Based on a previous study that has shown that not all
cRPGRIP1Ins/Ins dogs develop clinically recognizable retinal degeneration,
11,12 a recent genome-wide association study in
cRPGRIP1Ins/Ins dogs stratified by phenotype has mapped an independent locus which, in the homozygous state, correlates with an early-onset phenotype.
14 The newly identified locus is located approximately 35 Mb from
RPGRIP1 on CFA15, and the genes in its 1.49-Mb interval are being analyzed to determine a role as a
cord1 disease modifier (Keiko Miyadera et al., unpublished data). While the identification of the second locus does not necessarily lend further support to c
RPGRIP1Ins/Ins being causal to
cord1, it is essential to unequivocally establish the disease gene at the first locus. Mapping of the first locus to a 14.15-Mb interval by Mellersh et al.
5 benefited from the use of the research colony, which subsequently was shown to be fixed for the second locus.
14 The involvement of the first locus is definitive, based on the perfect association with
cord1 in the AHT research colony.
RPGRIP1 is located within the mapped
cord1 region of 14.15 Mb on CFA15,
5 as well as within the narrowed 1.74-Mb critical disease interval,
11 and has been the most likely disease candidate given the predicted severity of the insertion. However, despite its important functional role in photoreceptors, and its interactions with a number of ciliary proteins in visual cells,
29,30,35 our study indicated that mutations in
RPGRIP1 are not the primary or sole cause of
cord1, and the real causative mutation representing the locus initially mapped by Mellersh et al.
5 is in physical proximity with
RPGRIP1 in the narrowed 1.74-Mb critical disease interval.
11 In such a case,
cRPGRIP1 Ins44 could represent a benign polymorphism that has been fixed in some populations, for example, AHT research colony
14 and many ESSs, or could be a
cord1 disease modifier. For that reason, identification of the direct causal gene/mutation will provide new insights into animal and human retinopathies.