Newly Identified Gene Deletion in Standard Poodles Sheds Light on Severe Vision Disorder

Inherited retinal diseases form a broad and complex group of genetic conditions that cause progressive vision loss and blindness. Dogs, like humans, are susceptible to many such disorders. Because of their genetic diversity and similarities to human retinal biology, dogs are invaluable partners in understanding why these diseases arise and how they might be prevented or treated.

In a new study, vision researchers at the University of Pennsylvania’s School of Veterinary Medicine (Penn Vet) have identified the genetic causes of early-onset, day-vision loss, cone-rod dystrophy in the Standard Poodle. Using a wide range of analytic techniques and canine databases, investigators detected a large structural variant, or deletion, that removed the functional part of two different genes, SPATA7 and PTPN21, both of which are expressed in the retina. Because this variant affected two genes in the canine retina, researchers had to determine if SPATA7 or PTPN21 was responsible for the vision loss, or both. Further study and comparative analysis identified a single gene, SPATA7, as the primary cause of early-onset vision loss.

“When you see a variant that takes out parts of two genes, the question becomes: are both involved or is only one actually causing the disease?” said Leonardo Murgiano, PhD, lead author of the study and senior research investigator in the Sylvia M. Van Sloun Laboratory for Canine Genomic Analysis. “That’s where functional work becomes essential.”

Researchers examined cells from affected dogs and observed a complete absence of the SPATA7 protein from the photoreceptor cilium, the cellular bridge that is critical for transporting proteins between the inner and outer segments of the light-sensitive nerve cells in the eyes, known as photoreceptors. The research team also demonstrated that separate Ptpn21-deficient (knockout) murine models had a normally functioning retina, reinforcing the PTPN21 noninvolvement in the disease process.

“This was a key finding,” said Murgiano. “The connecting cilium acts like the photoreceptor’s lifeline. When SPATA7 is missing, the transport system breaks down, and the cells simply cannot survive.”

Mutations in SPATA7 are known to cause vision impairment in children, including Leber congenital amaurosis and juvenile retinitis pigmentosa. With SPATA7 identified as the disease gene, researchers hope to advance therapeutic approaches, including gene therapies, which have shown promise in other inherited retinal diseases.

“Every new model expands our understanding of vision and blindness with a new level of detail, said Gustavo ‘Gus’ Aguirre, VMD, PhD, DACVO, professor of Medical Genetics and Ophthalmology, and senior author of the study. “This one brings us a step closer to helping not only affected dogs, but also children and families living with SPATA7-associated retinal degeneration.”

This multiauthor study represented the contribution of collaborators outside of the University of Pennsylvania, and of current and past* members of the eye research laboratory: Jessica K. Niggel, Kei Takahashi, Valérie L. Dufour, *Catharina R. Grubaugh, Raghavi Sudharsan, Jennifer C. Kwok, *Doreen Becker, *Esha Banerjee, and William A. Beltran.

The work was supported in part by NEI/NIH RO1-EY006855, EY017549, The Foundation Fighting Blindness, the Poodle Club of America Foundation, Inc., and the Van Sloun Fund for Canine Genetic Research.