Friederich 2021 Mol Genet Metab

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Friederich MW, Geddes GC, Wortmann SB, Punnoose A, Wartchow E, Knight KM, Prokisch H, Creadon-Swindell G, Mayr JA, Van Hove JLK (2021) Pathogenic variants in MRPL44 cause infantile cardiomyopathy due to a mitochondrial translation defect. Mol Genet Metab 133:362-71.

Β» PMID: 34140213

Friederich Marisa W, Geddes Gabrielle C, Wortmann Saskia B, Punnoose Ann, Wartchow Eric, Knight Kaz M, Prokisch Holger, Creadon-Swindell Geralyn, Mayr Johannes A, Van Hove Johan L K (2021) Mol Genet Metab

Abstract: 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. β€’ Keywords: Cardiomyopathy, Combined deficiency, Genetic cause, Mitochondrial ribosome, Mitochondrial translation β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: US CO Denver Van Hove J

Labels: MiParea: Respiration, mtDNA;mt-genetics, Patients  Pathology: Cardiovascular, Myopathy  Stress:Mitochondrial disease  Organism: Human  Tissue;cell: Fibroblast 

Coupling state: LEAK, OXPHOS, ET  Pathway:HRR: Oxygraph-2k 


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