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Identification of a new mutant allele, Grm6nob7, for complete congenital stationary night blindness

Published online by Cambridge University Press:  11 May 2015

HAOHUA QIAN ,
RUI JI ,
RONALD G. GREGG  and
NEAL S. PEACHEY
HAOHUA QIAN
Affiliation:
Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, Maryland
RUI JI
Affiliation:
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky
RONALD G. GREGG
Affiliation:
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky
NEAL S. PEACHEY*
Affiliation:
Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
*
*Address correspondence to: Neal Peachey, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: [email protected]
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Abstract

Electroretinogram (ERG) studies identified a new mouse line with a normal a-wave but lacking the b-wave component. The ERG phenotype of this new allele, nob7, matched closely that of mouse mutants for Grm6, Lrit3, Trpm1, and Nyx, which encode for proteins expressed in depolarizing bipolar cells (DBCs). To identify the underlying mutation, we first crossed nob7 mice with Grm6nob3 mutants and measured the ERGs in offspring. All the offspring lacked the b-wave, indicating that nob7 is a new allele for Grm6: Grm6nob7. Sequence analyses of Grm6nob7 cDNAs identified a 28 base pair insertion between exons 8 and 9, which would result in a frameshift mutation in the open reading frame that encodes the metabotropic glutamate receptor 6 (Grm6). Sequencing both the cDNA and genomic DNA from exon 8 and intron 8, respectively, from the Grm6nob7 mouse revealed a G to A transition at the last position in exon 8. This mutation disrupts splicing and the normal exon 8 is extended by 28 base pairs, because splicing occurs 28 base pairs downstream at a cryptic splice donor. Consistent with the impact of the resulting frameshift mutation, there is a loss of mGluR6 protein (encoded by Grm6) from the dendritic tips of DBCs in the Grm6nob7 retina. These results indicate that Grm6nob7 is a new model of the complete form of congenital stationary night blindness, a human condition that has been linked to mutations of GRM6.

Keywords

Congenital stationary night blindnessElectroretinogramMetabotropic glutamate receptor 6
Type
Research Article
Information
Visual Neuroscience , Volume 32 , 2015 , E004
Copyright
Copyright © Cambridge University Press 2015 

