding problems was also identified to have another novel mutation in MPV17 gene leading to stop gain mutation (c.277C > T: p.(Gln93*)).

          Conclusions

          These patients had overlapping clinical features with tyrosinemia. MDS should be considered a differential diagnosis in patients presenting with signs and symptoms of tyrosinemia.

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          Most cited references28

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          Mitochondrial diseases in man and mouse.

          Over the past 10 years, mitochondrial defects have been implicated in a wide variety of degenerative diseases, aging, and cancer. Studies on patients with these diseases have revealed much about the complexities of mitochondrial genetics, which involves an interplay between mutations in the mitochondrial and nuclear genomes. However, the pathophysiology of mitochondrial diseases has remained perplexing. The essential role of mitochondrial oxidative phosphorylation in cellular energy production, the generation of reactive oxygen species, and the initiation of apoptosis has suggested a number of novel mechanisms for mitochondrial pathology. The importance and interrelationship of these functions are now being studied in mouse models of mitochondrial disease.
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            COFACTOR: improved protein function prediction by combining structure, sequence and protein–protein interaction information

            Abstract The COFACTOR web server is a unified platform for structure-based multiple-level protein function predictions. By structurally threading low-resolution structural models through the BioLiP library, the COFACTOR server infers three categories of protein functions including gene ontology, enzyme commission and ligand-binding sites from various analogous and homologous function templates. Here, we report recent improvements of the COFACTOR server in the development of new pipelines to infer functional insights from sequence profile alignments and protein–protein interaction networks. Large-scale benchmark tests show that the new hybrid COFACTOR approach significantly improves the function annotation accuracy of the former structure-based pipeline and other state-of-the-art functional annotation methods, particularly for targets that have no close homology templates. The updated COFACTOR server and the template libraries are available at http://zhanglab.ccmb.med.umich.edu/COFACTOR/.
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              Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options.

              Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and C10orf2). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. Myopathic MDS, caused by mutations in TK2, usually present before the age of 2 years with hypotonia and muscle weakness. Encephalomyopathic MDS, caused by mutations in SUCLA2, SUCLG1, or RRM2B, typically present during infancy with hypotonia and pronounced neurological features. Hepatocerebral MDS, caused by mutations in DGUOK, MPV17, POLG, or C10orf2, commonly have an early-onset liver dysfunction and neurological involvement. Finally, TYMP mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. Nutritional modulation and cofactor supplementation may be beneficial. Liver transplantation remains controversial. Finally, stem cell transplantation in MNGIE disease shows promising results.
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                Author and article information

                Contributors
                Dastgheib@sums.ac.ir
                Journal
                BMC Med Genet
                BMC Med. Genet
                BMC Medical Genetics
                BioMed Central (London )
                1471-2350
                29 October 2019
                29 October 2019
                2019
                : 20
                : 167
                Affiliations
                [1 ]ISNI 0000 0000 8819 4698, GRID grid.412571.4, Persian BayanGene Research and Training Center, , Shiraz University of Medical Sciences, ; Shiraz, Iran
                [2 ]ISNI 0000 0000 8819 4698, GRID grid.412571.4, Student Research Committee, , Shiraz University of Medical Sciences, ; Shiraz, Iran
                [3 ]ISNI 0000 0001 2336 6580, GRID grid.7605.4, Italian Institute for Genomic Medicine (IIGM), , University of Turin, ; Turin, Italy
                [4 ]ISNI 0000 0000 8819 4698, GRID grid.412571.4, Department of Pediatrics, , Shiraz University of Medical Sciences, ; Shiraz, Iran
                [5 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, , University of Miami Miller School of Medicine, ; Miami, USA
                [6 ]ISNI 0000 0000 8819 4698, GRID grid.412571.4, Department of Medical Genetics, School of Medicine, , Shiraz University of Medical Sciences, ; Shiraz, Iran
                Author information
                http://orcid.org/0000-0003-4781-301X
                Article
                893
                10.1186/s12881-019-0893-9
                6819644
                31664948
                bcce0eaf-eaa9-4383-bc05-390138be2973
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 May 2019
                : 10 September 2019
                Funding
                Funded by: NIMAD
                Award ID: 940714
                Award Recipient :
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2019

                Genetics
                mitochondrial dna depletion syndrome,dguok,mpv17,mitochondrial disorders
                Genetics
                mitochondrial dna depletion syndrome, dguok, mpv17, mitochondrial disorders

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