Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/8559 |
Resumo: | 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. |
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Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvementLETM1Wolf-Hirschhorn SyndromeGeneticsMitochondriaMitochondrial DiseasesNeurodegenerationNeurologyOxidative PhosphorylationPotassium TransportVolume HomeostasisDoenças GenéticasLeucine 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.This 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).Elsevier/Cell PressRepositório Científico do Instituto Nacional de SaúdeKaiyrzhanov, RauanMohammed, Sami E.M.Maroofian, RezaHusain, Ralf A.Catania, AlessiaTorraco, AlessandraAlahmad, AhmadDutra-Clarke, MarinaGrønborg, SabineSudarsanam, AnnapurnaVogt, JulieArrigoni, FilippoBaptista, JuliaHaider, ShahzadFeichtinger, René G.Bernardi, PaoloZulian, AlessandraGusic, MirjanaEfthymiou, StephanieBai, RenkuiBibi, FarahHorga, AlejandroMartinez-Agosto, Julian A.Lam, AmandaManole, AndreeaRodriguez, Diego-PerezDurigon, RominaPyle, AngelaAlbash, ButhainaDionisi-Vici, CarloMurphy, DavidMartinelli, DiegoBugiardini, EnricoAllis, KatrinaLamperti, CostanzaReipert, SiegfriedRisom, LotteLaugwitz, LuciaDi Nottia, MichelaMcFarland, RobertVilarinho, LauraHanna, MichaelProkisch, HolgerMayr, Johannes A.Bertini, Enrico SilvioGhezzi, DanieleØstergaard, ElsebetWortmann, Saskia B.Carrozzo, RosalbaHaack, Tobias B.Taylor, Robert W.Spinazzola, AntonellaNowikovsky, KarinHoulden, Henry2023-03-17T15:44:58Z2022-09-012022-09-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/8559engAm J Hum Genet. 2022 Sep 1;109(9):1692-1712. doi: 10.1016/j.ajhg.2022.07.0070002-929710.1016/j.ajhg.2022.07.007info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:42:38Zoai:repositorio.insa.pt:10400.18/8559Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:43:12.101127Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement |
title |
Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement |
spellingShingle |
Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement Kaiyrzhanov, Rauan LETM1 Wolf-Hirschhorn Syndrome Genetics Mitochondria Mitochondrial Diseases Neurodegeneration Neurology Oxidative Phosphorylation Potassium Transport Volume Homeostasis Doenças Genéticas |
title_short |
Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement |
title_full |
Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement |
title_fullStr |
Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement |
title_full_unstemmed |
Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement |
title_sort |
Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement |
author |
Kaiyrzhanov, Rauan |
author_facet |
Kaiyrzhanov, Rauan Mohammed, Sami E.M. Maroofian, Reza Husain, Ralf A. Catania, Alessia Torraco, Alessandra Alahmad, Ahmad Dutra-Clarke, Marina Grønborg, Sabine Sudarsanam, Annapurna Vogt, Julie Arrigoni, Filippo Baptista, Julia Haider, Shahzad Feichtinger, René G. Bernardi, Paolo Zulian, Alessandra Gusic, Mirjana Efthymiou, Stephanie Bai, Renkui Bibi, Farah Horga, Alejandro Martinez-Agosto, Julian A. Lam, Amanda Manole, Andreea Rodriguez, Diego-Perez Durigon, Romina Pyle, Angela Albash, Buthaina Dionisi-Vici, Carlo Murphy, David Martinelli, Diego Bugiardini, Enrico Allis, Katrina Lamperti, Costanza Reipert, Siegfried Risom, Lotte Laugwitz, Lucia Di Nottia, Michela McFarland, Robert Vilarinho, Laura Hanna, Michael Prokisch, Holger Mayr, Johannes A. Bertini, Enrico Silvio Ghezzi, Daniele Østergaard, Elsebet Wortmann, Saskia B. Carrozzo, Rosalba Haack, Tobias B. Taylor, Robert W. Spinazzola, Antonella Nowikovsky, Karin Houlden, Henry |