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References

Barthel, L.K. & Raymond, P.A. (1990). Improved method for obtaining 3-microns cryosections for immunocytochemistry. Journal of Histochemistry & Cytochemistry 38, 1383–1388.CrossRefGoogle ScholarPubMed
Bijveld, M.C., Florijn, R.J., Bergen, A.B.B., van den Born, L.I., Kamermans, M., Prick, L., Riemslag, F.C.C., van Schooneveld, M.J., Kappers, A.M.L. & van Genderen, M.M. (2013). Genotype and phenotype of 101 Dutch patients with congenital stationary night blindness. Ophthalmology 120, 2072–2081.CrossRefGoogle ScholarPubMed
Cao, Y., Posokhova, E. & Martemyanov, K.A. (2011). TRPM1 forms complexes with nyctalopin in vivo and accumulates in postsynaptic compartment of ON-bipolar neurons in mGluR6-dependent manner. Journal of Neuroscience 31, 11521–11526.CrossRefGoogle ScholarPubMed
Dryja, T.P., McGee, T.L., Berson, E.L., Fishman, G.A., Sandberg, M.A., Alexander, K.R., Derlacki, D.J. & Rajagopalan, A.S. (2005). Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proceedings of the National Academy of Sciences of the United States of America 102, 4884–4889.CrossRefGoogle ScholarPubMed
Farrar, G.J., Millington-Ward, S., Chadderton, N., Mansergh, F.C. & Palfi, A. (2014). Gene therapies for inherited retinal disorders. Visual Neuroscience 31, 298–307.Google ScholarPubMed
Fletcher, E.L., Jobling, A.I., Vessey, K.A., Luu, C., Guymer, R.H. & Baird, P.N. (2011). Animal models of retinal disease. Progress in Molecular Biology and Translational Science 100, 211–286.CrossRefGoogle ScholarPubMed
Godara, P., Cooper, R.F., Sergouniotis, P.I., Diederichs, M.A., Streb, M.R., Genead, M.A., McAnany, J.J., Webster, A.R., Moore, A.T., Dubis, A.M., Neitz, M., Dubra, A., Stone, E.M., Fishman, G.A., Han, D.P., Michaelides, M. & Carroll, J. (2012). Assessing retinal structure in complete congenital stationary night blindness and Oguchi disease. American Journal of Ophthalmology 154, 987–1001.CrossRefGoogle ScholarPubMed
Gregg, R.G., Kamermans, M., Klooster, J., Lukasiewicz, P.D., Peachey, N.S., Vessey, K.A. & McCall, M.A. (2007). Nyctalopin expression in retinal bipolar cells restores visual function in a mouse model of complete X-linked congenital stationary night blindness. Journal of Neurophysiology 98, 3023–3033.CrossRefGoogle Scholar
Kofuji, P., Ceelen, P., Zahs, K.R., Surbeck, L.W., Lester, H.A. & Newman, E.A. (2000). Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: Phenotypic impact in retina. Journal of Neuroscience 20, 5733–5740.CrossRefGoogle ScholarPubMed
Koike, C., Obara, T., Uriu, Y., Numata, T., Sanuki, R., Miyata, K., Koyasu, T., Ueno, S., Funabiki, K., Tani, A., Ueda, H., Kondo, M., Mori, Y., Tachibana, M. & Furukawa, T. (2010). TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade. Proceedings of the National Academy of Sciences of the United States of America 107, 332–337.CrossRefGoogle ScholarPubMed
Maddox, D.M., Vessey, K.A., Yarbrough, G.L., Invergo, B.M., Cantrell, D.R., Inayat, S., Balannik, V., Hicks, W.L., Hawes, N.L., Byers, S., Smith, R.S., Hurd, R., Howell, D., Gregg, R.G., Chang, B., Naggert, J.K., Troy, J.B., Pinto, L.H., Nishina, P.M. & McCall, M.A. (2008). Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses. Journal of Physiology 586, 4409–4424.CrossRefGoogle ScholarPubMed
Masu, M., Iwakabe, H., Tagawa, Y., Miyoshi, T., Yamashita, M., Fukuda, Y., Sasaki, H., Hiroi, K., Nakamura, Y., Shigemoto, R., Takada, M., Nakamura, K., Nakao, K., Katsuki, M. & Nakanishi, S. (1995). Specific deficit of the ON response in visual transmission by targeted disruption of the mGIuR6 gene. Cell 80, 757–765.CrossRefGoogle ScholarPubMed
Morgans, C.W., Brown, R.L. & Duvoisin, R.M. (2010). TRPM1: The endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cells. BioEssays 32, 609–614.CrossRefGoogle ScholarPubMed
Morgans, C.W., Zhang, J., Jeffrey, B.G., Nelson, S.M., Burke, N.S., Duvoisin, R.M. & Brown, R.L. (2009). TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells. Proceedings of the National Academy of Sciences of the United States of America 106, 19174–19178.CrossRefGoogle ScholarPubMed
