Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype

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.

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Publication Details

Journal
The American Journal of Human Genetics
Published
2024-12-18
DOI
https://doi.org/10.1016/j.ajhg.2024.11.007
Citations
6
Primary Topic
Microtubule and mitosis dynamics
Type
article
Field-Weighted Citation Impact
1.96

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article

Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype

Manuel Schiff, Simon G. Williams, Wyatt W. Yue, Thomas B. Friedman et al.
6 citations
The American Journal of Human Genetics
Microtubule and mitosis dynamics
1.96
article

Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype

Manuel Schiff, Simon G. Williams, Wyatt W. Yue, Thomas B. Friedman, Jill Urquhart, Alexander J. M. Blakes, Kyle Thompson, Thomas B. Smith, James O’Sullivan, Periyasamy Radhakrishnan, Melanie Barzik, Sanjeev S. Bhaskar, Hatem Azzouz, Monika Oláhová, Raymond T. O’Keefe, Ruth I.C. Glasgow, Leigh Demain, Holger Prokisch, Kevin J. Munro, Siddharth Banka, Mayuri Yeole, Amir Jahić, Inna A. Belyantseva, Gerard S. Conway, Monique Elmaleh, Emma M. Jenkinson, Huw B. Thomas, Jamie M. Ellingford, William G. Newman, Amel Ben Chehida, Henry Houlden, Robert Kopajtich, Christian Beetz, Alessandro Rea, Anju Shukla, Shelagh Joss, Samantha Carrera, Robert W. Taylor, Langping He
article en
6 citations

Abstract

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.

The American Journal of Human GeneticsVol. 112(1)
Délégation Paris 5 (FR), National Institutes of Health (US), Inserm (FR), Manipal Academy of Higher Education (IN), Queen Mary University of London (GB), Université Paris Cité (FR), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Karolinska Institutet (SE), University of Manchester (GB), Helmholtz Zentrum München (DE), Northumbria University (GB), St Mary's Hospital (GB), Manchester University NHS Foundation Trust (GB), Assistance Publique – Hôpitaux de Paris (FR), Hôpital La Rabta (TN), St Mary's Hospital (GB), London Women's Clinic (GB), Hôpital Robert-Debré (FR), Centogene (Germany) (DE), Wellcome Centre for Mitochondrial Research (GB), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Hôpitaux Universitaires de Strasbourg (FR), National Institute on Deafness and Other Communication Disorders (US), Queen Elizabeth University Hospital (GB), University College London (GB), Kasturba Medical College, Manipal (IN), Charité - Universitätsmedizin Berlin (DE), Newcastle University (GB)
Wellcome Trust, International Seafood Sustainability Foundation, Action Medical Research, National Institute for Health and Care Research, Department of Biotechnology, Ministry of Science and Technology, India, Bundesministerium für Bildung und Forschung, The Wellcome Trust DBT India Alliance, National Institutes of Health, Manchester Biomedical Research Centre, Medical Research Council, Wellcome Trust Centre for Mitochondrial Research, National Institute on Deafness and Other Communication Disorders
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Openalex Percentile: Top 14%
Microtubule and mitosis dynamics
1.96
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