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The Journal of Neuroscience, January 5, 2005, 25(1):252-259; doi:10.1523/JNEUROSCI.3054-04.2005

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Cellular/Molecular
Congenital Stationary Night Blindness Type 2 Mutations S229P, G369D, L1068P, and W1440X Alter Channel Gating or Functional Expression of Ca_v1.4 L-type Ca²⁺ Channels

Jean-Charles Hoda,¹ Francesca Zaghetto,^1,2 Alexandra Koschak,¹ and Jörg Striessnig¹

¹Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie, Universität Innsbruck, A-6020 Innsbruck, Austria, and ²Dipartimento di Farmacologia e Anestesiologia, Università Degli Studi Di Padova, 35131 Padova, Italy

Mutations in the CACNA1F gene (voltage-dependent L-type calcium channel 1F subunit) encoding retinal Ca_v1.4 L-type Ca²⁺ channels cause X-linked recessive congenital stationary night blindness type 2 (CSNB2). Many of them are predicted to yield nonfunctional channels. Complete loss of Ca_v1.4 function is therefore regarded as a pathogenetic mechanism for the impaired signaling from photoreceptors to second-order retinal neurons. We investigated the functional consequences of CSNB2 missense mutations S229P, G369D, and L1068P and the C-terminal truncation mutant W1440X.

After expression in Xenopus laevis oocytes or human embryonic kidney tsA-201 cells, inward Ca²⁺ current (I_Ca) and inward Ba²⁺ current (I_Ba) could be recorded from mutations G369D and L1068P. G369D shifted the half-maximal voltage for channel activation (V_0.5,act) significantly to more negative potentials (>11 mV), slowed inactivation, and removed Ca²⁺-dependent inactivation. The L1068P mutant yielded currents only in the presence of the channel activator BayK8644. Currents (I_Ba) inactivated faster than wild type (WT) and recovered more slowly from inactivation (I_Ba and I_Ca). No channel activity could be measured for mutants S229P and W1440X after oocyte expression. No W1440X 1 protein was detected after expression in tsA-201 cells, whereas S229P (as well as G369D and L1068P) 1 subunits were expressed at levels indistinguishable from WT (n = 3).

Our data provide unequivocal evidence that CSNB2 missense mutations can induce severe changes in Ca_v1.4 function, which may decrease (L1068P and S229P) or even increase (G369D) channel activity. The lower activation range of G369D can explain the reduced dynamic range of photoreceptor signaling. Moreover, we demonstrate that loss of channel function of one (L1068P) CSNB2 mutation can be rescued by a Ca²⁺ channel activator.

Key words: voltage-gated Ca²⁺ channels; congenital stationary night blindness; missense mutations; genetic diseases; sensory cells; channelopathies

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Received July 27, 2004; revised October 20, 2004; accepted November 8, 2004.

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				M. J. Sinnegger-Brauns, I. G. Huber, A. Koschak, C. Wild, G. J Obermair, U. Einzinger, J.-C. Hoda, S. B. Sartori, and J. Striessnig Expression and 1,4-Dihydropyridine-Binding Properties of Brain L-Type Calcium Channel Isoforms Mol. Pharmacol., February 1, 2009; 75(2): 407 - 414. [Abstract] [Full Text] [PDF]

				C Pieh, B Simonsz-Toth, and I Gottlob Nystagmus characteristics in congenital stationary night blindness (CSNB) Br J Ophthalmol, February 1, 2008; 92(2): 236 - 240. [Abstract] [Full Text] [PDF]

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