Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the human mitochondrial RNase P complex. Issue 10 (29th April 2015)

• Record Type: Journal Article
• Authors: Vilardo, Elisa; Rossmanith, Walter
• Is Part Of: Nucleic acids research. Volume 43:Issue 10(2015)
• Page Start: 5112
• Page End: 5119
• Publication Date: 2015-04-29
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkv408
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: SDR5C1 is an amino and fatty acid dehydrogenase/reductase, moonlighting as a component of human mitochondrial RNase P, which is the enzyme removing 5′-extensions of tRNAs, an early and crucial step in tRNA maturation. Moreover, a subcomplex of mitochondrial RNase P catalyzes the N 1 -methylation of purines at position 9, a modification found in most mitochondrial tRNAs and thought to stabilize their structure. Missense mutations in SDR5C1 cause a disease characterized by progressive neurodegeneration and cardiomyopathy, called HSD10 disease. We have investigated the effect of selected mutations on SDR5C1's functions. We show that pathogenic mutations impair SDR5C1-dependent dehydrogenation, tRNA processing and methylation. Some mutations disrupt the homotetramerization of SDR5C1 and/or impair its interaction with TRMT10C, the methyltransferase subunit of the mitochondrial RNase P complex. We propose that the structural and functional alterations of SDR5C1 impair mitochondrial RNA processing and modification, leading to the mitochondrial dysfunction observed in HSD10 patients.