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Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement

Kaiyrzhanov R 1 , Mohammed SEM 2 , Maroofian R 1 , Husain RA 3 , Catania A 4 , Torraco A 5 Show all authors , Alahmad A 6 , Dutra-Clarke M 7 , Grønborg S 8 , Sudarsanam A 9 , Vogt J 9 , Arrigoni F 10 , Baptista J 11 , Haider S 12 , Feichtinger RG 13 , Bernardi P 14 , Zulian A 14 , Gusic M 15 , Efthymiou S 1 , Bai R 16 , Bibi F 17 , Horga A 18 , Martinez-Agosto JA 19 , Lam A 20 , Manole A 1 , Rodriguez DP 21 , Durigon R 21 , Pyle A 22 , Albash B 23 , Dionisi-Vici C 24 , Murphy D 25 , Martinelli D 24 , Bugiardini E 1 , Allis K 16 , Lamperti C 4 , Reipert S 26 , Risom L 27 , Laugwitz L 28 , Di Nottia M 5 , McFarland R 29 , Vilarinho L 30 , Hanna M 1 , Prokisch H 31 , Mayr JA 13 , Bertini ES 5 , Ghezzi D 32 , Østergaard E 33 , Wortmann SB 34 , Carrozzo R 5 , Haack TB 35 , Taylor RW 29 , Spinazzola A 21 , Nowikovsky K 36 , Houlden H 37

Affiliations 

  • 1 Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK
  • 2 Department of Biomedical Sciences, Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine Vienna, Vienna 1210, Austria
  • 3 Department of Neuropediatrics, Jena University Hospital, Jena 07747, Germany; Center for Rare Diseases, Jena University Hospital, Jena 07747, Germany
  • 4 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20126, Italy
  • 5 Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy
  • 6 Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; Kuwait Medical Genetics Centre, Al-Sabah Medical Area 80901, Kuwait
  • 7 Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, the University of California at Los Angeles, Los Angeles, CA 90095, USA
  • 8 Center for Rare Diseases, Department of Pediatrics and Department of Genetics, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen 2100, Denmark
  • 9 West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham B15 2TG, UK
  • 10 Paediatric Radiology and Neuroradiology Department, V. Buzzi Children's Hospital, Milan 20154, Italy
  • 11 Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK
  • 12 Paediatrics Wah Medical College NUMS, Wah Cantonment, Punjab 44000, Pakistan
  • 13 University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg 5020, Austria
  • 14 Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, Padova 35131, Italy
  • 15 Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg 85764, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich 81675, Germany; Institute of Human Genetics, Technical University of Munich, Munich 81675, Germany
  • 16 GeneDx Inc, Gaithersburg, MD 20877, USA
  • 17 Institute of Biochemistry and Biotechnology, Pir Mehar Ali Shah Arid Agriculture University, Rawalpindi 44000, Pakistan
  • 18 Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK; Neuromuscular Diseases Unit, Department of Neurology, Hospital Clinico San Carlos and San Carlos Health Research Institute (IdISSC), Madrid 28040, Spain
  • 19 Department of Human Genetics, Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
  • 20 Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK; Department of Chemical Pathology, Great Ormond Street Hospital, WC1N 3BG London, UK
  • 21 Department of Clinical Movement Neurosciences, Royal Free Campus, University College of London, Queen Square Institute of Neurology, London WC1N 3BG, UK
  • 22 Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK
  • 23 Kuwait Medical Genetics Centre, Al-Sabah Medical Area 80901, Kuwait
  • 24 Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy
  • 25 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
  • 26 Core Facility of Cell Imaging and Ultrastructure Research, University of Vienna, Djerassiplatz 1, 1030 Wien, Austria
  • 27 Department of Genetics, Copenhagen University Hospital Rigshospitalet Blegdamsvej, Copenhagen 2100, Denmark
  • 28 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Tübingen 72076, Germany
  • 29 Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
  • 30 Unit of Neonatal Screening, Metabolism and Genetics, Department of Human Genetics, National Institute of Health Dr Ricardo Jorge, Porto 4000-055, Portugal
  • 31 Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg 85764, Germany; Institute of Human Genetics, Technical University of Munich, Munich 81675, Germany
  • 32 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20126, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
  • 33 Department of Genetics, Copenhagen University Hospital Rigshospitalet Blegdamsvej, Copenhagen 2100, Denmark; Institute for Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark
  • 34 University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg 5020, Austria; Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg 85764, Germany; Institute of Human Genetics, Technical University of Munich, Munich 81675, Germany; Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, Nijmegen 6525 EZ, the Netherlands
  • 35 Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Tübingen 72076, Germany; Centre for Rare Diseases, University of Tuebingen, Tübingen 72076, Germany
  • 36 Department of Biomedical Sciences, Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine Vienna, Vienna 1210, Austria; Department of Internal Medicine I, ASCTR and Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria. Electronic address: karin.nowikovsky@vetmeduni.ac.at
  • 37 Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK. Electronic address: h.houlden@ucl.ac.uk
Am J Hum Genet, 2022 Sep 01;109(9):1692-1712.
PMID: 36055214 DOI: 10.1016/j.ajhg.2022.07.007

Abstract

Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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