Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2.
Light-dependent conductance changes of voltage-gated Cav1.4 channels regulate neurotransmitter release at photoreceptor ribbon synapses. Mutations in the human CACNA1F gene encoding the α1F subunit of Cav1.4 channels cause an incomplete form of X-linked congenital stationary night blindness (CSNB2). Many CACNA1F mutations are loss-of-function mutations resulting in non-functional Cav1.4 channels, but some mutations alter the channels' gating properties and, presumably, disturb Ca(2+) influx at photoreceptor ribbon synapses. Notably, a CACNA1F mutation (I745T) was identified in a family with an uncommonly severe CSNB2-like phenotype, and, when expressed in a heterologous system, the mutation was shown to shift the voltage-dependence of channel activation, representing a gain-of-function. To gain insight into the pathomechanism that could explain the severity of this disorder, we generated a mouse model with the corresponding mutation in the murine Cacna1f gene (I756T) and compared it with a mouse model carrying a loss-of-function mutation (ΔEx14-17) in a longitudinal study up to eight months of age. In ΔEx14-17 mutants, the b-wave in the electroretinogram was absent, photoreceptor ribbon synapses were abnormal, and Ca(2+) responses to depolarization of photoreceptor terminals were undetectable. In contrast, I756T mutants had a reduced scotopic b-wave, some intact rod ribbon synapses, and a strong, though abnormal, Ca(2+) response to depolarization. Both mutants showed a progressive photoreceptor loss, but degeneration was more severe and significantly enhanced in the I756T mutants compared to the ΔEx14-17 mutants.
Department of Biology, Animal Physiology, FAU Erlangen-Nuremberg, Erlangen, Germany.
Hanna
H
Regus-Leidig
Department of Ophthalmology, University Hospital Erlangen, Erlangen, Germany.
Jenny
J
Atorf
Department of Biology, Animal Physiology, FAU Erlangen-Nuremberg, Erlangen, Germany.
Andreas
A
Feigenspan
Department of Ophthalmology, University Hospital Erlangen, Erlangen, Germany.
Jan
J
Kremers
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Marion A
MA
Maw
Department of Biology, Animal Physiology, FAU Erlangen-Nuremberg, Erlangen, Germany.
Johann Helmut
JH
Brandstätter
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020746:Calcium Channels, L-Type; D004596:Electroretinography / Q000379:methods; D015785:Eye Diseases, Hereditary / Q000235:genetics / Q000378:metabolism*; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D009216:Myopia / Q000235:genetics / Q000378:metabolism*; D009755:Night Blindness / Q000235:genetics / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism*; D051248:Retinal Horizontal Cells / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism
C480684:Cacna1f protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002118:Calcium