Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy

Carroll, Christopher J.; Isohanni, Pirjo; Pöyhönen, Rosanna; Euro, Liliya; Richter, Uwe; Brilhante, Virginia; Götz, Alexandra; Lahtinen, Taina; Paetau, Anders; Pihko, Helena; Battersby, Brendan J.; Tyynismaa, Henna; Suomalainen, Anu

doi:10.1136/jmedgenet-2012-101375

Cited by 91 publications

(75 citation statements)

References 46 publications

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“…7 Specifically, 7 of the 80 genes encoding mitochondrial ribosomal proteins have had pathogenic mutations reported, including autosomal-recessive mutations in MRPS7 (MIM: 611974), 8 MRPS16 (MIM: 609204), 9 MRPS22 (MIM: 605810), 10 MRPS23 (MIM: 611985), 11 MRPL3 (MIM: 607118), 12 MRPL12 (MIM: 602375), 13 and MRPL44 (MIM: 611849). 14 Disorders caused by mutations in mitoribosomal proteins are clinically heterogeneous and multi-systemic, with common features including neurodevelopmental disabilities, brain abnormalities, liver disease, kidney disease, cardiomyopathy, and lactic acidosis. 11,15 They generally lead to death in infancy or early childhood, 15 although survival into teenage years and adulthood has been reported.…”

Section: Introductionmentioning

confidence: 99%

“…11,15 They generally lead to death in infancy or early childhood, 15 although survival into teenage years and adulthood has been reported. 8,14,16 The small number of mitoribosomal genes known to underlie OXPHOS diseases is surprising, since nearly two-thirds of mitoribosomal genes are essential for OXPHOS based on a highthroughput knock-out death screen in cell models. 17 Here, we report four pathogenic recessive mutations in a small mitoribosome subunit gene, MRPS34, not previously associated with human disease that were identified in six individuals from four families with combined OXPHOS defects and Leigh syndrome or Leigh-like disease (MIM: 256000).…”

Section: Introductionmentioning

confidence: 99%

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Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Lake

Webb

Stroud

et al. 2017

The American Journal of Human Genetics

101

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Lake

Webb

Stroud

et al. 2017

The American Journal of Human Genetics

101

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“…Indeed, MRPL12 and MRPL44 mutant fibroblasts present with a reduction in fully assembled LSU without accumulation of subassembly particles at least containing the few subunits tested by immunoblotting (uL3, bL12, mL44 and uL13) [211,212]. Unfortunately, no information on the mitochondrial ribosome assembly status is available for SSU pathogenic mutants.…”

Section: Defective Ribosome Assembly and Human Diseasementioning

confidence: 95%

“…A homozygous MRPL12 mutation was associated with growth retardation and neurological deterioration in a single patient born to consanguineous parents [211]. Finally, a homozygous MRPL44 mutation was identified in two siblings suffering from recessive hypertrophic cardiomyopathy [212]. Since the mammalian mitoribosome (55S) contains more than 80 protein components that make up the 28S SSU and 39S LSU, it is likely that more pathogenic mutations in the constituent polypeptides will be uncovered in the near future.…”

Section: Defective Ribosome Assembly and Human Diseasementioning

confidence: 97%

“…Remarkably, mutations in SSU and LSU proteins lead to decreased steady state levels of 12S rRNA and 16S rRNA, respectively [206,207,[209][210][211][212] and apparent failure to accumulate assembly intermediates. Indeed, MRPL12 and MRPL44 mutant fibroblasts present with a reduction in fully assembled LSU without accumulation of subassembly particles at least containing the few subunits tested by immunoblotting (uL3, bL12, mL44 and uL13) [211,212].…”

Section: Defective Ribosome Assembly and Human Diseasementioning

confidence: 98%

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Mitochondrial ribosome assembly in health and disease

et al. 2015

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The ribosome is a structurally and functionally conserved macromolecular machine universally responsible for catalyzing protein synthesis. Within eukaryotic cells, mitochondria contain their own ribosomes (mitoribosomes), which synthesize a handful of proteins, all essential for the biogenesis of the oxidative phosphorylation system. High-resolution cryo-EM structures of the yeast, porcine and human mitoribosomal subunits and of the entire human mitoribosome have uncovered a wealth of new information to illustrate their evolutionary divergence from their bacterial ancestors and their adaptation to synthesis of highly hydrophobic membrane proteins. With such structural data becoming available, one of the most important remaining questions is that of the mitoribosome assembly pathway and factors involved. The regulation of mitoribosome biogenesis is paramount to mitochondrial respiration, and thus to cell viability, growth and differentiation. Moreover, mutations affecting the rRNA and protein components produce severe human mitochondrial disorders. Despite its biological and biomedical significance, knowledge on mitoribosome biogenesis and its deviations from the much-studied bacterial ribosome assembly processes is scarce, especially the order of rRNA processing and assembly events and the regulatory factors required to achieve fully functional particles. This article focuses on summarizing the current available information on mitoribosome assembly pathway, factors that form the mitoribosome assembly machinery, and the effect of defective mitoribosome assembly on human health.

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The Diseased Mitoribosome

2020

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Mitochondria control life and death in eukaryotic cells. Harboring a unique circular genome, a by-product of an ancient endosymbiotic event, mitochondria maintains a specialized and evolutionary divergent protein synthesis machinery, the mitoribosome. Mitoribosome biogenesis depends on elements encoded in both the mitochondrial genome (the RNA components) and the nuclear genome (all ribosomal proteins and assembly factors). Recent cryo-EM structures of mammalian mitoribosomes have illuminated their composition and provided hints regarding their assembly and elusive mitochondrial translation mechanisms. A growing body of literature involves the mitoribosome in inherited primary mitochondrial disorders. Mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors impede mitoribosome biogenesis, causing protein synthesis defects that lead to respiratory chain failure and mitochondrial disorders such as encephalo-and cardiomyopathy, deafness, neuropathy, and developmental delays. In this article, we review the current fundamental understanding of mitoribosome assembly and function, and the clinical landscape of mitochondrial disorders driven by mutations in mitoribosome components and assembly factors, to portray how basic and clinical studies combined help us better understand both mitochondrial biology and medicine.

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Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy

Abstract: These findings indicate that mitochondrial ribosomal subunit defects can generate tissue-specific manifestations, such as cardiomyopathy.

Cited by 91 publications

References 46 publications

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Mitochondrial ribosome assembly in health and disease

The Diseased Mitoribosome

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