MRPS22 mutation causes fatal neonatal lactic acidosis with brain and heart abnormalities

Baertling, Fabian; Haack, Tobias B.; Rodenburg, Richard J.; Schaper, Jörg; Seibt, Annette; Strom, Tim M.; Meitinger, Thomas; Mayatepek, Ertan; Hadzik, Berit; Selcan, Gündüz; Prokisch, Holger; Distelmaier, Felix

doi:10.1007/s10048-015-0440-6

Cited by 35 publications

(20 citation statements)

References 10 publications

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“…Thus, we consider that SILAC can distinguish between MRPs that participate at early and late stages in mitoribosome assembly. Interestingly, several MRPs implicated to date in serious mitochondrial disorders participate at early stages in mitoribosome assembly, including uL3, mL44, uS7m, mS22, and uS16m (Baertling et al, 2015; Carroll et al, 2013; Distelmaier et al, 2015; Emdadul Haque et al, 2008; Menezes et al, 2015; Miller et al, 2004; Saada et al, 2007; Smits et al, 2011). Lack of an early-binding protein may be more likely to disrupt mitoribosome structure and subsequent steps in assembly.…”

Section: Discussionmentioning

confidence: 99%

Kinetics and Mechanism of Mammalian Mitochondrial Ribosome Assembly

et al. 2018

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Summary Mammalian mtDNA encodes only 13 proteins, all essential components of respiratory complexes, synthesized by mitochondrial ribosomes. Mitoribosomes contain greatly truncated RNAs transcribed from mtDNA, including a structural tRNA in place of 5S RNA as a scaffold for binding 82 nucleus-encoded proteins, mitoribosomal proteins (MRPs). Cryoelectron microscopy (cryo-EM) studies have determined the structure of the mitoribosome, but its mechanism of assembly is unknown. Our SILAC pulse-labeling experiments determine the rates of mitochondrial import of MRPs and their assembly into intact mitoribosomes, providing a basis for distinguishing MRPs that bind at early and late stages in mitoribosome assembly to generate a working model for mitoribosome assembly. Mitoribosome assembly is a slow process initiated at the mtDNA nucleoid driven by excess synthesis of individual MRPs. MRPs that are tightly associated in the structure frequently join the complex in a coordinated manner. Clinically significant MRP mutations reported to date affect proteins that bind early on during assembly.

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Section: Discussionmentioning

confidence: 99%

Kinetics and Mechanism of Mammalian Mitochondrial Ribosome Assembly

et al. 2018

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“…Our report widens the clinical phenotype of VARS2 deficiency with severe neonatal lactic acidosis, cardiomyopathy, structural brain abnormalities as well as early-onset epileptic encephalopathy. This adds VARS2 to the list of genes that should be considered in the differential diagnosis of neonatal mitochondrial encephalocardiomyopathies similar to defects in mitochondrial translation elongation factors or mitochondrial ribosomal protein genes [4,[6][7][8][9]. Additional clinical reports are required to further define the clinical spectrum associated with VARS2 deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…SDS-PAGE and western blotting/immunodetection were performed as previously described [4]. 25µg of fibroblast whole cell protein were separated in a ready-to-use 4-12 % SDS-PAGE gradient gel (Invitrogen).…”

Section: Sodium Dodecyl Polyacrylamide Gel Electrophoresis (Sds-page)mentioning

confidence: 99%

Neonatal encephalocardiomyopathy caused by mutations in VARS2

et al. 2016

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VARS2 encodes a mitochondrial aminoacyl-tRNA-synthetase. Mutations in VARS2 have recently been identified as a cause of mitochondrial encephalomyopathy in three individuals. However, clinical information remained scarce. Exome sequencing lead us to identify compound heterozygous pathogenic VARS2 variants in a boy presenting with severe lactic acidosis, hypertrophic cardiomyopathy, epilepsy, and abnormalities on brain imaging including hypoplasia of corpus callosum and cerebellum as well as a massive lactate peak on MR-spectroscopy. Studies in patient-derived fibroblasts confirmed the functional relevance of the identified VARS2 variants. Our report expands the phenotypic spectrum associated with this rare mitochondrial defect, in that VARS2 deficiency may also cause severe neonatal presentations with cardiac involvement and structural brain abnormalities.

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“…Translation in the mitochondria is 5′‐CAP independent and shows marked similarities to bacterial translation. Mutations in mitochondrial ribosomal proteins preventing ribosome formation cause growth retardation and fatal lactic acidosis (Miller et al ., ; Baertling et al ., ).…”

Section: Mechanisms Contributing To the Maintenance Of Skeletal Musclmentioning

confidence: 97%

Muscle wasting in the presence of disease, why is it so variable?

2018

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Skeletal muscle wasting is a common clinical feature of many chronic diseases and also occurs in response to single acute events. The accompanying loss of strength can lead to significant disability, increased care needs and have profound negative effects on quality of life. As muscle is the most abundant source of amino acids in the body, it appears to function as a buffer for fuel and substrates that can be used to repair damage elsewhere and to feed the immune system. In essence, the fundamentals of muscle wasting are simple: less muscle is made than is broken down. However, although well-described mechanisms modulate muscle protein turnover, significant individual differences in the amount of muscle lost in the presence of a given severity of disease complicate the understanding of underlying mechanisms and suggest that individuals have different sensitivities to signals for muscle loss. Furthermore, the rate at which muscle protein is turned over under normal conditions means that clinically significant muscle loss can occur with changes in the rate of protein synthesis and/or breakdown that are too small to be measurable. Consequently, the changes in expression of factors regulating muscle turnover required to cause a decline in muscle mass are small and, except in cases of rapid wasting, there is no consistent pattern of change in the expression of factors that regulate muscle mass. MicroRNAs are fine tuners of cell phenotype and are therefore ideally suited to cause the subtle changes in proteome required to tilt the balance between synthesis and degradation in a way that causes clinically significant wasting. Herein we present a model in which muscle loss as a consequence of disease in non-muscle tissue is modulated by a set of microRNAs, the muscle expression of which is associated with severity of disease in the non-muscle tissue. These microRNAs alter fundamental biological processes including the synthesis of ribosomes and mitochondria leading to reduced protein synthesis and increased protein breakdown, thereby freeing amino acids from the muscle. We argue that the variability in muscle loss observed in the human population arises from at least two sources. The first is from pre-existing or disease-induced variation in the expression of microRNAs controlling the sensitivity of muscle to the atrophic signal and the second is from the expression of microRNAs from imprinted loci (i.e. only expressed from the maternally or paternally inherited allele) and may control the rate of myonuclear recruitment. In the absence of disease, these factors do not correlate with muscle mass, since there is no challenge to the established balance. However, in the presence of such a challenge, these microRNAs determine the rate of decline for a given disease severity. Together these mechanisms provide novel insight into the loss of muscle mass and its variation in the human population. The involvement of imprinted loci also suggests that genes that regulate early development also contribute to the ability of individuals...

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MRPS22 mutation causes fatal neonatal lactic acidosis with brain and heart abnormalities

Cited by 35 publications

References 10 publications

Kinetics and Mechanism of Mammalian Mitochondrial Ribosome Assembly

Kinetics and Mechanism of Mammalian Mitochondrial Ribosome Assembly

Neonatal encephalocardiomyopathy caused by mutations in VARS2

Muscle wasting in the presence of disease, why is it so variable?

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