Kaiyrzhanov, 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, Henry2023-03-172023-03-172022-09-01Am J Hum Genet. 2022 Sep 1;109(9):1692-1712. doi: 10.1016/j.ajhg.2022.07.0070002-9297http://hdl.handle.net/10400.18/8559Leucine 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.engLETM1Wolf-Hirschhorn SyndromeGeneticsMitochondriaMitochondrial DiseasesNeurodegenerationNeurologyOxidative PhosphorylationPotassium TransportVolume HomeostasisDoenças Genéticasjournal article10.1016/j.ajhg.2022.07.007