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

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.
AuthorsSimon 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 Wollnik, Carla M Koehler, Michael A Teitell, Abdelhamid Barakat, Christian Kubisch
JournalAmerican journal of human genetics (Am J Hum Genet) Vol. 91 Issue 5 Pg. 919-27 (Nov 2 2012) ISSN: 1537-6605 [Electronic] United States
PMID23084290 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Chemical References
  • RNA, mitochondrial
  • RNA
  • Exoribonucleases
  • PNPT1 protein, human
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line
  • Chromosome Mapping
  • Cochlea (metabolism, pathology)
  • Consanguinity
  • Exons
  • Exoribonucleases (chemistry, genetics, metabolism)
  • Female
  • Gene Expression
  • Hearing Loss, Sensorineural (genetics, metabolism)
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Protein Conformation
  • RNA (metabolism)
  • RNA Transport (genetics)
  • Zebrafish (genetics, metabolism)

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