A Mutation in PNPT1, Encoding Mitochondrial-RNA-Import Protein PNPase, Causes Hereditary Hearing Loss

作者：von Ameln Simon; 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; Wollnik Bernd; Koehler Carla M; Teitell Michael A; Barakat Abdelhamid; Kubisch Christian^*

来源：American Journal of Human Genetics, 2012, 91(5): 919-927.

DOI：10.1016/j.ajhg.2012.09.002

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%26gt;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.

• 出版日期2012-11-2