2
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Whole-exome sequencing reveals a novel mutation of MT-ND5 gene in a mitochondrial cardiomyopathy pedigree: Patients who show biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective:

          The aim of the present study was to determine whether pathogenic mutations were present in families with mitochondrial cardiomyopathy that presented during adolescence.

          Methods:

          The proband was a 21-year-old man who presented clinically with palpitations, chest tightness, pulmonary hypertension, and limited exercise tolerance. Cardiac magnetic resonance imaging studies showed biventricular cardiac hypertrophy. We determine whether pathogenic mutations were present by whole-exome sequencing (WES) in families.

          Results:

          Screening of the family using tandem mass spectrometry showed elevated lactic acid levels, glutaric aciduria, a mildly increased glutarylcarnitine-to-octanoylcarnitine ratio, and normal blood α-glucosidase, which was consistent with a respiratory chain complex 1 metabolic disorder. We identified a novel mutation of MT-ND5, c.1315A>G (p.Thr439Ala). Skeletal muscle biopsy histology showed predominantly ragged red fibers and few ragged blue fibers, which was consistent with mitochondrial myopathy.

          Conclusion:

          In the present study, we identified a novel mutation of MT-ND5, c.1315A>G (p.Thr439Ala), in a family pedigree using WES.

          Related collections

          Most cited references20

          • Record: found
          • Abstract: found
          • Article: not found

          Bovine complex I is a complex of 45 different subunits.

          Mammalian mitochondrial complex I is a multisubunit membrane-bound assembly with a molecular mass approaching 1 MDa. By comprehensive analyses of the bovine complex and its constituent subcomplexes, 45 different subunits have been characterized previously. The presence of a 46th subunit was suspected from the consistent detection of a molecular mass of 10,566 by electrospray ionization mass spectrometry of subunits fractionated by reverse-phase high pressure liquid chromatography. The component was found associated with both the intact complex and subcomplex Ibeta, which represents most of the membrane arm of the complex, and it could not be resolved chromatographically from subunit SGDH (the subunit of bovine complex I with the N-terminal sequence Ser-Gly-Asp-His). It has now been characterized by tandem mass spectrometry of intact protein ions and shown to be a C-terminal fragment of subunit SGDH arising from a specific peptide bond cleavage between Ile-55 and Pro-56 during the electrospray ionization process. Thus, the subunit composition of bovine complex I has been established. It is a complex of 45 different proteins plus non-covalently bound FMN and eight iron-sulfur clusters.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Opportunities and challenges of whole-genome and -exome sequencing

            Recent advances in the development of sequencing technologies provide researchers with unprecedented possibilities for genetic analyses. In this review, we will discuss the history of genetic studies and the progress driven by next-generation sequencing (NGS), using complex inflammatory bowel diseases as an example. We focus on the opportunities, but also challenges that researchers are facing when working with NGS data to unravel the genetic causes underlying diseases.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy.

              Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM.
                Bookmark

                Author and article information

                Journal
                Anatol J Cardiol
                Anatol J Cardiol
                Anatolian Journal of Cardiology
                Kare Publishing (Turkey )
                2149-2263
                2149-2271
                January 2019
                18 December 2018
                : 21
                : 1
                : 18-24
                Affiliations
                [1]Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Disease, Shanghai Institute of Medical Imaging; Shanghai- China
                [* ]Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Disease, Shanghai Institute of Medical Imaging; Shanghai- China
                Author notes
                Address for correspondence: Xianhong Shu, MD, Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Disease, Shanghai Institute of Medical Imaging; Shanghai- China E-mail: shu.xianhong@ 123456zs-hospital.sh.cn
                Article
                AJC-21-18
                10.14744/AnatolJCardiol.2018.53258
                6382902
                30587702
                90f8c174-dda3-4614-9993-62bb9ef37fb3
                Copyright: © 2018 Turkish Society of Cardiology

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

                History
                : 07 September 2018
                Categories
                Original Investigation

                mt-nd5,whole-exome sequencing,cardiomyopathy,pulmonary hypertension

                Comments

                Comment on this article