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Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3’-end processing
- Source :
- Human Mutation
- Publication Year :
- 2018
- Publisher :
- Cold Spring Harbor Laboratory, 2018.
-
Abstract
- Dysfunction of mitochondrial gene expression, caused by mutations in either the mitochondrial or nuclear genomes, is associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism. For instance, pathogenic mutations have been identified in the genes encoding enzymes involved in the precursor transcript processing, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, which is responsible for endonucleolytic cleavage of the 3’ ends of mitochondrial pre-tRNAs. Here, we report the identification of sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy and lactic acidosis. We provided further evidence for the pathogenicity of the three previously reported variants by studying the RNase Z activity in an in vitro system and applied this recombinant system to investigate all novel missense variants, confirming the pathogenic role of these new ELAC2 mutations. We also modelled the residues affected by missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the individuals with novel ELAC2 variants have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of hypertrophic cardiomyopathy and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, possibly indicating a functional link between tumorigenesis and mitochondrial RNA metabolism.
- Subjects :
- Male
Protein Conformation
Gene Expression
Mitochondrion
Substrate Specificity
Cohort Studies
0302 clinical medicine
RNA, Transfer
Mitochondrial tRNA 3'-end processing
Missense mutation
RNA Processing, Post-Transcriptional
Genetics (clinical)
Research Articles
Genetics
0303 health sciences
030305 genetics & heredity
Enzyme structure
Neoplasm Proteins
Mitochondria
ddc
3. Good health
mitochondrial disease
ELAC2
Genes, Mitochondrial
Phenotype
Mitochondrial respiratory chain
Female
Research Article
Mitochondrial DNA
Genotype
RNase P
Mitochondrial disease
Biology
Structure-Activity Relationship
03 medical and health sciences
medicine
Humans
Genetic Predisposition to Disease
Protein Interaction Domains and Motifs
Gene
Alleles
Genetic Association Studies
030304 developmental biology
RNA
Infant
Cardiomyopathy, Hypertrophic
medicine.disease
Enzyme Activation
Kinetics
Amino Acid Substitution
Mutation
cardiomyopathy
Biomarkers
030217 neurology & neurosurgery
RNase Z
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Human Mutation
- Accession number :
- edsair.doi.dedup.....0ac075772d2415f0cd5d47cbd312f37e