A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss.
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.
Institute of Human Genetics, University of Ulm, Ulm, Germany.
Simon
S
von Ameln
Geng
G
Wang
Redouane
R
Boulouiz
Mark A
MA
Rutherford
Geoffrey M
GM
Smith
Yun
Y
Li
Hans-Martin
HM
Pogoda
Gudrun
G
Nürnberg
Barbara
B
Stiller
Alexander E
AE
Volk
Guntram
G
Borck
Jason S
JS
Hong
Richard J
RJ
Goodyear
Omar
O
Abidi
Peter
P
Nürnberg
Kay
K
Hofmann
Guy P
GP
Richardson
Matthias
M
Hammerschmidt
Tobias
T
Moser
Bernd
B
Wollnik
Carla M
CM
Koehler
Michael A
MA
Teitell
Abdelhamid
A
Barakat
Christian
C
Kubisch
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002874:Chromosome Mapping; D003051:Cochlea / Q000378:metabolism / Q000473:pathology; D003241:Consanguinity; D005091:Exons; D005095:Exoribonucleases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D012313:RNA / Q000378:metabolism*; D034443:RNA Transport / Q000235:genetics*; D000077278:RNA, Mitochondrial; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins
D005095:Exoribonucleases; D012313:RNA; D000077278:RNA, Mitochondrial; C476417:PNPT1 protein, human; D024101:Mitochondrial Proteins