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

2022-09-01Journal article Restricted access
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dc.contributor.authorKaiyrzhanov, Rauan
dc.contributor.authorMohammed, Sami E.M.
dc.contributor.authorMaroofian, Reza
dc.contributor.authorHusain, Ralf A.
dc.contributor.authorCatania, Alessia
dc.contributor.authorTorraco, Alessandra
dc.contributor.authorAlahmad, Ahmad
dc.contributor.authorDutra-Clarke, Marina
dc.contributor.authorGrønborg, Sabine
dc.contributor.authorSudarsanam, Annapurna
dc.contributor.authorVogt, Julie
dc.contributor.authorArrigoni, Filippo
dc.contributor.authorBaptista, Julia
dc.contributor.authorHaider, Shahzad
dc.contributor.authorFeichtinger, René G.
dc.contributor.authorBernardi, Paolo
dc.contributor.authorZulian, Alessandra
dc.contributor.authorGusic, Mirjana
dc.contributor.authorEfthymiou, Stephanie
dc.contributor.authorBai, Renkui
dc.contributor.authorBibi, Farah
dc.contributor.authorHorga, Alejandro
dc.contributor.authorMartinez-Agosto, Julian A.
dc.contributor.authorLam, Amanda
dc.contributor.authorManole, Andreea
dc.contributor.authorRodriguez, Diego-Perez
dc.contributor.authorDurigon, Romina
dc.contributor.authorPyle, Angela
dc.contributor.authorAlbash, Buthaina
dc.contributor.authorDionisi-Vici, Carlo
dc.contributor.authorMurphy, David
dc.contributor.authorMartinelli, Diego
dc.contributor.authorBugiardini, Enrico
dc.contributor.authorAllis, Katrina
dc.contributor.authorLamperti, Costanza
dc.contributor.authorReipert, Siegfried
dc.contributor.authorRisom, Lotte
dc.contributor.authorLaugwitz, Lucia
dc.contributor.authorDi Nottia, Michela
dc.contributor.authorMcFarland, Robert
dc.contributor.authorVilarinho, Laura
dc.contributor.authorHanna, Michael
dc.contributor.authorProkisch, Holger
dc.contributor.authorMayr, Johannes A.
dc.contributor.authorBertini, Enrico Silvio
dc.contributor.authorGhezzi, Daniele
dc.contributor.authorØstergaard, Elsebet
dc.contributor.authorWortmann, Saskia B.
dc.contributor.authorCarrozzo, Rosalba
dc.contributor.authorHaack, Tobias B.
dc.contributor.authorTaylor, Robert W.
dc.contributor.authorSpinazzola, Antonella
dc.contributor.authorNowikovsky, Karin
dc.contributor.authorHoulden, Henry
dc.date.accessioned2023-03-17T15:44:58Z
dc.date.available2023-03-17T15:44:58Z
dc.date.issued2022-09-01
dc.description.abstractLeucine 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.pt_PT
dc.description.sponsorshipThis research was supported using resources of the Core Facility Cell Imaging and Ultrastructure Research, University of Vienna, a member of the Vienna Life-Science Instruments (VLSI) and the VetCore Facility (Imaging) of the University of Veterinary Medicine Vienna. We acknowledge International Centre for Genomic Medicine in Neuromuscular Diseases. This research was funded in part, by the Wellcome Trust (WT093205MA, WT104033AIA, and the Synaptopathies Strategic Award, 165908). This study was funded by the Medical Research Council (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetrees Trust, Ataxia UK, Multiple System Atrophy Trust, Brain Research United Kingdom, Sparks Great Ormond Street Hospital Charity, Muscular Dystrophy United Kingdom (MDUK), Muscular Dystrophy Association (MDA USA) and Senior Non-Clinical Fellow ship to A. Spinazzola, (MC_PC_13029). K.N. and S.E.M.M. were supported by the Austrian Science Funds FWF-P29077 and P31471. A. Spinazzola receives support also from The Lily Foun dation and Brain Research UK. R.K. was supported by European Academy of Neurology Research Training Fellowship and Rosetrees Trust PhD Plus award (PhD2022\100042).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAm J Hum Genet. 2022 Sep 1;109(9):1692-1712. doi: 10.1016/j.ajhg.2022.07.007pt_PT
dc.identifier.doi10.1016/j.ajhg.2022.07.007pt_PT
dc.identifier.issn0002-9297
dc.identifier.urihttp://hdl.handle.net/10400.18/8559
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevier/Cell Presspt_PT
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0002929722003111?via%3Dihubpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectLETM1pt_PT
dc.subjectWolf-Hirschhorn Syndromept_PT
dc.subjectGeneticspt_PT
dc.subjectMitochondriapt_PT
dc.subjectMitochondrial Diseasespt_PT
dc.subjectNeurodegenerationpt_PT
dc.subjectNeurologypt_PT
dc.subjectOxidative Phosphorylationpt_PT
dc.subjectPotassium Transportpt_PT
dc.subjectVolume Homeostasispt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleBi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvementpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1712pt_PT
oaire.citation.issue9pt_PT
oaire.citation.startPage1692pt_PT
oaire.citation.titleThe American Journal of Human Geneticspt_PT
oaire.citation.volume109pt_PT
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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