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dc.contributor.authorPereira Baptista, JDC
dc.date.accessioned2022-06-07T16:43:37Z
dc.date.issued2022-09-01
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.urihttp://hdl.handle.net/10026.1/19280
dc.descriptionFile replaced (incorrect version) on 23/9/2022 by KT (LDS).
dc.description.abstract

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.

dc.format.extent1692-1712
dc.format.mediumPrint
dc.languageen
dc.language.isoen
dc.publisherCell Press
dc.subjectLETM1
dc.subjectWolf-Hirschhorn syndrome
dc.subjectgenetics
dc.subjectmitochondria
dc.subjectmitochondrial diseases
dc.subjectneurodegeneration
dc.subjectneurology
dc.subjectoxidative phosphorylation
dc.subjectpotassium transport
dc.subjectvolume homeostasis
dc.subjectCalcium-Binding Proteins
dc.subjectHomeostasis
dc.subjectHumans
dc.subjectMembrane Proteins
dc.subjectMitochondria
dc.subjectMitochondrial Diseases
dc.subjectMitochondrial Proteins
dc.subjectNervous System
dc.subjectSaccharomyces cerevisiae
dc.titleBi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement
dc.typejournal-article
dc.typeArticle
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/36055214
plymouth.issue9
plymouth.volume109
plymouth.publisher-urlhttp://dx.doi.org/10.1016/j.ajhg.2022.07.007
plymouth.publication-statusPublished
plymouth.journalAmerican Journal of Human Genetics
dc.identifier.doi10.1016/j.ajhg.2022.07.007
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
dc.publisher.placeUnited States
dcterms.dateAccepted2022-05-31
dc.rights.embargodate2022-9-24
dc.identifier.eissn1537-6605
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1016/j.ajhg.2022.07.007
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review


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