author_role |
author |
author2 |
Mohammed, Sami E.M. Maroofian, Reza Husain, Ralf A. Catania, Alessia Torraco, Alessandra Alahmad, Ahmad Dutra-Clarke, Marina Grønborg, Sabine Sudarsanam, Annapurna Vogt, Julie Arrigoni, Filippo Baptista, Julia Haider, Shahzad Feichtinger, René G. Bernardi, Paolo Zulian, Alessandra Gusic, Mirjana Efthymiou, Stephanie Bai, Renkui Bibi, Farah Horga, Alejandro Martinez-Agosto, Julian A. Lam, Amanda Manole, Andreea Rodriguez, Diego-Perez Durigon, Romina Pyle, Angela Albash, Buthaina Dionisi-Vici, Carlo Murphy, David Martinelli, Diego Bugiardini, Enrico Allis, Katrina Lamperti, Costanza Reipert, Siegfried Risom, Lotte Laugwitz, Lucia Di Nottia, Michela McFarland, Robert Vilarinho, Laura Hanna, Michael Prokisch, Holger Mayr, Johannes A. Bertini, Enrico Silvio Ghezzi, Daniele Østergaard, Elsebet Wortmann, Saskia B. Carrozzo, Rosalba Haack, Tobias B. Taylor, Robert W. Spinazzola, Antonella Nowikovsky, Karin Houlden, Henry |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Kaiyrzhanov, Rauan Mohammed, Sami E.M. Maroofian, Reza Husain, Ralf A. Catania, Alessia Torraco, Alessandra Alahmad, Ahmad Dutra-Clarke, Marina Grønborg, Sabine Sudarsanam, Annapurna Vogt, Julie Arrigoni, Filippo Baptista, Julia Haider, Shahzad Feichtinger, René G. Bernardi, Paolo Zulian, Alessandra Gusic, Mirjana Efthymiou, Stephanie Bai, Renkui Bibi, Farah Horga, Alejandro Martinez-Agosto, Julian A. Lam, Amanda Manole, Andreea Rodriguez, Diego-Perez Durigon, Romina Pyle, Angela Albash, Buthaina Dionisi-Vici, Carlo Murphy, David Martinelli, Diego Bugiardini, Enrico Allis, Katrina Lamperti, Costanza Reipert, Siegfried Risom, Lotte Laugwitz, Lucia Di Nottia, Michela McFarland, Robert Vilarinho, Laura Hanna, Michael Prokisch, Holger Mayr, Johannes A. Bertini, Enrico Silvio Ghezzi, Daniele Østergaard, Elsebet Wortmann, Saskia B. Carrozzo, Rosalba Haack, Tobias B. Taylor, Robert W. Spinazzola, Antonella Nowikovsky, Karin Houlden, Henry |
dc.subject.por.fl_str_mv |
LETM1 Wolf-Hirschhorn Syndrome Genetics Mitochondria Mitochondrial Diseases Neurodegeneration Neurology Oxidative Phosphorylation Potassium Transport Volume Homeostasis Doenças Genéticas |
topic |
LETM1 Wolf-Hirschhorn Syndrome Genetics Mitochondria Mitochondrial Diseases Neurodegeneration Neurology Oxidative Phosphorylation Potassium Transport Volume Homeostasis Doenças Genéticas |
description |
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. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-09-01 2022-09-01T00:00:00Z 2023-03-17T15:44:58Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.18/8559 |
url |
http://hdl.handle.net/10400.18/8559 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Am J Hum Genet. 2022 Sep 1;109(9):1692-1712. doi: 10.1016/j.ajhg.2022.07.007 0002-9297 10.1016/j.ajhg.2022.07.007 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier/Cell Press |
publisher.none.fl_str_mv |
Elsevier/Cell Press |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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