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Y. Claassen, J. Bakker, J. Klooster, M. van Genderen, M. Bijveld, R. Florijn, F. Riemslag, A. A. B. Bergen, M. Kamermans; Trpm1-Channels in Humans Are Localized at the on Bipolar Cell Dendrites and Mediate On-Bipolar Cell Activity. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4130.
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Congenital stationary night blindness (CSNB) type 1 is a retinal disorder characterized by non-progressive impaired night vision and variable decreased visual acuity. So far two genes have been identified causing this disease: GRM6 and NYX. Both of them are involved in the signaling cascade of ON-bipolar cells. Recently it has been shown that TrpM1 knockout mice, lack the b-wave in the ERG (Bellone et al., 2008; 19Shen et al., 2009). In this study we investigated whether CNSB type 1 patients without mutations in either NYX or GMR6 have mutations in TRPM1.
standard genetic, morphological and ERG techniques were used.
First we determined the localization of TRPM1 in the human retina on light and EM level. TRPM1 is localized the ON bipolar cell dendrites in the outer plexifom layer, a localization close to nyctalopin (NYX) and mGluR6 (GMR6). Next eight female probands with CSNB type 1, without GRM6 and NYX mutations were screened for mutations in TRPM1. In six of them mutations were found. In one patient a homozygous deletion was found, in the five others compound heterozygous mutations were identified. All mutations are predicted to have severe effects on channel function. The normal flash ERG and the scotopic 15 Hz ERG of these patients were analyzed and compared to those of patients with mutations in GRM6 or NYX. It was found thatpatients in all three groups lacked the scotopic b-wave and that the 15Hz ERG differed from normal. Interestingly, the 15 Hz ERG of the probands with GRM6 mutations differed significantly from those NYX and TRPM1 probands.
Our results are consistent with the suggestion that TRPM1 is the channel gated by the mGluR6 - Nyctalopin signaling cascade in ON bipolar cells. Although all three proteins are likely to function in the same cascade, they seem to affect ON-bipolar cell function differently.
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