Full characterization of this model will lead to a better understanding of the human disease and will be a valuable resource to develop targeted therapies for treatment. Interestingly, this is the first USH model to show a light dependent rescue of retinal dysfunction at early ages. Data are consistent with USH patients having a later onset visual impairment compared to hearing loss. This model also shows hair cell abnormalities and retinal degeneration. This mouse is the first USH2A model with a human mutation. This light dependent rescue seen in KI animals is only evident at P30, not in older animals, and is dependent on mice being born in the higher lighting conditions (1200 lux). Furthermore, KI mice reared in a higher cyclic lighting condition (1200 lux) show a rescue of the delay in scotopic recovery and arrestin translocation at P30.
KI mice at P360 have a significant decline in scotopic amplitudes and delay in scotopic ERG recovery as early as P30. Retinal evaluations via IHC and ERG up to P180 appear normal however there is a delay in transducin and arrestin translocation upon light exposure as early as P30. SEM evaluation of the cochlea showed outer hair cell abnormalities consistent with hearing loss at postnatal day 180 (P180). The KI mutation is present in the endogenous locus, truncated message is stable, and the mutant protein is expressed in photoreceptors and hair cells. Electroretinography (ERG) was used to assess retinal function in animals reared in both 30 lux and 1200 lux 12hr light/12hr dark cyclic lighting conditions. Transmission electron microscopy (TEM), scanning electron microscopy (SEM) and immunohistochemistry (IHC) were used to evaluate retinal and cochlear structure.
Message and protein levels were evaluated by RT-PCR and immunoblotting. The c.2299delG mutation causes a frame shift and premature stop codon. To study the role of usherin in audiovisual impairment we have generated and characterized a knockin (KI) mouse model expressing the human c.2299delG mutation. The c.2299delG mutation in usherin is the most common cause for USH type 2A in patients. Usher syndrome (USH) is a devastating disease that leads to combined deafness and blindness the disease mechanisms of this sensory loss remain elusive.
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