ArticleAmerican journal of human genetics2022
Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.
Open access · hybridAbstract read
In one paragraph
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
1.6field-weighted citation impact, top 17% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- Loss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay.EMBO molecular medicine · 2026Article
- Tmbim5 and Slc8b1 cooperate in tissue-specific mitochondrial calcium regulation in zebrafish.Communications biology · 2026Article
- Distinct Pathogenic Mechanisms of Two Novel NHS Mutations Identified in Chinese Han Families With Nance-Horan Syndrome.Human mutation · 2026Article
- Neurogenetic Disorders with Hearing Loss: Mechanisms, Classifications, and Emerging Insights.Current neurology and neuroscience reports · 2025Review
- The SLC-ome of membrane transport: From molecular discovery to physiology and clinical applications.Physiological reviews · 2025Review
- Generation of human induced pluripotent stem cell lines derived from Wolf-Hirschhorn syndrome patients with chromosomal 4p deletion.Human cell · 2025Article
- Elevated levels of Letm1 drives mitochondrial dysfunction and cardiomyocyte stress-mediated apoptosis in cultured cardiomyocytes.Cell communication and signaling : CCS · 2025Article
- A Unique Derivative Chromosome 4 with a Predominant 4p16.3 Microduplication Phenotype and a Literature Review.Molecular syndromology · 2025Article
- Calcium signaling in mitochondrial intermembrane space.Biochemical Society transactions · 2024Review
- Deciphering the SOX4/MAPK1 regulatory axis: a phosphoproteomic insight into IQGAP1 phosphorylation and pancreatic Cancer progression.Journal of translational medicine · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
54 authors at 20 institutions in 11 countries.
Rauan KaiyrzhanovDepartment of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK.
Sami E M MohammedDepartment of Biomedical Sciences, Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine Vienna, Vienna 1210, Austria.
Reza MaroofianDepartment of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK.
Ralf A HusainDepartment of Neuropediatrics, Jena University Hospital, Jena 07747, Germany; Center for Rare Diseases, Jena University Hospital, Jena 07747, Germany.
Alessia CataniaUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20126, Italy.
Alessandra TorracoUnit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy.
Ahmad AlahmadWellcome 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.
Marina Dutra-ClarkeDivision of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, the University of California at Los Angeles, Los Angeles, CA 90095, USA.
Sabine GrønborgCenter for Rare Diseases, Department of Pediatrics and Department of Genetics, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen 2100, Denmark.
Annapurna SudarsanamWest Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham B15 2TG, UK.
Julie VogtWest Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham B15 2TG, UK.
Filippo ArrigoniPaediatric Radiology and Neuroradiology Department, V. Buzzi Children's Hospital, Milan 20154, Italy.
Julia BaptistaPeninsula Medical School, Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK.
Shahzad HaiderPaediatrics Wah Medical College NUMS, Wah Cantonment, Punjab 44000, Pakistan.
René G FeichtingerUniversity Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg 5020, Austria.
Paolo BernardiDepartment of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, Padova 35131, Italy.
Alessandra ZulianDepartment of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, Padova 35131, Italy.
Mirjana GusicInstitute 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.
Stephanie EfthymiouDepartment of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK.
Renkui BaiGeneDx Inc, Gaithersburg, MD 20877, USA.
Farah BibiInstitute of Biochemistry and Biotechnology, Pir Mehar Ali Shah Arid Agriculture University, Rawalpindi 44000, Pakistan.
Alejandro HorgaDepartment 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.
Julian A Martinez-AgostoDepartment 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.
Amanda LamNeurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK; Department of Chemical Pathology, Great Ormond Street Hospital, WC1N 3BG London, UK.
Andreea ManoleDepartment of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK.
Diego-Perez RodriguezDepartment of Clinical Movement Neurosciences, Royal Free Campus, University College of London, Queen Square Institute of Neurology, London WC1N 3BG, UK.
Romina DurigonDepartment of Clinical Movement Neurosciences, Royal Free Campus, University College of London, Queen Square Institute of Neurology, London WC1N 3BG, UK.
