Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies

Metodiev, Metodi D.; Thompson, Kyle R.; Alston, Charlotte L.; Morris, Andrew A. M.; He, Lili; Assouline, Zarah; Rio, Marlène; Bahi‐Buisson, Nadia; Pyle, Angela; Griffin, Helen; Siira, Stefan J.; Filipovska, Aleksandra; Münnich, Arnold; Chinnery, Patrick F.; McFarland, Robert; Rötig, Agnès; Taylor, Robert W.

doi:10.1016/j.ajhg.2016.06.013

Cited by 40 publications

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“…2B). A similar, but more pronounced, OXPHOS defect was also observed in patients with pathogenic variants in TRMT10C (41) and HSD17B10 (encoding SDR5C1) (42). OXPHOS deficiency has also been associated with Perrault syndrome in patients with variants in ERAL1 (10).…”

Section: Discussionsupporting

confidence: 55%

“…We observed normal levels of PRORP in patient fibroblasts (Fig. 2A), which contrasts with the reduction of the other two subunits of mtRNase P, SDR5C1 (28, 40) and TRMT10C (41) in patients with inherited deficiencies of those proteins. Accumulation of multiple unprocessed transcripts in patient fibroblasts indicated a generalised defect in mitochondrial tRNA processing (Fig.…”

Section: Discussionmentioning

confidence: 74%

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A homozygous variant in mitochondrial RNase P subunit PRORP is associated with Perrault syndrome characterized by hearing loss and primary ovarian insufficiency

Hochberg

Demain

Urquhart

et al. 2017

Preprint

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Perrault syndrome is a rare autosomal recessive condition characterised by sensorineural hearing loss in both sexes and primary ovarian insufficiency in 46 XX, females. It is genetically heterogeneous with biallelic variants in six genes identified to date (HSD17B4, HARS2, LARS2, CLPP, C10orf2 and ERAL1). Most genes possessing variants associated with Perrault syndrome are involved in mitochondrial translation. We describe a consanguineous family with three affected individuals homozygous for a novel missense variant c.1454C>T; p.(Ala485Val) in KIAA0391, encoding proteinaceous RNase P (PRORP), the metallonuclease subunit of the mitochondrial RNase P complex, responsible for the 5’-end processing of mitochondrial precursor tRNAs. In RNase P activity assays, RNase P complexes containing the PRORP disease variant produced ~35-45% less 5’-processed tRNA than wild type PRORP. Consistently, the accumulation of unprocessed polycistronic mitochondrial transcripts was observed in patient dermal fibroblasts, leading to an observable loss of steady-state levels of mitochondrial oxidative phosphorylation components. Expression of wild type KIAA0391 in patient fibroblasts rescued tRNA processing. Immunohistochemistry analyses of the auditory sensory epithelium from postnatal and adult mouse inner ear showed a high level of PRORP in the efferent synapses and nerve fibres of hair cells, indicating a possible mechanism for the sensorineural hearing loss observed in affected individuals. We have identified a variant in an additional gene associated with Perrault syndrome. With the identification of this disease-causing variant in KIAA0391, reduced function of each of the three subunits of mitochondrial RNase P have now been associated with distinct clinical presentations.Author SummaryPerrault syndrome is a rare genetic condition which results in hearing loss in both sexes and ovarian dysfunction in females. Perrault syndrome may also cause neurological symptoms in some patients. Here, we present the features and genetic basis of the condition in three sisters affected by Perrault syndrome. The sisters did not have pathogenic variants in any of the genes previously associated with Perrault syndrome. We identified a change in the gene KIAA0391, encoding PRORP, a subunit of the mitochondrial RNase P complex. Mitochondrial RNase P is a key enzyme in RNA processing in mitochondria. Impaired RNA processing reduces protein production in mitochondria, which we observed in patient cells along with high levels of unprocessed RNA. When we expressed wild type PRORP in patient cells, the RNA processing improved. We also investigated PRORP localisation in the mouse inner ear and found high levels in the synapses and nerve fibers that transmit sound. It may be that disruption of RNA processing in the mitochondria of these cells causes hearing loss in this family.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 74%

A homozygous variant in mitochondrial RNase P subunit PRORP is associated with Perrault syndrome characterized by hearing loss and primary ovarian insufficiency

