Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
04 Sep 2024
04 Sep 2024
Historique:
revised:
08
08
2024
received:
03
06
2024
accepted:
15
08
2024
medline:
4
9
2024
pubmed:
4
9
2024
entrez:
4
9
2024
Statut:
aheadofprint
Résumé
Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes. Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells. We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T-lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands' fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies. Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T-lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
ID : 202020
Pays : United Kingdom
Organisme : Dino Ferrari
Organisme : JDM Fund for mitochondrial research
Organisme : Geof Barker
Organisme : Fundación Alfonso Martín Escudero
Organisme : Agència de Gestió d'Ajuts Universitaris i de Recerca
ID : 2017:SGR 1428
Organisme : Agència de Gestió d'Ajuts Universitaris i de Recerca
ID : 2021:SGR 01423
Organisme : Common Fund
ID : 35GM139453
Organisme : Common Fund
ID : P01 HD32062
Organisme : NINDS NIH HHS
ID : U54 NS078059
Pays : United States
Organisme : HORIZON EUROPE 2021-2027
ID : 101065857
Organisme : Dipartimenti di Eccellenza
Organisme : European Reference Network
Organisme : Instituto de Salud Carlos III
ID : ER20P2AC737
Organisme : Instituto de Salud Carlos III
ID : PI19/01310
Organisme : Instituto de Salud Carlos III
ID : PI21/00554
Organisme : Instituto de Salud Carlos III
ID : PI22/00856
Organisme : European Regional Development Fund
Organisme : Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, SEQMD
ID : PNC-E3-2022-23683266
Organisme : Shuman Mitochondrial Disease Fundation
Organisme : Congressionally Directed Medical Research Programs
ID : W81XWH2010807
Informations de copyright
© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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