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:
CreatorsEmailORCIDORCID Put Code
von Ameln, SimonUNSPECIFIEDorcid.org/0000-0002-2242-3165UNSPECIFIED
Wang, GengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boulouiz, RedouaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rutherford, Mark A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, Geoffrey M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pogoda, Hans-MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stiller, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volk, Alexander E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borck, GuntramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hong, Jason S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goodyear, Richard J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abidi, OmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofmann, KayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richardson, Gu Y. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moser, TobiasUNSPECIFIEDorcid.org/0000-0001-7145-0533UNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koehler, Carla M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teitell, Michael A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barakat, AbdelhamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDorcid.org/0000-0003-4220-0978UNSPECIFIED
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:
KeywordsLanguage
HUMAN POLYNUCLEOTIDE PHOSPHORYLASE; ESCHERICHIA-COLI; DEGRADATION; DISEASE; GENES; DNAMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47913

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