title: Mitochondrial deafness alleles confer misreading of the genetic code.
abstract: Despite the fact that important genetic diseases are caused by mutant mitochondrial ribosomes, the molecular mechanisms by which such ribosomes result in a clinical phenotype remain largely unknown. The absence of experimental models for mitochondrial diseases has also prevented the rational search for therapeutic interventions. Here, we report on the construction of bacterial hybrid ribosomes that contain various versions of the mitochondrial decoding region of ribosomal RNA. We show that the pathogenic mutations A1555G and C1494T decrease the accuracy of translation and render the ribosomal decoding site hypersusceptible to aminoglycoside antibiotics. This finding suggests misreading of the genetic code as an important molecular mechanism in disease pathogenesis.
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 32, CH-8006 Zurich, Switzerland.
authors.forename: Sven N
authors.initials: SN
authors.lastname: Hobbie
authors.forename: Christian M
authors.initials: CM
authors.lastname: Bruell
authors.forename: Subramanian
authors.initials: S
authors.lastname: Akshay
authors.forename: Sarath K
authors.initials: SK
authors.lastname: Kalapala
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shcherbakov
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
mesh_terms: D000483:Alleles; D000617:Aminoglycosides / Q000235:genetics / Q000502:physiology; D002678:Chimera; D003638:Deafness / Q000235:genetics*; D050259:Genes, Mitochondrial / Q000502:physiology*; D005815:Genetic Code; D006319:Hearing Loss, Sensorineural; D028361:Mitochondrial Diseases / Q000235:genetics*; D017354:Point Mutation; D014176:Protein Biosynthesis; D012329:RNA, Bacterial; D012335:RNA, Ribosomal / Q000235:genetics; D012270:Ribosomes / Q000235:genetics*
chemical_list: D000617:Aminoglycosides; D012329:RNA, Bacterial; D012335:RNA, Ribosomal