Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement
dc.contributor.author | Baptista, Julia | |
dc.date.accessioned | 2022-06-07T16:43:37Z | |
dc.date.issued | 2022-09-01 | |
dc.identifier.issn | 0002-9297 | |
dc.identifier.issn | 1537-6605 | |
dc.identifier.uri | http://hdl.handle.net/10026.1/19280 | |
dc.description | File 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.extent | 1692-1712 | |
dc.format.medium | ||
dc.language | en | |
dc.language.iso | en | |
dc.publisher | Cell Press | |
dc.subject | LETM1 | |
dc.subject | Wolf-Hirschhorn syndrome | |
dc.subject | genetics | |
dc.subject | mitochondria | |
dc.subject | mitochondrial diseases | |
dc.subject | neurodegeneration | |
dc.subject | neurology | |
dc.subject | oxidative phosphorylation | |
dc.subject | potassium transport | |
dc.subject | volume homeostasis | |
dc.subject | Calcium-Binding Proteins | |
dc.subject | Homeostasis | |
dc.subject | Humans | |
dc.subject | Membrane Proteins | |
dc.subject | Mitochondria | |
dc.subject | Mitochondrial Diseases | |
dc.subject | Mitochondrial Proteins | |
dc.subject | Nervous System | |
dc.subject | Saccharomyces cerevisiae | |
dc.title | Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement | |
dc.type | journal-article | |
dc.type | Journal Article | |
dc.type | Research Support, Non-U.S. Gov't | |
plymouth.author-url | https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000877624100011&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008 | |
plymouth.issue | 9 | |
plymouth.volume | 109 | |
plymouth.publication-status | Published | |
plymouth.journal | American Journal of Human Genetics | |
dc.identifier.doi | 10.1016/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.place | United States | |
dcterms.dateAccepted | 2022-05-31 | |
dc.rights.embargodate | 2022-9-24 | |
dc.identifier.eissn | 1537-6605 | |
dc.rights.embargoperiod | Not known | |
rioxxterms.versionofrecord | 10.1016/j.ajhg.2022.07.007 | |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.type | Journal Article/Review |