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

Simon von Ameln (1, 2) , Geng Wang (3) , Redouane Boulouiz (4) , Mark A Rutherford (5) , Geoffrey M Smith (6) , Yun Li (7, 2) , Hans-Martin Pogoda (8) , Gudrun Nürnberg (9, 10) , Barbara Stiller (1, 2) , Alexander E Volk (1, 2) , Guntram Borck (1, 2) , Jason S Hong (6) , Richard J Goodyear (11) , Omar Abidi (4) , Peter Nürnberg (7, 10, 12) , Kay Hofmann (13) , Guy P Richardson (11) , Matthias Hammerschmidt (7, 8, 12) , Tobias Moser (14) , Bernd Wollnik (2, 7, 12) , Carla M Koehler (15) , Michael A Teitell (6, 15, 16) , Abdelhamid Barakat (4) , Christian Kubisch (1, 2)

1 Institute of Human Genetics
2 Institute of Human Genetics [Cologne]
3 Department of Chemistry and Biochemistry
4 Institut Pasteur du Maroc
5 InnerEarLab, Department of Otolaryngology
6 David Geffen School of Medicine [Los Angeles]
7 Center for Molecular Medicine Cologne
8 Institute for Developmental Biology
9 General Pediatrics
10 Cologne Center for Genomics
11 School of Life Sciences
12 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases
13 Institute for Genetics
14 InnerEarLab
15 Molecular Biology Institute
16 Jonsson Comprehensive Cancer Center, Broad Stem Cell Research Center

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: Life Sciences [q-bio]; Genetics; Human genetics

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⟩