Genetic basis - Caused by a heterozygous nonsense mutation in the SIX6 gene on chromosome 9 (c.487C>T, p.(Gln163*)). This mutation truncates about one-third of the SIX6 protein, a homeobox transcription factor critical for eye development. The disease shows an autosomal dominant inheritance pattern with incomplete penetrance — not all dogs with the mutation develop clinical signs. Dogs with two copies of the mutation tend to have more severe and earlier onset symptoms compared to heterozygotes.
Pathophysiology - SIX6 is essential for early eye formation, including retina and optic nerve development. Mutations cause various congenital eye structural defects, including: Retinal dysplasia (abnormal retina formation), Optic nerve hypoplasia or aplasia (underdeveloped or absent optic nerve), Retinal detachment, Congenital cataracts, Nystagmus (involuntary eye movement). Abnormal eye development leads to vision impairment ranging from mild to blindness. Severity varies widely, even within affected litters.
Complications - Visual impairment or blindness, sometimes affecting one or both eyes. Abnormal eye movements (nystagmus). Ataxia and bumping into objects in severely affected puppies. Variable expressivity with mild cases sometimes showing no obvious phenotype. Some affected puppies euthanized due to welfare concerns from severe defects.
Why This Matters to Breeders and Vets - Breeders: Important to test breeding stock to avoid producing affected pups. Because of incomplete penetrance, carriers may appear healthy, complicating breeding decisions without genetic testing. Vets: Early diagnosis allows appropriate management and owner counseling. Genetic testing assists in confirming diagnosis and advising breeders.