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Antonicka, H.* ; Weraarpachai, W.* ; Szigety, K.M.* ; Kopajtich, R. ; Gibson, J.B.* ; van Hove, J.L.K.* ; Friederich, M.W.* ; Lopriore, P.* ; Neuhofer, C. ; Van Hove, R.A.* ; Cole, M.A.* ; Reisdorph, R.* ; Peterson, J.T.* ; Dempsey, K.J.* ; Ganetzky, R.D.* ; Mancuso, M.* ; Prokisch, H. ; Shoubridge, E.A.*

Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.

Am. J. Hum. Genet. 112, 1699-1710 (2025)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Using exome sequencing, we identified compound heterozygous variants of unknown significance in FASTKD5, a gene that codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript, in three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia. Among the three subjects, we identified three missense variants and two frameshift variants leading to a premature stop codon. Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense mutations, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. Two of the three identified missense mutations resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability. These cases of mitochondrial disease associated with bi-allelic variants in FASTKD5 add to a growing list of primary genetic mutations causing Leigh syndrome associated with complex IV deficiency.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Fastkd5 ; Leigh Syndrome ; Rna Processing ; Cytochrome C Oxidase Deficiency ; Mitochondrial Dna ; Mitochondrial Disease ; Mitochondrial Gene Expression ; Mitochondrial Translation ; Neurodegenerative Disease; Rnase P; Mitochondrial; Fastkd2; Identification; Disease; Proteins; Subunits
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 112, Heft: 7, Seiten: 1699-1710 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503292-001
Förderungen Children's Hospital of Philadelphia residency program
Children's Hospital Colorado Riders for Samantha
University of Central Florida
National Institutes of Health
NCATS
NIH/NCCR
European Joint Programme on Rare Diseases
European Union-NextGenerationEU-National Recovery and Resilience Plan (NRRP) - MISSION4 COMPONENT 2, INVESTIMENT N. 1.1, CALL PRIN 2022
BMBF (German Federal Ministry of Education and Research) through the German Center for Child and Adolescent Health (DZKJ)
MitoNET German Network for Mitochondrial Diseases
PerMiM Personalized Mitochondrial Medicine
EJP RD project GENOMIT - European Union
Canadian Institutes of Health Research
DOI 10.1016/j.ajhg.2025.05.007
WOS ID 001538733500014
Scopus ID 105007804449
PubMed ID 40499538
Erfassungsdatum 2025-06-26
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