Congenital stationary night blindness in mice - a tale of two Cacna1f mutants.

Background: Mutations in CACNA1F, which encodes the Ca(v) 1.4 subunit of a voltage-gated L-type calcium channel, cause X-linked incomplete congenital stationary night blindness (CSNB2), a condition of defective retinal neurotransmission which results in night blindness, reduced visual acuity, and diminished ERG b-wave. We have characterized two putative murine CSNB2 models: an engineered null-mutant, with a stop codon (G305X); and a spontaneous mutant with an ETn insertion in intron 2 of Cacna1f (nob2). Methods: Cacna1f(G305X): Adults were characterized by visual function (photopic optokinetic response, OKR); gene expression (microarray) and by cell death (TUNEL) and synaptic development (TEM). Cacna1f(nob2): Adults were characterized by properties of Cacna1f mRNA (cloning and sequencing) and expressed protein (immunoblotting, electrophysiology, filamin [cytoskeletal protein] binding), and OKR. Results: The null mutation in Cacna1f(G305X) mice caused loss of cone cell ribbons, failure of OPL synaptogenesis, ERG b-wave and absence of OKR. In Cacna1f(nob2) mice alternative ETn splicing produced similar to 90% Cacna1f mRNA having a stop codon, but similar to 10% mRNA encoding a complete polypeptide. Cacna1f(nob2) mice had normal OKR, and alternatively-spliced complete protein had WT channel properties, but alternative ETn splicing abolished N-terminal protein binding to filamin. Conclusions: Ca(v) 1.4 plays a key role in,photoreceptor synaptogenesis and synaptic function in mouse retina. Cacna1f(G305X) is a true knockout model for human CSNB2, with prominent defects in cone and rod function. Cacna1f(nob2) is an incomplete knockout model for CSNB2, because alternative splicing in an ETn element