Angela PyleWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
Buthaina AlbashKuwait Medical Genetics Centre, Al-Sabah Medical Area 80901, Kuwait.
Carlo Dionisi-ViciDivision of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy.
David MurphyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Diego MartinelliDivision of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy.
Enrico BugiardiniDepartment of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK.
Katrina AllisGeneDx Inc, Gaithersburg, MD 20877, USA.
Costanza LampertiUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20126, Italy.
Siegfried ReipertCore Facility of Cell Imaging and Ultrastructure Research, University of Vienna, Djerassiplatz 1, 1030 Wien, Austria.
Lotte RisomDepartment of Genetics, Copenhagen University Hospital Rigshospitalet Blegdamsvej, Copenhagen 2100, Denmark.
Lucia LaugwitzInstitute 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.
Michela Di NottiaUnit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy.
Robert McFarlandWellcome 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.
Laura VilarinhoUnit of Neonatal Screening, Metabolism and Genetics, Department of Human Genetics, National Institute of Health Dr Ricardo Jorge, Porto 4000-055, Portugal.
Michael HannaDepartment of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK.
Holger ProkischInstitute of Neurogenomics, Helmholtz Zentrum München, Neuherberg 85764, Germany; Institute of Human Genetics, Technical University of Munich, Munich 81675, Germany.
Johannes A MayrUniversity Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg 5020, Austria.
Enrico Silvio BertiniUnit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy.
Daniele GhezziUnit 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.
Elsebet ØstergaardDepartment of Genetics, Copenhagen University Hospital Rigshospitalet Blegdamsvej, Copenhagen 2100, Denmark; Institute for Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark.
Saskia B WortmannUniversity 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.
Rosalba CarrozzoUnit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy.
Tobias B HaackDepartment of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Tübingen 72076, Germany; Centre for Rare Diseases, University of Tuebingen, Tübingen 72076, Germany.
Robert W TaylorWellcome 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.
Antonella SpinazzolaDepartment of Clinical Movement Neurosciences, Royal Free Campus, University College of London, Queen Square Institute of Neurology, London WC1N 3BG, UK.
Karin NowikovskyDepartment 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.
Henry HouldenDepartment of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London WC1N 3BG, UK. Electronic address: h.houlden@ucl.ac.uk.
National Hospital for Neurology and Neurosurgery · GBBambino Gesù Children's Hospital · ITThe Royal Free Hospital · GBBirmingham Women's Hospital · GBCopenhagen University Hospital · DKFondazione IRCCS Istituto Neurologico Carlo Besta · ITHelmholtz Zentrum München · DEKuwait Institute for Medical Specialization · KWNewcastle upon Tyne Hospitals NHS Foundation Trust · GBParacelsus Medical University · ATTH Bingen University of Applied Sciences · DEUniversity of California, Los Angeles · USUniversity of Padua · ITUniversity of Veterinary Medicine Vienna · ATGreat Ormond Street Hospital · GBHospital Clínico San Carlos · ESJena University Hospital · DENational Institute of Health Dr. Ricardo Jorge · PTOspedale dei Bambini Vittore Buzzi · ITPir Mehr Ali Shah Arid Agriculture University · PK
Funding
Austrian Science Fund FWF P 29077Austrian Science Fund FWF P 31471Medical Research Council G0601943Medical Research Council MC_PC_13029/2Medical Research Council MR/S005021/1Medical Research Council MR/S01165X/1Wellcome Trust
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
Indexed as
Calcium-Binding ProteinsMitochondrial DiseasesHomeostasisHumansMembrane ProteinsMitochondriaMitochondrial ProteinsNervous SystemSaccharomyces cerevisiaeCalcium-Binding ProteinsLETM1 protein, humanMembrane ProteinsMitochondrial ProteinsgeneticsLETM1mitochondriamitochondrial diseasesneurodegenerationneurologyoxidative phosphorylationpotassium transportvolume homeostasisWolf-Hirschhorn syndrome
Identifiers
What OpenQuestion holds
Textmetadata
LicenceCC BY
Read underepoch 390
Registered trials
None linked
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.