A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss.
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A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss. / von Ameln, Simon; Wang, Geng; Boulouiz, Redouane; Rutherford, Mark A; Smith, Geoffrey M; Li, Yun; Pogoda, Hans-Martin; Nürnberg, Gudrun; Stiller, Barbara; Volk, Alexander; Borck, Guntram; Hong, Jason S; Goodyear, Richard J; Abidi, Omar; Nürnberg, Peter; Hofmann, Kay; Richardson, Guy P; Hammerschmidt, Matthias; Moser, Tobias; Wollnik, Bernd; Koehler, Carla M; Teitell, Michael A; Barakat, Abdelhamid; Kubisch, Christian.
in: AM J HUM GENET, Jahrgang 91, Nr. 5, 5, 2012, S. 919-927.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss.
AU - von Ameln, Simon
AU - Wang, Geng
AU - Boulouiz, Redouane
AU - Rutherford, Mark A
AU - Smith, Geoffrey M
AU - Li, Yun
AU - Pogoda, Hans-Martin
AU - Nürnberg, Gudrun
AU - Stiller, Barbara
AU - Volk, Alexander
AU - Borck, Guntram
AU - Hong, Jason S
AU - Goodyear, Richard J
AU - Abidi, Omar
AU - Nürnberg, Peter
AU - Hofmann, Kay
AU - Richardson, Guy P
AU - Hammerschmidt, Matthias
AU - Moser, Tobias
AU - Wollnik, Bernd
AU - Koehler, Carla M
AU - Teitell, Michael A
AU - Barakat, Abdelhamid
AU - Kubisch, Christian
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Male
KW - Female
KW - Mice
KW - Amino Acid Sequence
KW - Molecular Sequence Data
KW - Base Sequence
KW - Models, Molecular
KW - Gene Expression
KW - Pedigree
KW - Consanguinity
KW - Chromosome Mapping
KW - Protein Conformation
KW - Cell Line
KW - Exons
KW - Mutation
KW - Cochlea/metabolism/pathology
KW - Exoribonucleases/chemistry/genetics/metabolism
KW - Hearing Loss, Sensorineural/genetics/metabolism
KW - RNA/metabolism
KW - RNA Transport/genetics
KW - Zebrafish/genetics/metabolism
KW - Animals
KW - Humans
KW - Male
KW - Female
KW - Mice
KW - Amino Acid Sequence
KW - Molecular Sequence Data
KW - Base Sequence
KW - Models, Molecular
KW - Gene Expression
KW - Pedigree
KW - Consanguinity
KW - Chromosome Mapping
KW - Protein Conformation
KW - Cell Line
KW - Exons
KW - Mutation
KW - Cochlea/metabolism/pathology
KW - Exoribonucleases/chemistry/genetics/metabolism
KW - Hearing Loss, Sensorineural/genetics/metabolism
KW - RNA/metabolism
KW - RNA Transport/genetics
KW - Zebrafish/genetics/metabolism
M3 - SCORING: Journal article
VL - 91
SP - 919
EP - 927
JO - AM J HUM GENET
JF - AM J HUM GENET
SN - 0002-9297
IS - 5
M1 - 5
ER -