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Kaiyrzhanov, R.* ; Mohammed, S.E.M.* ; Maroofian, R.* ; Husain, R.A.* ; Catania, A.* ; Torraco, A.* ; Alahmad, A.* ; Dutra-Clarke, M.* ; Grønborg, S.* ; Sudarsanam, A.* ; Vogt, J.* ; Arrigoni, F.* ; Baptista, J.* ; Haider, S.* ; Feichtinger, R.G.* ; Bernardi, P.* ; Zulian, A.* ; Gusic, M. ; Efthymiou, S.* ; Bai, R.* ; Bibi, F.* ; Horga, A.* ; Martinez-Agosto, J.A.* ; 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, J.A.* ; Bertini, E.S.* ; Ghezzi, D.* ; Østergaard, E.* ; Wortmann, S. ; Carrozzo, R.* ; Haack, T.B.* ; Taylor, R.W.* ; Spinazzola, A.* ; Nowikovsky, K.* ; Houlden, H.*

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

Am. J. Hum. Genet. 109, 1692-1712 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genetics ; Letm1 ; Mitochondria ; Mitochondrial Diseases ; Neurodegeneration ; Neurology ; Oxidative Phosphorylation ; Potassium Transport ; Volume Homeostasis ; Wolf-hirschhorn Syndrome
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 109, Issue: 9, Pages: 1692-1712 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)