A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations.

Hug, Petra; Anderegg, Linda; Dürig, Nicole; Lepori, Vincent; Jagannathan, Vidya; Spiess, Bernhard; Richter, Marianne; Leeb, Tosso (2019). A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations. Genes, 10(6) MDPI, Molecular Diversity Preservation International 10.3390/genes10060454

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Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies had unilateral or bilateral retina dysplasia and/or optic nerve hypoplasia. The four litters shared the same father or grandfather suggesting a heritable condition with an autosomal dominant mode of inheritance. The genome of one affected dog was sequenced and compared to 601 control genomes. A heterozygous private nonsense variant, c.487C>T, was found in the gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*). We genotyped all available family members and 464 unrelated Golden Retrievers. All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases. The SIX6 protein is a homeobox transcription factor with a known role in eye development. In humans and other species, loss of function variants were reported to cause congenital eye malformations. This strongly suggests that the c.487C>T variant detected contributed to the observed eye malformations. We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Hug, Petra; Anderegg, Linda; Dürig, Nicole; Lepori, Vincent; Jagannathan, Vidya and Leeb, Tosso

Subjects:

500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2073-4425

Publisher:

MDPI, Molecular Diversity Preservation International

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

22 Jul 2019 14:30

Last Modified:

22 Jul 2019 14:30

Publisher DOI:

10.3390/genes10060454

PubMed ID:

31207931

Uncontrolled Keywords:

Canis lupus familiaris animal model development dog homeobox nystagmus ophthalmology optic nerve retinal dysplasia whole genome sequence

BORIS DOI:

10.7892/boris.131508

URI:

https://boris.unibe.ch/id/eprint/131508

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