Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.
LETM1
Wolf-Hirschhorn syndrome
genetics
mitochondria
mitochondrial diseases
neurodegeneration
neurology
oxidative phosphorylation
potassium transport
volume homeostasis
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
01 09 2022
01 09 2022
Historique:
received:
27
03
2022
accepted:
01
07
2022
entrez:
2
9
2022
pubmed:
3
9
2022
medline:
9
9
2022
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 36055214
pii: S0002-9297(22)00311-1
doi: 10.1016/j.ajhg.2022.07.007
pmc: PMC9502063
pii:
doi:
Substances chimiques
Calcium-Binding Proteins
0
LETM1 protein, human
0
Membrane Proteins
0
Mitochondrial Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1692-1712Subventions
Organisme : Medical Research Council
ID : MC_PC_13029/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S005021/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S01165X/1
Pays : United Kingdom
Organisme : Austrian Science Fund FWF
ID : P 31471
Pays : Austria
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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