by Anushri Bhattacharya
Inherited retinal dystrophy- Retinitis pigmentosa (RP), which is a degenerative disease of the retina, could be a common explanation for blindness, with approximately 2,000,000 people suffering from this disorder, globally. In dogs, this illness is named - ‘Progressive Retinal Atrophy’ (PRA). Retinal dystrophy has been described in over 100 dog breeds, with related investigations helping to spot new genes associated and pathogenic mechanisms with blindness across different breeds. With regard to the present topic, we’ll be looking at the mutation within the IFT122 gene that was uncovered in blind dogs.
A study by the University of Helsinki, has recently uncovered a mutation within the intraflagellar transport 122 (IFT122) gene in blind dogs. The intraflagellar transport 122 gene codes for the intraflagellar transport protein 122 homolog, which is responsible for the synthesis and maintenance of cilia which participate in transmitting signals within and between cells, and this is important for the development and function of many kinds of cells and tissues, including the light-sensitive tissue at the back of the eye (the retina). As per the results of the study, the gene mutation that was discovered, leads to the progressive destruction of photoreceptor cells, eventually causing retinal dystrophy. Data encompassing approximately more than 1000 Lapponian Herders (563 purebred LHs) and Finnish Lapphunds (577 FLs) from a canine DNA biobank were utilized in the study. The variant in this gene interrupts a highly conserved residue, p.(R1059H), in IFT122 and this likely impairs its function. Through a subsequent whole-genome sequencing of an affected Lapponian Herder, it was revealed that a missense variant, c.3176G>A, in the intraflagellar transport 122 (IFT122) gene was present. Thus, a gene test in support of breeding and diagnostics has been developed to support the findings.
Gene tests can now distinguish between retinal dystrophies related to different genes in breeds, which makes a difference in monitoring disease progression, making prognoses, and developing treatments associated to the disease, this helps us to ascertain the fact that in some dogs, this disease is caused by the IFT122 gene mutation. As mentioned previously, this gene discovery helps us to better understand the nature of retinal biology in canines, and that, the IFT122 is part of a protein complex linked with ciliary function within the retina.
Lapponian Herder
The age at which the variation gets expressed, plays a very significant role in influencing the rate of disease progression in dogs. The IFT122 gene contributes to the transport of opsin (a group of proteins made light-sensitive) in photoreceptor cells. The gene variant disrupts the transport of opsin thereby leading to in progressive blinding. Since IFT122 is related to cilia's function, which is very important to the body, the researchers studied a few of the dogs even more closely with respect to other issues potentially linked with cilia-related disturbances, like renal abnormalities or serious developmental disorders of the internal organs so as to regulate the other extraneous variables that would have potentially affected the results of the study. It was found that the damage seemed to be limited to the retina alone. This information helped them to understand the gene's mechanisms of action. The findings will also aid to formulate further plans that aim to remove the disease from different breeds so as to prevent blinding . As a result, in the Lapponian Herders and Finnish Lapphunds, the share of individuals carrying the gene variant was 28% and 12%, respectively.
Figure (a) shown above is a Schematic presentation of the IFT122 gene with exons marked in red, UTR sequences in orange, and introns in gray. A missense variant c.3176G>A in exon 26 was identified in whole-genome sequencing data. Furthermore, figure (d) shows a schematic presentation of the IFT122 protein with the canine PRA associated missense variant p.(R1059H) highlighted in red.
In conclusion, Maria Kaukonen, Doctor of Veterinary Medicine, explains that this is a recessively inherited disease, which means that a dog that will become blind, inherits the variant from both parents, who are both carriers of the variant. With the aid of gene testing, carrier-carrier combinations in genes can now be detected and avoided, thereby easily preventing the birth of dogs with this gene variant which causes blindness. Recently, Dr.Kaukonen transferred to a research group active at the University of Oxford, that specializes in developing gene therapies for retinal dystrophy. At the same time, Dr.Kaukonen and Professor Lohi are continuing close collaboration to survey a range of eye diseases together with the Helsinki University Hospital and other operators, while the affected breed will benefit from further genetic tests for detecting a recessive condition. Moreover, based on the findings of this study, conducted at the University of Helsinki, a new dog model was established to facilitate better understanding of the IFT122 gene in Retinitis pigmentosa biology. Lastly, the IFT122 is additionally a new replacement cause for retinal dystrophy in humans , suggested by the results of a gene test in support of breeding and diagnostics that has been developed based on this finding.
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