Antonicka, Hana and Weraarpachai, Woranontee and Szigety, Katherine M. and Kopajtich, Robert and Gibson, James B. and Hove, Johan L. K. Van and Friederich, Marisa W. and Lopriore, Piervito and Neuhofer, Christiane and Hove, Roxanne A. Van and Cole, Michel A. and Reisdorph, Richard and Peterson, James T. and Dempsey, Katherine J. and Ganetzky, Rebecca D. and Mancuso, Michelangelo and Prokisch, Holger and Shoubridge, Eric A. (2025) Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early-to late-onset Leigh syndrome. AMERICAN JOURNAL OF HUMAN GENETICS, 112 (7). pp. 1699-1710. ISSN 0002-9297, 1537-6605
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RNASE P; MITOCHONDRIAL; FASTKD2; IDENTIFICATION; DISEASE; PROTEINS; SUBUNITS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Mar 2026 08:50 |
| Last Modified: | 31 Mar 2026 08:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67855 |
Actions (login required)
 |
View Item |
