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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1863

Article

Oerum, Stephanie¹  Roovers, Martine²  Leichsenring, Michael³  Acquaviva-Bourdain, Cecile⁴  Beermann, Frauke⁵  Gemperle-Britschgi, Corinne^6,7  Fouilhoux, Alain⁸  Korwitz-Reichelt, Anne⁹  Bailey, Henry J.¹  Droogmans, Louis¹⁰  Oppermann, Udo^1,11  Sass, Joern Oliver^5,6,7,9  Yue, Wyatt W.¹ 

[1] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Old Rd Campus,Roosevelt Dr, Oxford OX3 7DQ, England

[2] Inst Recherches Microbiol Jean Marie Wiame, Brussels, Belgium

[3] Ulm Univ, Dept Children & Adolescent Med, Med Sch, Ulm, Germany

[4] Grp Hosp Est, Ctr Biol Est, Serv Malad Hereditaires Metabol, Bron, France

[5] Univ Freiburg, Lab Clin Biochem & Metab, Childrens Hosp, Freiburg, Germany

[6] Univ Childrens Hosp, Zurich, Switzerland

[7] Childrens Res Ctr, Clin Chem & Biochem, Zurich, Switzerland

[8] HCL, Ctr Reference Malad Hereditaires Metab, Bron, France

[9] Bonn Rhein Sieg Univ Appl Sci, Dept Nat Sci, von Liebig Str, D-53359 Rheinbach, Germany

[10] Univ Libre Bruxelles, Lab Microbiol, Brussels, Belgium

[11] Botnar Res Ctr, NIHR Oxford Biomed Res Unit, Oxford, England

关键词: Dehydrogenase;    Mitochondrial tRNA;    HSD10;    Methyltransferase;    tRNA processing;    MRPP;   

DOI  :  10.1016/j.bbadis.2017.09.002

来源: Elsevier

【 摘 要 】

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. Va112 and Va1176 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.

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