Browse by author
Lookup NU author(s): Dr Kyle Thompson, Dr Monika Olahova, Dr Langping He, Professor Wyatt YueORCiD, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Author(s)The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA, and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with bi-allelic variants in death-associated protein 3 (DAP3), a nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Protein modeling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated that DAP3 variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability, and DAP3 GTPase activity. Our study presents genetic and functional evidence that bi-allelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction.
Author(s): Smith TB, Kopajtich R, Demain LAM, Rea A, Thomas HB, Schiff M, Beetz C, Joss S, Conway GS, Shukla A, Yeole M, Radhakrishnan P, Azzouz H, Ben Chehida A, Elmaleh-Berges M, Glasgow RIC, Thompson K, Olahova M, He L, Jenkinson EM, Jahic A, Belyantseva IA, Barzik M, Urquhart JE, O'Sullivan J, Williams SG, Bhaskar SS, Carrera S, Blakes AJM, Banka S, Yue WW, Ellingford JM, Houlden H, Munro KJ, Friedman TB, Taylor RW, Prokisch H, O'Keefe RT, Newman WG
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2025
Volume: 112
Issue: 1
Pages: 59-74
Print publication date: 02/01/2025
Online publication date: 18/12/2024
Acceptance date: 19/11/2024
Date deposited: 13/01/2025
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2024.11.007
DOI: 10.1016/j.ajhg.2024.11.007
Data Access Statement: The DAP3 variants were submitted to ClinVar (https://www.ncbi. nlm.nih.gov/clinvar/) (GenBank: NM_004632.4; ClinVar: SCV0042 28990–SCV004228993; and ClinVar: VCV003066057.1)
PubMed id: 39701103
Altmetrics provided by Altmetric
