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Lookup NU author(s): Dr Monika Olahova, Dr Kyle Thompson, Dr Langping He, Professor Robert TaylorORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.
Author(s): Thomas HB, Demain LAM, Cabrera-Orefice A, Schrauwen I, Shamseldin HE, Rea A, Bharadwaj T, Smith TB, Olahova M, Thompson K, He L, Kaur N, Shukla A, Abukhalid M, Ansar M, Rehman S, Riazuddin S, Abdulwahab F, Smith JM, Stark Z, Mancilar H, Tumer S, Esen FN, Uctepe E, Topcu V, Yesilyurt A, Afzal E, Salari M, Carroll C, Zifarelli G, Bauer P, Kor D, Bulut FD, Houlden H, Maroofian R, Carrera S, Yue WW, Munro KJ, Alkuraya FS, Jamieson P, Ahmed ZM, Leal SM, Taylor RW, Wittig I, O'Keefe RT, Newman WG
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2025
Volume: 112
Issue: 4
Pages: 952-962
Print publication date: 03/04/2025
Online publication date: 04/03/2025
Acceptance date: 06/02/2025
Date deposited: 10/04/2025
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2025.02.005
DOI: 10.1016/j.ajhg.2025.02.005
Data Access Statement: The MRPL49 variants were submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) (GenBank: NM_004927.4; accession numbers SCV004242144–SCV004242147). The exome datasets supporting this study have not been deposited in a public repository because of ethical restrictions but are available from the corresponding author upon request. The mass spectrometry data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD056347 and 10.6019/PXD056347.
PubMed id: 40043708
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