Antenatal mitochondrial disease caused by mitochondrial ribosomal protein (MRPS22) mutation

Saada, Ann; Shaag, Avraham; Arnon, Shmuel; Dolfin, Tzipora; Miller, Chaya; Fuchs-Telem, Dana; Lombès, Anne; Elpeleg, Orly

doi:10.1136/jmg.2007.053116

Cited by 147 publications

(100 citation statements)

References 10 publications

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“…Recently, a MRPS22 defect was shown to strongly hamper assembly of the small ribosomal subunit, whereas assembly of the large subunit and part of the small subunit were only mildly affected. 30 This is consistent with both our and previous findings that mutations in mitochondrial ribosomal small subunit proteins cause a marked decrease in the abundance of the 12S rRNA transcript and nearly no reduction in the level of 16S rRNA, 6,7 as rRNAs are readily degraded unless they are incorporated into a ribosomal subunit. 31 Thus, although MRPS22 is evolutionary not well conserved, it is indispensable for the assembly of the human mitochondrial ribosome and consequently, as we have shown, for effective mitochondrial protein synthesis.…”

Section: Discussionsupporting

confidence: 81%

“…31 Thus, although MRPS22 is evolutionary not well conserved, it is indispensable for the assembly of the human mitochondrial ribosome and consequently, as we have shown, for effective mitochondrial protein synthesis. Previously, a missense mutation in MRPS22 (Arg170His) 7 and a non-sense mutation in MRPS16 (Arg111X), 6 which is highly conserved and essential for ribosome assembly, 29,30,32 were reported to be lethal. The clinical phenotypes of patients with MRPS16 or MRPS22 mutations bear resemblances.…”

Section: Discussionmentioning

confidence: 99%

“…Control and patient cells were infected with the lentiviral construct carrying the wild-type MRPS22, and clones of stably transfected cells were established by blasticin (4 mg/ml) selection and by selection on glucose-free medium. 7,25 Patient cells were also transiently transfected with the lentiviral vector carrying an expression control plasmid, pLenti6/V5-GW/lacZ (Invitrogen).…”

Section: Transfection With Wild-type Mrps22 Cdnamentioning

confidence: 99%

“…All other mitochondrial proteins, including over 70 OXPHOS subunits and all proteins of the mitochondrial translation machinery, are encoded by nuclear genes. The majority of mutations associated with combined OXPHOS deficiencies because of impaired mitochondrial translation are located in mtDNA genes; 1 however, the list of nDNA mutations is steadily growing with defects reported in mitochondrial translation factors, 2-5 mitochondrial ribosomal proteins, 6,7 mitochondrial tRNA synthetases [8][9][10] and tRNA-modifying enzymes. [11][12][13] We investigated a group of 33 patients with combined OXPHOS deficiencies (and normal complex II activities) by mutational analysis of the entire mtDNA, polymerase gamma and nuclear genes implicated in mitochondrial translation.…”

Section: Introductionmentioning

confidence: 99%

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Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy

et al. 2010

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The oxidative phosphorylation (OXPHOS) system is under control of both the mitochondrial and the nuclear genomes; 13 subunits are synthesized by the mitochondrial translation machinery. We report a patient with Cornelia de Lange-like dysmorphic features, brain abnormalities and hypertrophic cardiomyopathy, and studied the genetic defect responsible for the combined OXPHOS complex I, III and IV deficiency observed in fibroblasts. The combination of deficiencies suggested a primary defect associated with the synthesis of mitochondrially encoded OXPHOS subunits. Analysis of mitochondrial protein synthesis revealed a marked impairment in mitochondrial translation. Homozygosity mapping and sequence analysis of candidate genes revealed a homozygous mutation in MRPS22, a gene encoding a mitochondrial ribosomal small subunit protein. The mutation predicts a Leu215Pro substitution at an evolutionary conserved site. Mutations in genes implicated in Cornelia de Lange syndrome or copy number variations were not found. Transfection of patient fibroblasts, in which MRPS22 was undetectable, with the wild-type MRPS22 cDNA restored the amount and activity of OXPHOS complex IV, as well as the 12S rRNA transcript level to normal values. These findings demonstrate the pathogenicity of the MRPS22 mutation and stress the significance of mutations in nuclear genes, including genes that have no counterparts in lower species like bacteria and yeast, for mitochondrial translation defects.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Transfection With Wild-type Mrps22 Cdnamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy

et al. 2010

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“…[4][5][6] Molecular defects that impair different components of the mitochondrial translation machinery can cause combined OXPHOS deficiency. 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.…”

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

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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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Antenatal mitochondrial disease caused by mitochondrial ribosomal protein (MRPS22) mutation

Cited by 147 publications

References 10 publications

Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy

Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy

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

The Diseased Mitoribosome

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