A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss

Simon Von Ameln, Geng Wang, Redouane Boulouiz, Mark A. Rutherford, Geoffrey M. Smith, Yun Li, Hans Martin Pogoda, Gudrun Nürnberg, Barbara Stiller, Alexander E. Volk, Guntram Borck, Jason S. Hong, Richard J. Goodyear, Omar Abidi, Peter Nürnberg, Kay Hofmann, Guy P. Richardson, Matthias Hammerschmidt, Tobias Moser, Bernd WollnikCarla M. Koehler, Michael A. Teitell, Abdelhamid Barakat, Christian Kubisch

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


A subset of nuclear-encoded RNAs has to be imported into mitochondria for the proper replication and transcription of the mitochondrial genome and, hence, for proper mitochondrial function. Polynucleotide phosphorylase (PNPase or PNPT1) is one of the very few components known to be involved in this poorly characterized process in mammals. At the organismal level, however, the effect of PNPase dysfunction and impaired mitochondrial RNA import are unknown. By positional cloning, we identified a homozygous PNPT1 missense mutation (c.1424A>G predicting the protein substitution p.Glu475Gly) of a highly conserved PNPase residue within the second RNase-PH domain in a family affected by autosomal-recessive nonsyndromic hearing impairment. In vitro analyses in bacteria, yeast, and mammalian cells showed that the identified mutation results in a hypofunctional protein leading to disturbed PNPase trimerization and impaired mitochondrial RNA import. Immunohistochemistry revealed strong PNPase staining in the murine cochlea, including the sensory hair cells and the auditory ganglion neurons. In summary, we show that a component of the mitochondrial RNA-import machinery is specifically required for auditory function.

Original languageEnglish
Pages (from-to)919-927
Number of pages9
JournalAmerican journal of human genetics
Issue number5
StatePublished - Nov 2 2012


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