Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

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.

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Publication Details

Journal
The American Journal of Human Genetics
Published
2025-03-04
DOI
https://doi.org/10.1016/j.ajhg.2025.02.005
Citations
5
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
4.03

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article

Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

Sait Tümer, Wyatt W. Yue, Ilka Wittig, Hanifenur Mancılar et al.
5 citations
The American Journal of Human Genetics
RNA regulation and disease
4.03
article

Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

Sait Tümer, Wyatt W. Yue, Ilka Wittig, Hanifenur Mancılar, Christopher J. Carroll, Fatma Nisa Esen, Deniz Kör, Kyle Thompson, Thomas B. Smith, Vehap Topçu, Ahmet Yeşilyurt, Thashi Bharadwaj, Isabelle Schrauwen, Eyyüp Üçtepe, Monika Oláhová, Namanpreet Kaur, Erum Afzal, Raymond T. O’Keefe, Leigh Demain, Janine Smith, Kevin J. Munro, Peter Jamieson, Alfredo Cabrera‐Orefice, Fatma Derya Bulut, Zornitza Stark, Giovanni Zifarelli, Huw B. Thomas, Musaad Abukhalid, Hanan E. Shamseldin, William G. Newman, Peter Bauer, Henry Houlden, Reza Maroofian, Fowzan Sami Alkuraya, Muhammad Ansar, Suzanne M. Leal, Sakina Rehman, Alessandro Rea, Anju Shukla, Mehri Salari, Zubair M. Ahmed, Samantha Carrera, Robert W. Taylor, Langping He, Saima Riazuddin, Firdous Abdulwahab
article en
5 citations

Abstract

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.

The American Journal of Human GeneticsVol. 112(4)
Goethe University Frankfurt (DE), Quaid-i-Azam University (PK), University of Maryland, Baltimore (US), Alfaisal University (SA), University of Arizona (US), Manipal Academy of Higher Education (IN), St George's, University of London (GB), University of the Punjab (PK), Justus-Liebig-Universität Gießen (DE), Columbia University Irving Medical Center (US), King Faisal Specialist Hospital & Research Centre (SA), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), University of Manchester (GB), Northumbria University (GB), St Mary's Hospital (GB), Manchester University NHS Foundation Trust (GB), St Mary's Hospital (GB), Victorian Clinical Genetics Services (AU), German Centre for Cardiovascular Research (DE), Centogene (Germany) (DE), Wellcome Centre for Mitochondrial Research (GB), Centre of Excellence in Molecular Biology (PK), National Institute of Child Health (PK), Sydney Children’s Hospitals Network (AU), National Hospital for Neurology and Neurosurgery (GB), Genomics (United Kingdom) (GB), Intergen (Turkey) (TR), St. Mary's Hospital (GB), University College London (GB), Cukurova University (TR), Shahid Beheshti University of Medical Sciences (IR), Kasturba Medical College, Manipal (IN), Newcastle University (GB)
Wellcome Trust, Action Medical Research, National Institute for Health and Care Research, 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, National Institute of Child Health and Human Development
Openalex Percentile: Top 7%
RNA regulation and disease
4.03
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