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Friederich, M.W.* ; Geddes, G.C.* ; Wortmann, S.B.* ; Punnoose, A.* ; Wartchow, E.* ; Knight, K.M.* ; Prokisch, H. ; Creadon-Swindell, G.* ; Mayr, J.A.* ; van Hove, J.L.K.*

Pathogenic variants in MRPL44 cause infantile cardiomyopathy due to a mitochondrial translation defect.

Mol. Genet. Metab. 133, 362-371 (2021)

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Cardiac dysfunction is a common phenotypic manifestation of primary mitochondrial disease with multiple nuclear and mitochondrial DNA pathogenic variants as a cause, including disorders of mitochondrial translation. To date, five patients have been described with pathogenic variants in MRPL44, encoding the ml44 protein which is part of the large subunit of the mitochondrial ribosome (mitoribosome). Three presented as infants with hypertrophic cardiomyopathy, mild lactic acidosis, and easy fatigue and muscle weakness, whereas two presented in adolescence with myopathy and neurological symptoms. We describe two infants who presented with cardiomyopathy from the neonatal period, failure to thrive, hypoglycemia and in one infant lactic acidosis. A decompensation of the cardiac function in the first year resulted in demise. Exome sequencing identified compound heterozygous variants in the MRPL44 gene including the known pathogenic variant c.467 T > G and two novel pathogenic variants. We document a combined respiratory chain enzyme deficiency with emphasis on complex I and IV, affecting heart muscle tissue more than skeletal muscle or fibroblasts. We show this to be caused by reduced mitochondrial DNA encoded protein synthesis affecting all subunits, and resulting in dysfunction of complex I and IV assembly. The degree of oxidative phosphorylation dysfunction correlated with the impairment of mitochondrial protein synthesis due to different pathogenic variants. These functional studies allow for improved understanding of the pathogenesis of MRPL44-associated mitochondrial disorder.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cardiomyopathy ; Combined Deficiency ; Genetic Cause ; Mitochondrial Ribosome ; Mitochondrial Translation; Mutations Cause; Large Subunit; Ribosome; Disease; Deficiency

ISSN (print) / ISBN 1096-7192

e-ISSN 1096-7192

Journal Molecular Genetics and Metabolism

Quellenangaben Volume: 133, Issue: 4, Pages: 362-371

Publisher Elsevier

Publishing Place 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants Horizon2020 through ERA PerMed project PerMiM
Horizon2020 through the ERare project GENOMIT
German BMBF
German Federal Ministry of Education and Research (BMBF, Bonn, Germany) research grant "German Network for Mitochondrial Disorders" (mitoNET)
Austrian Science Fund (FWF)
NCATS
National Institutes of Health
Children's Hospital Colorado Foundation