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Kristin Koehl, Joshua Laske, Jennifer Rivera-Avales, Christine Harman, Andras M Komaromy; Incomplete Achromatopsia in a Subgroup of Related CNGB3-Mutant Dog. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4651.
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The objective of this study was the detailed phenotyping of a sub-group of 7 related, achromatopsia (ACHM)-affected dogs with functional day-vision. All of these dogs shared the same mother and were homozygous for the D262N missense mutation in the CNGB3 gene.
Phenotyping of the 7 dogs (3 males and 4 females; median age: 7 months, range: 6-39 months) with incomplete ACHM (iACHM) consisted of photopic (700 lux) and scotopic (0.02 lux) visual behavior testing in a well established, 3.71-m long obstacle course and routine electroretinography (ERG). For comparison, we also tested 4 wildtype (wt) and 5 CNGB3(D262N)-mutant dogs with complete ACHM (cACHM), including the mother of the iACHM-affected dogs. Each dog was run though the obstacle course 60 times over an 8-month time period. All the animals enrolled in this study were maintained under identical environmental conditions. Following functional testing, retinal immunohistochemistry (IHC) was performed with specific focus on the established markers for functional cone outer segments (COS): CNGA3, CNGB3, and GNAT2.
The 7 iACHM-affected dogs with were identified because their transit times through the obstacle course did not differ significantly under photopic conditions from wt dogs, and they did not collide with any obstacles. In comparison, the group of dogs with cACHM had significantly longer transit times than wt animals under photopic conditions (p<0.05, Student’s t-test), and they typically collided with at least one of the 5 obstacles in the course. 1- and 30-Hz cone ERG responses were non-recordable in both groups of ACHM-affected dogs. In contrast to the retinas of cACHM-affected dogs, where no CNGA3, CNGB3, and GNAT2 could be seen in the mutant COS, we found small aggregations of mutant COS with normal localization of these essential functional markers in dogs with iACHM.
To the best of our knowledge, this is the first detailed report about iACHM in CNGB3-mutant dogs, a well established disease model. Since all the ACHM-animals evaluated were affected by the same D262N missense mutation in CNGB3, we suspect that genetic modifiers were responsible for the proper trafficking of key phototransduction components, incl. cyclic nucleotide-gated channels, into a small number of mutant COS of iACHM dogs.
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