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...

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Published in:American journal of human genetics 2022-09, Vol.109 (9), p.1692-1712
Main Authors: 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
Format: Article
Language:English
Subjects:
Calcium-Binding Proteins - genetics
genetics
Homeostasis - genetics
Humans
LETM1
Membrane Proteins - genetics
mitochondria
Mitochondria - genetics
Mitochondria - metabolism
mitochondrial diseases
Mitochondrial Diseases - genetics
Mitochondrial Diseases - metabolism
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Nervous System - metabolism
neurodegeneration
neurology
oxidative phosphorylation
potassium transport
Saccharomyces cerevisiae - metabolism
volume homeostasis
Wolf-Hirschhorn syndrome
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Summary: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. [Display omitted] Kaiyrzhanov et al. describe 18 affected individuals with bi-allelic variants in the leucine zipper-EF-hand containing transmembrane protein 1 gene presenting with clinical features suggestive of a mitochondrial disease. Functional studies showed defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of mitochondrial oxidative phosphorylation protein components.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2022.07.007