Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein

Oerum, Stephanie; Roovers, Martine; Leichsenring, Michael; Acquaviva‐Bourdain, Cécile; Beermann, Frauke; Gemperle-Britschgi, Corinne; Fouilhoux, Alain; Korwitz-Reichelt, Anne; Bailey, H.; Droogmans, Louis; Oppermann, U.; Sass, J. O.; Yue, Wyatt W.

doi:10.1016/j.bbadis.2017.09.002

Cited by 37 publications

(33 citation statements)

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“…In patients in whom the diagnosis of MATD was based on metabolite data only (without rather labile 2methylacetoacetic acid), but not confirmed on enzyme and/or mutation level, it needs to be considered that patients were possibly not affected by MATD but by HSD10 mitochondrial disease (HSD10MD; OMIM 300438). HSD10 mitochondrial disease is caused by a hemizygous or heterozygous mutation in the HSD17B10 gene [23,24]. The suspicion that patients actually had HSD10 mitochondrial disease prompted us to exclude two brothers from this study, who have been reported as beta-ketothiolase deficient by Jänisch et al 1993 andHesse et al 2004 [25,26], but in whom we consider published clinical and enzyme data rather nonsuggestive for MATD.…”

Section: Discussionmentioning

confidence: 99%

2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways

Grünert

Sass

2020

Orphanet J Rare Dis

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Background: 2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD; deficiency of mitochondrial acetoacetylcoenzyme A thiolase T2/ "beta-ketothiolase") is an autosomal recessive disorder of ketone body utilization and isoleucine degradation due to mutations in ACAT1. Methods: We performed a systematic literature search for all available clinical descriptions of patients with MATD. Two hundred forty-four patients were identified and included in this analysis. Clinical course and biochemical data are presented and discussed. Results: For 89.6% of patients at least one acute metabolic decompensation was reported. Age at first symptoms ranged from 2 days to 8 years (median 12 months). More than 82% of patients presented in the first 2 years of life, while manifestation in the neonatal period was the exception (3.4%). 77.0% (157 of 204 patients) of patients showed normal psychomotor development without neurologic abnormalities. Conclusion: This comprehensive data analysis provides a systematic overview on all cases with MATD identified in the literature. It demonstrates that MATD is a rather benign disorder with often favourable outcome, when compared with many other organic acidurias.

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Section: Discussionmentioning

confidence: 99%

2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways

Grünert

Sass

2020

Orphanet J Rare Dis

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“…MRPP2 (also known as HSD10/SDR5C1) belongs to the short-chain dehydrogenase/reductases (SDR) family and is involved in the catabolism of isoleucine and steroid metabolism [ 14 ]. MRPP2 also interacts in a complex with MRPP1 (TRMT10C) and MRPP3 (also known as PRORP), proteins involved in 5′-end processing of mitochondrial precursor tRNA [ 5 ].…”

Section: Maturation Of the Primary Transcript: Pre-rna Processingmentioning

confidence: 99%

“…Two additional patients were reported with variable severity of developmental delay, epilepsy, and cardiac involvement. As a hallmark of the disease, urinary organic acid analysis showed elevated levels of 2-methyl-3-hydroxybutyric acid and tiglylglycine, and abnormalities were also detected in the acyl-carnitine spectrum in some cases [ 14 ].…”

Section: Maturation Of the Primary Transcript: Pre-rna Processingmentioning

confidence: 99%

Mitochondrial DNA transcription and translation: clinical syndromes

Boczonadi

Ricci

Horvath

2018

Essays in Biochemistry

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Diagnosing primary mitochondrial diseases is challenging in clinical practice. Although, defective oxidative phosphorylation (OXPHOS) is the common final pathway, it is unknown why different mtDNA or nuclear mutations result in largely heterogeneous and often tissue -specific clinical presentations. Mitochondrial tRNA (mt-tRNA) mutations are frequent causes of mitochondrial diseases both in children and adults. However numerous nuclear mutations involved in mitochondrial protein synthesis affecting ubiquitously expressed genes have been reported in association with very tissue specific clinical manifestations suggesting that there are so far unknown factors determining the tissue specificity in mitochondrial translation. Most of these gene defects result in histological abnormalities and multiple respiratory chain defects in the affected organs. The clinical phenotypes are usually early-onset, severe, and often fatal, implying the importance of mitochondrial translation from birth. However, some rare, reversible infantile mitochondrial diseases are caused by very specific defects of mitochondrial translation. An unbiased genetic approach (whole exome sequencing, RNA sequencing) combined with proteomics and functional studies revealed novel factors involved in mitochondrial translation which contribute to the clinical manifestation and recovery in these rare reversible mitochondrial conditions.

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“…This last Trm10 homolog is a component of the mitochondrial RNaseP complex (Holzmann et al 2008), in which TrmT10C forms a subcomplex with the dehydrogenase HSD10. Association of TrmT10C with HSD10 is required for tRNA MTase activity (Vilardo and Rossmanith 2015;Oerum et al 2017b).…”

Section: Introductionmentioning

confidence: 99%

Structural and biochemical analysis of the dual-specificity Trm10 enzyme from Thermococcus kodakaraensis prompts reconsideration of its catalytic mechanism

Singh

Feller

Roovers³

et al. 2018

RNA

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tRNA molecules get heavily modified post-transcriptionally. The N-1 methylation of purines at position 9 of eukaryal and archaeal tRNA is catalyzed by the SPOUT methyltranferase Trm10. Remarkably, while certain Trm10 orthologs are specific for either guanosine or adenosine, others show a dual specificity. Structural and functional studies have been performed on guanosine- and adenosine-specific enzymes. Here we report the structure and biochemical analysis of the dual-specificity enzyme from (Trm10). We report the first crystal structure of a construct of this enzyme, consisting of the N-terminal domain and the catalytic SPOUT domain. Moreover, crystal structures of the SPOUT domain, either in the apo form or bound to -adenosyl-l-methionine or-adenosyl-l-homocysteine reveal the conformational plasticity of two active site loops upon substrate binding. Kinetic analysis shows that Trm10 has a high affinity for its tRNA substrates, while the enzyme on its own has a very low methyltransferase activity. Mutation of either of two active site aspartate residues (Asp206 and Asp245) to Asn or Ala results in only modest effects on the N-1 methylation reaction, with a small shift toward a preference for mG formation over mA formation. Only a double D206A/D245A mutation severely impairs activity. These results are in line with the recent finding that the single active-site aspartate was dispensable for activity in the guanosine-specific Trm10 from yeast, and suggest that also dual-specificity Trm10 orthologs use a noncanonical tRNA methyltransferase mechanism without residues acting as general base catalysts.

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Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein

Cited by 37 publications

References 37 publications

2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways

2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways

Mitochondrial DNA transcription and translation: clinical syndromes

Structural and biochemical analysis of the dual-specificity Trm10 enzyme from Thermococcus kodakaraensis prompts reconsideration of its catalytic mechanism

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