title: ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy.
abstract: The human mitochondrial genome encodes RNA components of its own translational machinery to produce the 13 mitochondrial-encoded subunits of the respiratory chain. Nuclear-encoded gene products are essential for all processes within the organelle, including RNA processing. Transcription of the mitochondrial genome generates large polycistronic transcripts punctuated by the 22 mitochondrial (mt) tRNAs that are conventionally cleaved by the RNase P-complex and the RNase Z activity of ELAC2 at 5' and 3' ends, respectively. We report the identification of mutations in ELAC2 in five individuals with infantile hypertrophic cardiomyopathy and complex I deficiency. We observed accumulated mtRNA precursors in affected individuals muscle and fibroblasts. Although mature mt-tRNA, mt-mRNA, and mt-rRNA levels were not decreased in fibroblasts, the processing defect was associated with impaired mitochondrial translation. Complementation experiments in mutant cell lines restored RNA processing and a yeast model provided additional evidence for the disease-causal role of defective ELAC2, thereby linking mtRNA processing to human disease.
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.forename: Robert
authors.initials: R
authors.lastname: Kopajtich
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Joanna
authors.initials: J
authors.lastname: Rorbach
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nicholls
authors.forename: Enrico
authors.initials: E
authors.lastname: Baruffini
authors.forename: Anett
authors.initials: A
authors.lastname: Walther
authors.forename: Katharina
authors.initials: K
authors.lastname: Danhauser
authors.forename: Franz A
authors.initials: FA
authors.lastname: Zimmermann
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Husain
authors.forename: Jessica
authors.initials: J
authors.lastname: Schum
authors.forename: Helen
authors.initials: H
authors.lastname: Mundy
authors.forename: Ileana
authors.initials: I
authors.lastname: Ferrero
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Michal
authors.initials: M
authors.lastname: Minczuk
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
mesh_terms: D000595:Amino Acid Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004579:Electron Transport / Q000235:genetics; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005816:Genetic Complementation Test; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: C421605:ELAC2 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal; C029305:mitochondrial messenger RNA; D012343:RNA, Transfer; D004722:Endoribonucleases