Nakajima, Y., Iwakabe, H., Akazawa, C., Nawa, H., Shigemoto, R., Mizuno, N. & Nakanishi, S. (1993). Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2-amino-4-phosphonobutyrate. Journal of Biological Chemistry 268, 11868–11873.CrossRefGoogle ScholarPubMed
Neuillé, M., El Shamieh, S., Orhan, E., Michiels, C., Antonio, A., Lancelot, M.E., Condroyer, C., Bujakowska, K., Poch, O., Sahel, J.A., Audo, I. & Zeitz, C. (2014). Lrit3 deficient mouse (nob6): A novel model of complete congenital stationary night blindness (cCSNB). PLoS One 9, e90342.CrossRefGoogle ScholarPubMed
Pardue, M.T., McCall, M.A., LaVail, M.M., Gregg, R.G. & Peachey, N.S. (1998). A naturally-occurring mouse model of X-linked congenital stationary night blindness. Investigative Ophthalmology & Visual Science 39, 2443–2449.Google ScholarPubMed
Pardue, M.T. & Peachey, N.S. (2014). Mouse b-wave mutants. Documenta Ophthalmologica 128, 77–89.CrossRefGoogle ScholarPubMed
Peachey, N.S., Goto, Y., al-Ubaidi, M.R. & Naash, M.I. (1993). Properties of the mouse cone-mediated electroretinogram during light adaptation. Neuroscience Letters 162, 9–11.CrossRefGoogle ScholarPubMed
Peachey, N.S., Pearring, J.N., Bojang, P. Jr., Hirschtritt, M.E., Sturgill-Short, G., Ray, T.A., Furukawa, T., Koike, C., Goldberg, A.F., Shen, Y., McCall, M.A., Nawy, S., Nishina, P.M. & Gregg, R.G. (2012 a). Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. Journal of Neurophysiology 108, 2442–2451.CrossRefGoogle ScholarPubMed
Peachey, N.S., Ray, T.A., Florijn, R., Rowe, L.B., Sjoerdsma, T., Contreras-Alcantara, S., Baba, K., Tosini, G., Pozdeyev, N., Iuvone, P.M., Bojang, P. Jr., Pearring, J.N., Simonsz, H.J., van Genderen, M., Birch, D.G., Traboulsi, E.I., Dorfman, A., Lopez, I., Ren, H., Goldberg, A.F.X., Nishina, P.M., Lachapelle, P., McCall, M.A., Koenekoop, R.K., Bergen, A.A.B., Kamermans, M. & Gregg, R.G. (2012 b). GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night blindness. American Journal of Human Genetics 90, 331–339.CrossRefGoogle ScholarPubMed
Penn, R.D. & Hagins, W.A. (1969). Signal transmission along retinal rods and the origin of the electroretinographic a-wave. Nature 223, 201–204.CrossRefGoogle ScholarPubMed
Pinto, L.H., Vitaterna, M.H., Shimomura, K., Siepka, S.M., Balannik, V., McDearmon, E.L., Omura, C., Lumayag, S., Invergo, B.M., Glawe, B., Cantrell, D.R., Inayat, S., Olvera, M.A., Vessey, K.A., McCall, M.A., Maddox, D., Morgans, C.W., Young, B., Pletcher, M.T., Mullins, R.F., Troy, J.B. & Takahashi, J.S. (2007). Generation, identification and functional characterization of the nob4 mutation of Grm6 in the mouse. Visual Neuroscience 24, 111–123.CrossRefGoogle ScholarPubMed
Samuels, I.S., Sturgill, G.M., Grossman, G.H., Rayborn, M.E., Hollyfield, J.G. & Peachey, N.S. (2010). Light-evoked responses of the retinal pigment epithelium: Changes accompanying photoreceptor loss in the mouse. Journal of Neurophysiology 104, 391–402.CrossRefGoogle ScholarPubMed
Schmitz, F., Königstorfer, A. & Südhof, T.C. (2000). RIBEYE, a component of synaptic ribbons: A protein’s journey through evolution provides insight into synaptic ribbon function. Neuron 28, 857–872.CrossRefGoogle ScholarPubMed
Sergouniotis, P.I., Robson, A.G., Li, Z., Devery, S., Holder, G.E., Moore, A.T. & Webster, A.R. (2012). A phenotypic study of congenital stationary night blindness (CSNB) associated with mutations in the GRM6 gene. Acta Ophthalmologica 90, e192–e197.CrossRefGoogle ScholarPubMed
Sharma, S., Ball, S.L. & Peachey, N.S. (2005). Pharmacological studies of the mouse cone electroretinogram. Visual Neuroscience 22, 631–636.CrossRefGoogle ScholarPubMed
Shirato, S., Maeda, H., Miura, G. & Frishman, L.J. (2008). Postreceptoral contributions to the light-adapted ERG of mice lacking b-waves. Experimental Eye Research 86, 914–928.CrossRefGoogle Scholar
Wu, J., Marmorstein, A.D., Kofuji, P. & Peachey, N.S. (2004). Contribution of Kir4.1 to the mouse electroretinogram. Molecular Vision 10, 650–654.Google Scholar
Zeitz, C., van Genderen, M., Neidhardt, J., Luhmann, U.F., Hoeben, F., Forster, U., Wycisk, K., Mátyás, G., Hoyng, C.B., Riemslag, F., Meire, F., Cremers, F.P. & Berger, W. (2005). Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Investigative Ophthalmology & Visual Science 46, 4328–4335.CrossRefGoogle ScholarPubMed