Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits

Glasgow, Ruth I.C.; Thompson, Kyle; Barbosa, Inês A.; He, Langping; Alston, Charlotte L.; Deshpande, Charu; Simpson, Michael A.; Morris, Andrew A. M.; Neu, Axel; Löbel, Ulrike; Hall, Julie; Prokisch, Holger; Haack, Tobias B.; Hempel, Maja; McFarland, Robert; Taylor, Robert W.

doi:10.1007/s10048-017-0526-4

Cited by 14 publications

(11 citation statements)

References 28 publications

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“…In the GWAS catalog, GFM1 appears associated with the electrocardiographic PR interval, diastolic blood pressure, and diarrhea. Mutations in GFM2 result in COXPD39 with complex IV deficiency and subsequent ataxic hypotonia followed by Leigh syndrome leukodystrophy [ 68 ]. For TUFM, mutations trigger COXPD4 with complex IV deficiency and rapidly progressive encephalopathy [ 69 ].…”

Section: Genotype–phenotype Correlationmentioning

confidence: 99%

The Bacterial ClpXP-ClpB Family Is Enriched with RNA-Binding Protein Complexes

Auburger

Key

Gispert

2022

Cells

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In the matrix of bacteria/mitochondria/chloroplasts, Lon acts as the degradation machine for soluble proteins. In stress periods, however, proteostasis and survival depend on the strongly conserved Clp/Hsp100 family. Currently, the targets of ATP-powered unfoldases/disaggregases ClpB and ClpX and of peptidase ClpP heptameric rings are still unclear. Trapping experiments and proteome profiling in multiple organisms triggered confusion, so we analyzed the consistency of ClpP-trap targets in bacteria. We also provide meta-analyses of protein interactions in humans, to elucidate where Clp family members are enriched. Furthermore, meta-analyses of mouse complexomics are provided. Genotype–phenotype correlations confirmed our concept. Trapping, proteome, and complexome data retrieved consistent coaccumulation of CLPXP with GFM1 and TUFM orthologs. CLPX shows broad interaction selectivity encompassing mitochondrial translation elongation, RNA granules, and nucleoids. CLPB preferentially attaches to mitochondrial RNA granules and translation initiation components; CLPP is enriched with them all and associates with release/recycling factors. Mutations in CLPP cause Perrault syndrome, with phenotypes similar to defects in mtDNA/mtRNA. Thus, we propose that CLPB and CLPXP are crucial to counteract misfolded insoluble protein assemblies that contain nucleotides. This insight is relevant to improve ClpP-modulating drugs that block bacterial growth and for the treatment of human infertility, deafness, and neurodegeneration.

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Section: Genotype–phenotype Correlationmentioning

confidence: 99%

The Bacterial ClpXP-ClpB Family Is Enriched with RNA-Binding Protein Complexes

Auburger

Key

Gispert

2022

Cells

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“…In the GWAS catalog, GFM1 appears associated with the electrocardiographic PR interval, diastolic blood pressure, and diarrhea. Mutations in GFM2 result in COXPD39 with complex IV deficiency and subsequent ataxic hypotonia followed by Leigh syndrome leukodystrophy [64]. For TUFM, mutations trigger COXPD4 with complex IV deficiency and rapidly progressive encephalopathy [65].…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

The Bacterial ClpXP-ClpB Family is Enriched with RNA-Binding Protein Complexes

Auburger¹,

Key²,

Gispert³

2022

Preprint

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In the matrix of bacteria/mitochondria/chloroplasts, Lon acts as the degradation machine for soluble proteins. In stress periods, however, proteostasis and survival depend on the strongly conserved Clp/Hsp100 family. Currently, the targets of ATP-powered unfoldases/disaggregases ClpB and ClpX, and of peptidase ClpP heptameric rings, are still unclear. Trapping experiments and proteome profiling in multiple organisms triggered confusion, so we analyzed the consistency of ClpP-trap targets in bacteria. We also provide meta-analyses of protein interactions in humans, to elucidate where Clp family members are enriched. Furthermore, meta-analyses of mouse complexomics are provided. Genotype-phenotype correlations confirmed our concept. Trapping, proteome, and complexome data retrieved consistent coaccumulation of ClpXP with GFM1 and TUFM orthologs. ClpX shows broad interaction selectivity encompassing mitochondrial translation elongation, RNA granule, and nucleoid; ClpB preferentially attaches to mitochondrial RNA granule and translation initiation components; ClpP is enriched with them all, and associates with release/recycling factors. Mutations in ClpP cause Perrault syndrome, with phenotypes similar to defects in mtDNA/mtRNA. Thus, we propose that ClpB and ClpXP are crucial to counteract misfolded insoluble protein assemblies that contain nucleotide-phosphates. This insight is relevant to improve ClpP-modulating drugs that block bacterial growth, and for the treatment of human infertility, deafness and neurodegeneration.

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“…WES was used to identify compound heterozygous (c.569G>A, p.Arg190Gln; c.636delA, p.Glu213Argfs * 3) and homozygous (c.275A>C, p.Tyr92Ser) recessive variants of GFM2 in patients presenting in early childhood with global developmental delay, elevated cerebrospinal fluid levels of lactate, and abnormalities on cranial magnetic resonance imaging (Zhang et al, 2016). Further research also identified these recessive GFM2 variants in two unrelated patients with early-onset neurological presentations of mitochondrial disease (Glasgow et al, 2017).…”

Section: Mitochondrial Translation Recyclingmentioning

confidence: 99%

“…The mtEF-G1 elongation factor displays mitoribosome translocation activity. The EF-G2mt factor disassembles the mitoribosome at the end of translation to allow a subsequent protein-synthesis cycle ( Glasgow et al, 2017 ).…”

Section: Mitochondrial Translation Elongation and Diseasementioning

confidence: 99%

Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease

Wang

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Mitochondria are one of the most important organelles in cells. Mitochondria are semi-autonomous organelles with their own genetic system, and can independently replicate, transcribe, and translate mitochondrial DNA. Translation initiation, elongation, termination, and recycling of the ribosome are four stages in the process of mitochondrial protein translation. In this process, mitochondrial protein translation factors and translation activators, mitochondrial RNA, and other regulatory factors regulate mitochondrial protein translation. Mitochondrial protein translation abnormalities are associated with a variety of diseases, including cancer, cardiovascular diseases, and nervous system diseases. Mutation or deletion of various mitochondrial protein translation factors and translation activators leads to abnormal mitochondrial protein translation. Mitochondrial tRNAs and mitochondrial ribosomal proteins are essential players during translation and mutations in genes encoding them represent a large fraction of mitochondrial diseases. Moreover, there is crosstalk between mitochondrial protein translation and cytoplasmic translation, and the imbalance between mitochondrial protein translation and cytoplasmic translation can affect some physiological and pathological processes. This review summarizes the regulation of mitochondrial protein translation factors, mitochondrial ribosomal proteins, mitochondrial tRNAs, and mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in the mitochondrial protein translation process and its relationship with diseases. The regulation of mitochondrial protein translation and cytoplasmic translation in multiple diseases is also summarized.

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Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits

Cited by 14 publications

References 28 publications

The Bacterial ClpXP-ClpB Family Is Enriched with RNA-Binding Protein Complexes

The Bacterial ClpXP-ClpB Family Is Enriched with RNA-Binding Protein Complexes

The Bacterial ClpXP-ClpB Family is Enriched with RNA-Binding Protein Complexes

Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease

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