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

• Main Author: Kaiyrzhanov, Rauan
• Publication Date: 2022
• Other Authors: 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
• Format: Article
• Language: eng
• Source: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Download full: http://hdl.handle.net/10400.18/8559
• topic: LETM1; Wolf-Hirschhorn Syndrome; Genetics; Mitochondria; Mitochondrial Diseases; Neurodegeneration; Neurology; Oxidative Phosphorylation; Potassium Transport; Volume Homeostasis; Doenças Genéticas

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.