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D. M. Maddox, W. L. Hicks, A. Ikeda, S. Ikeda, R. S. Smith, N. L. Hawes, B. Chang, J. K. Naggert, P. M. Nishina; An Early Stop Codon in the Giant Scaffolding Protein Synaptic Nuclear Envelope 2 (Syne2) May Lead to Altered Synapse Morphology and Disorganization of the Outer Plexiform Layer (OPL) in Diminished Cone Electroretinogram (dice) Mice. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2987.
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The dice mutation arose spontaneously on the B6.129S7-Ifingr<tm1 Agt> background. Mice homozygous for the dice mutation exhibit diminished cone electroretinogram (ERG) readings at three weeks of age. The purpose of this study was to better characterize the dice mutant and to identify the molecular lesion underlying the dice phenotype.
Homozygous mutant mice were mated to DBA/2J mice to produce F1 progeny. The F1 progeny were then intercrossed to produce 252 F2 mice that were phenotyped by electroretinography and genotyped through the use of simple sequence length polymorphisms (SSLPs) and single nucleotide polymorphisms (SNPs). The dice mutation was mapped to a 1.86 megabase (Mb) region of mouse Chromosome 12 containing 13 annotated genes. All genes contained within the critical region were sequenced, and a premature stop codon was discovered in the Syne2 gene. Development of the retinas of dice mutant mice was studied through a combination of histological and immunofluorescent techniques.
The development of mutant retinas was monitored by histological examination, and the earliest defect observed was a failure of the OPL to develop normally at postnatal day 8 (P8). Histological examination also revealed that many photoreceptor and amacrine cell nuclei failed to segregate to their appropriate position relative to the OPL. Immunohistological examination of wild-type (WT) eyes with an antibody developed against the C-terminus of SYNE2 showed staining predominantly within the OPL. As the staining appeared to be localized to synapses, scanning transmission electron microscopy (STEM) was performed, and many of the synaptic complexes within the OPL are abnormally formed in dice mutant mice. Additional studies with markers for amacrine and horizontal cells verified the histological findings. Studies utilizing cone cell markers indicated a reduction in the overall number of cone photoreceptors.
The dice mutation causes a unique phenotype in which the organization of the OPL is disrupted. Seemingly as a result of this disruption, cone cells are greatly reduced in number in dice mutant mice, leading to diminished amplitude of the cone ERG. This is the first report suggesting a function of SYNE2 within the retina, and future investigation may determine a role for SYNE2 in human laminopathies.
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