2. Academic Validation
  3. Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein

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

  • Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3294-3302. doi: 10.1016/j.bbadis.2017.09.002.
Stephanie Oerum 1,  Martine Roovers 2,  Michael Leichsenring 3,  Cécile Acquaviva-Bourdain 4,  Frauke Beermann 5,  Corinne Gemperle-Britschgi 6,  Alain Fouilhoux 7,  Anne Korwitz-Reichelt 8,  Henry J Bailey 1,  Louis Droogmans 9,  Udo Oppermann 10,  Jörn Oliver Sass 11,  Wyatt W Yue 12
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, OX3 7DQ Oxford, UK.
  • 2 Institut de Recherches Microbiologiques Jean-Marie Wiame, Bruxelles, Belgium.
  • 3 Department for Children and Adolescent Medicine, Ulm University Medical School, Ulm, Germany.
  • 4 Groupement Hospitalier Est, Centre de Biologie Est, Service Maladies Héréditaires du Métabolisme, Bron, France.
  • 5 University of Freiburg Children's Hospital, Laboratory of Clinical Biochemistry and Metabolism, Freiburg, Germany.
  • 6 University Children's Hospital and Children's Research Center, Clinical Chemistry & Biochemistry, Zürich, Switzerland.
  • 7 Centre de Référence des Maladies Héréditaires du Métabolisme, HCL, Bron, France.
  • 8 Bonn-Rhein-Sieg University of Applied Sciences, Department of Natural Sciences, von-Liebig-Str. 20, 53359 Rheinbach, Germany.
  • 9 Laboratoire de Microbiologie, Universite libre de Bruxelles, Belgium.
  • 10 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, OX3 7DQ Oxford, UK; Botnar Research Centre, NIHR Oxford Biomedical Research Unit, Oxford, UK.
  • 11 University of Freiburg Children's Hospital, Laboratory of Clinical Biochemistry and Metabolism, Freiburg, Germany; University Children's Hospital and Children's Research Center, Clinical Chemistry & Biochemistry, Zürich, Switzerland; Bonn-Rhein-Sieg University of Applied Sciences, Department of Natural Sciences, von-Liebig-Str. 20, 53359 Rheinbach, Germany. Electronic address: joern.oliver.sass@h-brs.de.
  • 12 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, OX3 7DQ Oxford, UK. Electronic address: wyatt.yue@sgc.ox.ac.uk.
PMID: 28888424 DOI: 10.1016/j.bbadis.2017.09.002
Abstract

MRPP2 (also known as HSD10/SDR5C1) is a multifunctional protein that harbours both catalytic and non-catalytic functions. The protein belongs to the short-chain dehydrogenase/reductases (SDR) family and is involved in the catabolism of isoleucine in vivo and steroid metabolism in vitro. MRPP2 also moonlights in a complex with the MRPP1 (also known as TRMT10C) protein for N1-methylation of purines at position 9 of mitochondrial tRNA, and in a complex with MRPP1 and MRPP3 (also known as PRORP) proteins for 5'-end processing of mitochondrial precursor tRNA. Inherited mutations in the HSD17B10 gene encoding MRPP2 protein lead to a childhood disorder characterised by progressive neurodegeneration, cardiomyopathy or both. Here we report two patients with novel missense mutations in the HSD17B10 gene (c.34G>C and c.526G>A), resulting in the p.V12L and p.V176M substitutions. Val12 and Val176 are highly conserved residues located at different regions of the MRPP2 structure. Recombinant mutant proteins were expressed and characterised biochemically to investigate their effects towards the functions of MRPP2 and associated complexes in vitro. Both mutant proteins showed significant reduction in the dehydrogenase, methyltransferase and tRNA processing activities compared to wildtype, associated with reduced stability for protein with p.V12L, whereas the protein carrying p.V176M showed impaired kinetics and complex formation. This study therefore identified two distinctive molecular mechanisms to explain the biochemical defects for the novel missense patient mutations.

Keywords

Dehydrogenase; HSD10; MRPP; Methyltransferase; Mitochondrial tRNA; tRNA processing.

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