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

Lookup NU author(s): Ahmad Alahmad, Dr Angela Pyle, Professor Bobby McFarlandORCiD, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 The Authors. 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.

Publication metadata

Author(s): Kaiyrzhanov R, Mohammed SEM, Maroofian R, Husain RA, Catania A, Torraco A, Alahmad A, Dutra-Clarke M, Gronborg S, Sudarsanam A, Vogt J, Arrigoni F, Baptista J, Haider S, Feichtinger RG, Bernardi P, Zulian A, Gusic M, Efthymiou S, Bai R, Bibi F, Horga A, Martinez-Agosto JA, Lam A, Manole A, Rodriguez D-P, Durigon R, Pyle A, Albash B, Dionisi-Vici C, Murphy D, Martinelli D, Bugiardini E, Allis K, Lamperti C, Reipert S, Risom L, Laugwitz L, Di Nottia M, McFarland R, Vilarinho L, Hanna M, Prokisch H, Mayr JA, Bertini ES, Ghezzi D, Ostergaard E, Wortmann SB, Carrozzo R, Haack TB, Taylor RW, Spinazzola A, Nowikovsky K, Houlden H

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2022

Volume: 109

Issue: 9

Pages: 1692-1712

Online publication date: 01/09/2022

Acceptance date: 01/07/2022

Date deposited: 05/10/2022

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2022.07.007


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Funder referenceFunder name
MR/S005021/1Medical Research Council (MRC)
Synaptopathies Strategic Award, 165908