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Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement
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 sy...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502063/ https://www.ncbi.nlm.nih.gov/pubmed/36055214 http://dx.doi.org/10.1016/j.ajhg.2022.07.007 |
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author | 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_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_sort | Kaiyrzhanov, Rauan |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-9502063 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-95020632022-09-24 Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement 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 Am J Hum Genet Article 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. Elsevier 2022-09-01 2022-09-01 /pmc/articles/PMC9502063/ /pubmed/36055214 http://dx.doi.org/10.1016/j.ajhg.2022.07.007 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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 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 |
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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502063/ https://www.ncbi.nlm.nih.gov/pubmed/36055214 http://dx.doi.org/10.1016/j.ajhg.2022.07.007 |
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