Hochberg

Demain

Urquhart

et al. 2017

Preprint

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“…Of these, TRMT10C localizes to mitochondria and modifies mitochondrial tRNAs while TRMT10A and TRMT10B modify cytoplasmic tRNAs [165]. In accordance with its localized function, mutations in TRMT10C cause mitochondrial disorders [166]. Association of mutations in TRMT10A with microcephaly and young onset diabetes reaffirms its regulatory role in lineage differentiation [167,168,169,170,171].…”

Section: Amplification and Diversification Of Eukaryal Trna Methymentioning

confidence: 99%

Factors That Shape Eukaryotic tRNAomes: Processing, Modification and Anticodon–Codon Use

Maraia

Arimbasseri

2017

Biomolecules

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Transfer RNAs (tRNAs) contain sequence diversity beyond their anticodons and the large variety of nucleotide modifications found in all kingdoms of life. Some modifications stabilize structure and fit in the ribosome whereas those to the anticodon loop modulate messenger RNA (mRNA) decoding activity more directly. The identities of tRNAs with some universal anticodon loop modifications vary among distant and parallel species, likely to accommodate fine tuning for their translation systems. This plasticity in positions 34 (wobble) and 37 is reflected in codon use bias. Here, we review convergent evidence that suggest that expansion of the eukaryotic tRNAome was supported by its dedicated RNA polymerase III transcription system and coupling to the precursor-tRNA chaperone, La protein. We also review aspects of eukaryotic tRNAome evolution involving G34/A34 anticodon-sparing, relation to A34 modification to inosine, biased codon use and regulatory information in the redundancy (synonymous) component of the genetic code. We then review interdependent anticodon loop modifications involving position 37 in eukaryotes. This includes the eukaryote-specific tRNA modification, 3-methylcytidine-32 (m3C32) and the responsible gene, TRM140 and homologs which were duplicated and subspecialized for isoacceptor-specific substrates and dependence on i6A37 or t6A37. The genetics of tRNA function is relevant to health directly and as disease modifiers.

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“…MRPP1, 2, and 3 are required for the proper processing of mitochondrial transcripts in vivo, including transcripts that encode for respiratory chain complexes. Disruption of these processes leads to mitochondrial dysfunction and disease (14)(15)(16)(17). Recessive MRPP1 mutations destabilize the mutant protein and lead to inadequate processing of mt-tRNA and low levels of assembled respiratory chain complexes (15).…”

mentioning

confidence: 99%

“…Disruption of these processes leads to mitochondrial dysfunction and disease (14)(15)(16)(17). Recessive MRPP1 mutations destabilize the mutant protein and lead to inadequate processing of mt-tRNA and low levels of assembled respiratory chain complexes (15). Pathogenic mutations located in MRPP2 lead to a reduction in MRPP1 and MRPP2 protein levels and tRNA processing (18,19).…”

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confidence: 99%

Kinetic mechanism of human mitochondrial RNase P

Liu

Shanmuganathan

et al. 2019

Preprint

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A first step in processing mitochondrial precursor tRNA (pre-tRNA) is cleavage of the 5' leader catalyzed by ribonuclease P (RNase P). Human mitochondrial RNase P (mtRNase P) is composed of three protein subunits: mitochondrial RNase P protein (MRPP) 1, 2 and 3. Even though MRPP3 is the metallonuclease subunit responsible for catalysis, cleavage is observed only in the presence of the MRPP1/2 subcomplex. To understand the functional role of MRPP1/2, we reconstituted human mitochondrial RNase P in vitro and performed kinetic and thermodynamic analyses. MRPP1/2 significantly enhances both the catalytic activity and the apparent substrate affinity of mtRNase P. Additionally, pull-down and binding data demonstrate synergy between binding pre-tRNA and formation of a catalytically active MRPP1/2/3 complex. These data suggest that conformational changes in the MRPP1/2-pre-tRNA complex lead to protein-protein or protein-RNA interactions that increase both MRPP3 recognition and cleavage efficiency. This work presents the first kinetic model for human mtRNase P, providing a fundamental framework for the function of † The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

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Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies

Abstract: In the originally published version of this article, Table 1 unfortunately included c.542G>A instead of c.542G>T. This mutation was correctly notated as c.

Cited by 40 publications

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A homozygous variant in mitochondrial RNase P subunit PRORP is associated with Perrault syndrome characterized by hearing loss and primary ovarian insufficiency

A homozygous variant in mitochondrial RNase P subunit PRORP is associated with Perrault syndrome characterized by hearing loss and primary ovarian insufficiency

Factors That Shape Eukaryotic tRNAomes: Processing, Modification and Anticodon–Codon Use

Kinetic mechanism of human mitochondrial RNase P

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