Retinal atrophy, X-Linked (XLPRA1)

 

Gene: RPGR

Transmission:  X-linked inheritance

For a chromosome X-linked recessive genetic disease, a male animal must have one copy of the mutation in question to be at risk of developing the disease.  All affected males will pass on the mutation to all of its female progeny.  A female animal must have two copies of the mutation in question to be at risk of developing the disease.  Females that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutations:

Siberian Husky mutation: Deletion, RPGR gene; c.1028_1032 del.5bp,  p.(R1139I fs STOP 2), exon15

Weimaraner mutation: Deletion, PTGR gene; 5K deletion including first 4 exons of RPGR

Medical system: Ocular

Breeds: Samoyed, Siberian Husky, Weimaraner

Age of onset of symptoms: Young adult

Progressive retinal atrophy refers to a family of genetic diseases in the dog involving progressive degeneration or atrophy of the photoreceptor cell layer of the retina and resulting in visual deficits and blindness in the affected animal.  Over 20 genes and mutations have been identified that can contribute to PRA; for a given dog breed, one or several of these mutations may be involved in the disease pathology.  Seen in the Samoyed and Siberian Husky breeds, X-linked PRA1 (XLPRA1) is caused by a mutation within the RPGR gene.  Because the RPGR gene is found on the X-chromosome, the disease displays sex-linked heredity between generations: unaffected carrier female animals will pass the mutation and the disease to on average half of their male offspring, while half of their female offspring will be unaffected carriers.  Clinical signs are first observed in the young adult dog and involve loss of night vision due to degeneration of the rod receptor cells within the retina.  This is followed by loss of day vision due to degeneration of cone receptor cells.  The disease is progressive over the course of several years and will eventually result in blindness of the dog.

 

References:

OMIA link: [0831-9615]

Awadh Hashem S, Georgiou M, Ali RR, Michaelides M. (2023) RPGR-related retinopathy: clinical features, molecular genetics, and gene replacement therapy. Cold Spring Harb Perspect Med a041280. [pubmed/37188525]

Genetics Committee of the American College of Veterinary Ophthalmologists (2021) The Blue Book: Ocular disorders presumed to be inherited in purebred dogs. 13th Edition.  [https://ofa.org/wp-content/uploads/2022/10/ACVO-Blue-Book-2021.pdf]

Appelbaum T, Becker D, Santana E, Aguirre GD. (2016) Molecular studies of phenotype variation in canine RPGR-XLPRA1. Mol Vis 22:319-31, 2016. [pubmed/27122963]

Palanova A. (2016) The genetics of inherited retinal disorders in dogs: implications for diagnosis and management.  Vet Med (Auckl). 7:41-51. [pubmed/30050836]

Beltran WA, Hammond P, Acland GM, Aguirre GD. (2006) A frameshift mutation in RPGR exon ORF15 causes photoreceptor degeneration and inner retina remodeling in a model of X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci. 47(4):1669-81.  [pubmed/16565408]

Zhang Q, Acland GM, Wu WX et.al. (2002) Different RPGR ORF15 mutations in Canids provide insights into photoreceptor cell degeneration.  Muman Molecular Genetics 11(9):993-1003. [pubmed/11978759]