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S-opsin knockout mice with the endogenous M-opsin gene replaced by an L-opsin variant

Published online by Cambridge University Press:  17 December 2013

SCOTT H. GREENWALD ,
JAMES A. KUCHENBECKER ,
DANIEL K. ROBERSON ,
MAUREEN NEITZ  and
JAY NEITZ
SCOTT H. GREENWALD
Affiliation:
Vision Sciences, University of Washington, Graduate Program in Neurobiology and Behavior, Seattle, Washington
JAMES A. KUCHENBECKER
Affiliation:
Vision Sciences, University of Washington, Seattle, Washington
DANIEL K. ROBERSON
Affiliation:
Vision Sciences, University of Washington, Seattle, Washington
MAUREEN NEITZ*
Affiliation:
Vision Sciences, University of Washington, Seattle, Washington
JAY NEITZ*
Affiliation:
Vision Sciences, University of Washington, Seattle, Washington
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Abstract

Specific variants of human long-wavelength (L) and middle-wavelength (M) cone opsin genes have recently been associated with a variety of vision disorders caused by cone malfunction, including red-green color vision deficiency, blue cone monochromacy, myopia, and cone dystrophy. Strikingly, unlike disease-causing mutations in rhodopsin, most of the cone opsin alleles that are associated with vision disorders do not have deleterious point mutations. Instead, specific combinations of normal polymorphisms that arose by genetic recombination between the genes encoding L and M opsins appear to cause disease. Knockout/knock-in mice promise to make it possible to study how these deleterious cone opsin variants affect the structure, function, and viability of the cone photoreceptors. Ideally, we would like to evaluate different variants that cause vision disorders in humans against a control pigment that is not associated with vision disorders, and each variant should be expressed as the sole photopigment in each mouse cone, as is the case in humans. To evaluate the feasibility of this approach, we created a line of mice to serve as the control in the analysis of disease-causing mutations by replacing exon 2 through 6 of the mouse M-opsin gene with the corresponding cDNA for a human L-opsin variant that is associated with normal vision. Experiments reported here establish that the resulting pigment, which differs from the endogenous mouse M opsin at 35 amino acid positions, functions normally in mouse cones. This pigment was evaluated in mice with and without coexpression of the mouse short wavelength (S) opsin. Here, the creation and validation of two lines of genetically engineered mice that can be used to study disease-causing variants of human L/M-opsins, in vivo, are described.

Keywords

Cone photoreceptorCone photopigmentElectroretinogramImmunohistochemistryCone functionTargeted gene replacementPhotopigment mutationS-opsin knockout
Type
Research Articles
Information
Visual Neuroscience , Volume 31 , Issue 1 , January 2014 , pp. 25 - 37
Copyright
Copyright © Cambridge University Press 2013 

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