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

dc.contributor.authorFriederich, Marisa W.
dc.contributor.authorGeddes, Gabrielle C.
dc.contributor.authorWortmann, Saskia B.
dc.contributor.authorPunnoose, Ann
dc.contributor.authorWartchow, Eric
dc.contributor.authorKnight, Kaz M.
dc.contributor.authorProkisch, Holger
dc.contributor.authorCreadon-Swindell, Geralyn
dc.contributor.authorMayr, Johannes A.
dc.contributor.authorVan Hove, Johan L. K.
dc.contributor.departmentMedical and Molecular Genetics, School of Medicine
dc.date.accessioned2024-04-02T13:13:12Z
dc.date.available2024-04-02T13:13:12Z
dc.date.issued2021
dc.description.abstractCardiac 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.467T>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.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationFriederich MW, Geddes GC, Wortmann SB, et al. Pathogenic variants in MRPL44 cause infantile cardiomyopathy due to a mitochondrial translation defect. Mol Genet Metab. 2021;133(4):362-371. doi:10.1016/j.ymgme.2021.06.001
dc.identifier.urihttps://hdl.handle.net/1805/39683
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.ymgme.2021.06.001
dc.relation.journalMolecular Genetics and Metabolism
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectCardiomyopathy
dc.subjectCombined deficiency
dc.subjectGenetic cause
dc.subjectMitochondrial ribosome
dc.subjectMitochondrial translation
dc.titlePathogenic variants in MRPL44 causes infantile cardiomyopathy due to a mitochondrial translation defect
dc.typeArticle
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