A truncated form of the cGMP-gated cation channel β-subunit lacking the GARP2 region transiently restores rod...

The cGMP-gated channel β-subunit is required for phototransduction, disc morphogenesis, and structural integrity of rod cells. Its structural role may be mediated by its GARP2 (glutamic acid rich protein) domain. To assess domain functions, we generated transgenic mice expressing a truncated protein lacking the N-terminal region on a Cngb1 null background. In these mice, light microscopy showed normal disk morphology up to 6 months, and cryo-electron tomography revealed disc-to-plasma membrane connections similar to WT. However, the truncated protein was insufficient to prevent progressive degeneration leading to photoreceptor loss by 12-14 months. Truncated protein expression levels resembled WT β-subunit levels. The truncated protein localized both to the outer segment, like WT, but also elsewhere in rods. Electroretinography showed CNG channel function was comparable to WT at 1-month and remained so up to 7.5 months postnatal when marked declines appeared. Thus, the N-terminal extension of the β-subunit is required for long-term maintenance and survival of rod photoreceptors, whereas the major structural defects observed at early ages in the knockouts cannot be attributed to loss of the CNGB1a GARP2 domain or the GARP1 and GARP2 soluble proteins.