Atp1b2Atp1b1 Knock-In Mice Exhibit a Cone–Rod Dystrophy-Like Phenotype

The Na,K-ATPase is a heterodimeric ion pump consisting of various combinations of a catalytic α-subunit (α1, α2, α3, or α4, encoded by <i>ATP1A1-ATP1A4</i>) and a β-subunit (β1, β2, or β3, encoded by <i>ATP1B1-ATP1B3</i>). We have previously shown that <i>Atp1b2</i> knock-out (ko) mice exhibit rapid photoreceptor cell degeneration, whereas <i>Atp1b2^Atp1b1</i> knock-in (ki) mice, which express the β1-subunit instead of the β2-subunit under regulatory elements of the <i>Atp1b2</i> gene, exhibit slowly progressive retinal dystrophy. Here, we performed a detailed analysis of the retinal phenotype of the <i>Atp1b2^Atp1b1</i> ki mouse. We found that the number of cone photoreceptor cells in the mutant retinas was significantly reduced by postnatal day 28. The retinas of 4-month-old mice were almost devoid of cones. The early onset and rapid loss of cones was followed by a slowly progressive degeneration of rods. Other retinal cell types were unaffected. Nonradioactive <i>in situ</i> hybridization and immunohistochemistry revealed that wild-type photoreceptors expressed β3 and high levels of β2, while <i>Atp1b2^Atp1b1</i> ki photoreceptor cells expressed β3 and low levels of transgenic β1. Additionally, levels of retinoschisin, a secreted retina-specific protein that interacts directly with the β2-subunit, were greatly reduced in mutant retinas. The results demonstrate that the β1-subunit can functionally compensate, at least in part, for the absence of the β2-subunit. The results also show that cones are more susceptible to Na,K-ATPase dysfunction than rods. Taken together, the present study identifies the <i>Atp1b2^Atp1b1</i> ki mutant as a novel animal model of an early-onset and rapidly progressive cone-rod dystrophy.