A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss. - RIIP - Réseau International des Instituts Pasteur Access content directly
Journal Articles American Journal of Human Genetics Year : 2012

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

Tobias Moser
  • Function : Author

Abstract

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.

Domains

Human genetics

Dates and versions

pasteur-00796959 , version 1 (05-03-2013)

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Cite

Simon von Ameln, Geng Wang, Redouane Boulouiz, Mark A Rutherford, Geoffrey M Smith, et al.. A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss.. American Journal of Human Genetics, 2012, 91 (5), pp.919-27. ⟨10.1016/j.ajhg.2012.09.002⟩. ⟨pasteur-00796959⟩
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