Biallelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered intrinsic and extrinsic apoptosis and a Perrault syndrome-spectrum phenotype.

Autor:	Smith TB; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Kopajtich R; Institute of Human Genetics, Computational Health Center, Helmholtz Zentrum München, Neuherberg, 85764, Germany.; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, 81675, Germany., Demain LAM; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Rea A; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Thomas HB; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Schiff M; Université Paris Cité, Reference Center for Mitochondrial Disorders (CARAMMEL) and Reference Center Inborn Error of Metabolism, Department of Pediatrics, Necker-Enfants Malades Hospital, APHP, Filière G2M, Paris, France.; Inserm UMR_S1163, Institut Imagine, Université Paris Cité, Paris, France., Beetz C; Centogene GmbH, Rostock, Germany., Joss S; West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK., Conway GS; Institute for Women's Health, University College London, London, United Kingdom., Shukla A; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India., Yeole M; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India., Radhakrishnan P; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India., Azzouz H; Service de pédiatrie et des maladies métaboliques héréditaires, CHU la Rabta, 1007 Jabberi, Tunis, Tunisia., Ben Chehida A; Service de pédiatrie et des maladies métaboliques héréditaires, CHU la Rabta, 1007 Jabberi, Tunis, Tunisia., Elmaleh-Bergès M; Service de Radiologie Pédiatrique, Hôpital Robert-Debré, APHP, Paris, France., Glasgow RIC; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden., Thompson K; Mitochondrial Research Group, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Oláhová M; Mitochondrial Research Group, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; Department of Applied Sciences, Faculty of Health & Life Sciences, Northumbria University, Newcastle upon Tyne, UK., He L; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK., Jenkinson EM; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Jahic A; Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany., Belyantseva IA; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892-3729, USA., Barzik M; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892-3729, USA., Urquhart JE; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., O' Sullivan J; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Williams SG; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Bhaskar SS; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Carrera S; Genome Editing Unit, The University of Manchester, Manchester, M13 9PT, UK., Blakes AJM; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Banka S; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Yue WW; Newcastle University Biosciences Institute, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Ellingford JM; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK.; Genomics England, London, UK., Houlden H; Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, United Kingdom., Munro KJ; Manchester Centre for Audiology and Deafness (ManCAD), School of Health Sciences, The University of Manchester, Manchester, UK., Friedman TB; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892-3729, USA., Taylor RW; Mitochondrial Research Group, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK., Prokisch H; Institute of Human Genetics, Computational Health Center, Helmholtz Zentrum München, Neuherberg, 85764, Germany.; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, 81675, Germany., O'Keefe RT; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK., Newman WG; Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, M13 9PL, UK.; Manchester Centre for Genomic Medicine, St Mary's Hospital, The University of Manchester NHS Foundation Trust, Manchester, M13 9WL, UK.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 21. Date of Electronic Publication: 2024 Aug 21.
DOI:	10.1101/2024.08.19.24312079
Abstrakt:	The 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 biallelic variants in the DAP3 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 levels, and consequently decreased levels of additional protein components of the mitoribosomal small subunit, associated with a combined complex I and IV deficiency. 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 modelling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated 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 biallelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction. Competing Interests: Declaration of interest The authors declare no competing interests.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu