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Invest Ophthalmol Vis Sci. 2012 Aug 15;53(9):5486-501. doi: 10.1167/iovs.12-10178.

Exclusion of RPGRIP1 ins44 from primary causal association with early-onset cone-rod dystrophy in dogs.

Author information

1
Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Abstract

PURPOSE:

Canine cone-rod dystrophy 1 (cord1) has been previously mapped to CFA15, and a homozygous 44-bp insertion in exon 2 (Ins44) of canine RPGRIP1 (cRPGRIP1(Ins/Ins)) has been associated with the disease. However, from the recent identification of a significant discordance in genotype-phenotype association, we have reexamined the role of cRPGRIP1 in cord1.

METHODS:

Retinal structure and function was assessed by clinical retinal examination, noninvasive imaging, electroretinography, and histopathology/immunohistochemistry. cRPGRIP1 splicing was analyzed by RT-PCR. Retinal gene expression was determined by quantitative RT-PCR (qRT-PCR). Five markers spanning the entire cRPGRIP1 were identified and used for haplotyping.

RESULTS:

Electroretinography demonstrated that cone responses were absent or present in cRPGRIP1(Ins/Ins) individuals. Moreover, performance in vision testing and optical coherence tomography (OCT) were comparable in cRPGRIP1(Ins/Ins) dogs, regardless of the cone ERG status. While histologic changes in retinal structure were minimal, immunohistochemistry demonstrated a lack of cone opsin labeling in cRPGRIP1(Ins/Ins) dogs. cDNA analysis revealed that Ins44 disrupts a putative exonic splicing enhancer that allows for skipping of exon 2, while retaining the functional RPGR-interacting domain (RID) of the protein. New cRPGRIP1 sequence changes were identified, including a 3-bp deletion affecting the 3' acceptor splice site of alternative exon 19c. The extended haplotype spanning cRPGRIP1 was identical in cRPGRIP1(Ins/Ins) dogs with and without retinal degeneration. Gene expression analysis showed that expression levels were not associated with Ins44 genotype.

CONCLUSIONS:

The results indicated that cRPGRIP1 Ins44 is an unlikely primary cause of cord1, and that the causal gene and mutation are likely located elsewhere in the critical disease interval.

PMID:
22807295
PMCID:
PMC3422103
DOI:
10.1167/iovs.12-10178
[Indexed for MEDLINE]
Free PMC Article
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