Universität zu Köln

von Ameln, Simon ORCID: 0000-0002-2242-3165, Wang, Geng, Boulouiz, Redouane, Rutherford, Mark A., Smith, Geoffrey M., Li, Yun, Pogoda, Hans-Martin, Nuernberg, Gudrun, Stiller, Barbara, Volk, Alexander E., Borck, Guntram, Hong, Jason S., Goodyear, Richard J., Abidi, Omar, Nuernberg, Peter, Hofmann, Kay, Richardson, Gu Y. P., Hammerschmidt, Matthias, Moser, Tobias ORCID: 0000-0001-7145-0533, Wollnik, Bernd, Koehler, Carla M., Teitell, Michael A., Barakat, Abdelhamid and Kubisch, Christian ORCID: 0000-0003-4220-0978 (2012). A Mutation in PNPT1, Encoding Mitochondrial-RNA-Import Protein PNPase, Causes Hereditary Hearing Loss. Am. J. Hum. Genet., 91 (5). S. 919 - 928. CAMBRIDGE: CELL PRESS. ISSN 0002-9297

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code von Ameln, Simon UNSPECIFIED orcid.org/0000-0002-2242-3165 UNSPECIFIED Wang, Geng UNSPECIFIED UNSPECIFIED UNSPECIFIED Boulouiz, Redouane UNSPECIFIED UNSPECIFIED UNSPECIFIED Rutherford, Mark A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Smith, Geoffrey M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Yun UNSPECIFIED UNSPECIFIED UNSPECIFIED Pogoda, Hans-Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Stiller, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Volk, Alexander E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Borck, Guntram UNSPECIFIED UNSPECIFIED UNSPECIFIED Hong, Jason S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goodyear, Richard J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Abidi, Omar UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Kay UNSPECIFIED UNSPECIFIED UNSPECIFIED Richardson, Gu Y. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hammerschmidt, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Moser, Tobias UNSPECIFIED orcid.org/0000-0001-7145-0533 UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehler, Carla M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Teitell, Michael A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Barakat, Abdelhamid UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubisch, Christian UNSPECIFIED orcid.org/0000-0003-4220-0978 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-479134
DOI:	10.1016/j.ajhg.2012.09.002
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	91
Number:	5
Page Range:	S. 919 - 928
Date:	2012
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	0002-9297
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN POLYNUCLEOTIDE PHOSPHORYLASE; ESCHERICHIA-COLI; DEGRADATION; DISEASE; GENES; DNA Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47913