Prolyl 3-hydroxylase-1 null mice exhibit hearing impairment and abnormal morphology of the middle ear bone joints

Prolyl 3-hydroxylase1 (P3H1) is a collagen modifying enzyme which hydroxylates certain prolines in the Xaa position of conventional GlyXaaYaa triple helical sequence. Recent investigations have revealed that mutations in the LEPRE1 (gene encoding for P3H1) cause severe osteogenesis imperfecta (OI) in humans. Similarly LEPRE1 knockout mice display an OI-like phenotype. Significant hearing loss is a common problem for people with osteogenesis imperfecta. Here we report that hearing of the P3H1 null mice is substantially affected. Auditory brainstem responses (ABRs) of the P3H1 null mice show an average increase of 20–30 dB in auditory thresholds. Three dimensional reconstructions of the mutant middle ear bones by Micro-scale X-ray computed tomography (Micro-CT) demonstrate abnormal morphology of the incudostapedial and incudomalleal joints. We establish the LEPRE1 knockout mouse as a valuable model system to investigate the mechanism of hearing loss in recessive OI.

► We report that the hearing of P3H1 null mice is substantially affected with average increase of 20–30 dB in ABR thresholds. ► Micro-scale X-ray computed tomography of the mouse middle ear bones was performed at different postnatal stages. ► Micro-CT three dimensional reconstructions demonstrate abnormal morphology of the incudostapedial and incudomalleal joints. ► Joint malformations were found at two weeks, one month and one year old animals. ► Delayed calcification observed at postnatal day 9 is likely to contribute to the hearing phenotype.