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

  • 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.V12 L and p.V176 M 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.V12 L, whereas the protein carrying p.V176 M 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.

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Document Type:Article
Author:Stephanie Oerum, Martine Roovers, Michael Leichsenring, Cécile Acquaviva-Bourdain, Frauke Beermann, Corinne Gemperle-Britschgi, Alain Fouilhoux, Anne Korwitz-Reichelt, Henry J. Bailey, Louis Droogmans, Udo Oppermann, Jörn Oliver Sass, Wyatt W. Yue
Parent Title (English):Biochim Biophys Acta. (Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease)
First Page:3294
Last Page:3302
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=28888424
Date of first publication:2017/09/07
This work was funded by the Structural Genomics Consortium, which is a registered charity (number 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, T GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry PT of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust RIP (092809/Z/10/Z). The project was also supported by the “Startförderung 2016” of the Bonn-Rhein-Sieg-University of Applied Sciences to J.O.S.
Tag:Dehydrogenase; HSD10; MRPP; Methyltransferase; Mitochondrial tRNA; tRNA processing
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Entry in this database:2017/09/13