What Causes Granular Corneal Dystrophy?

Granular corneal dystrophy (GCD) is an inherited, progressive disorder characterized by the accumulation of discrete, crumb-like opacities within the corneal stroma. It is caused by autosomal dominant mutations in the *TGFBI* gene—located on chromosome 5q31—which encodes transforming growth factor-beta–induced protein (TGFBIp), also known as keratoepithelin. The most common pathogenic variants are the p.Arg124His (R124H) and p.Arg555Trp (R555W) substitutions; R124H is strongly associated with GCD type 1, while R555W is typically linked to GCD type 2 (also known as Avellino corneal dystrophy).

These missense mutations lead to abnormal folding and aggregation of TGFBIp within corneal keratocytes and the extracellular matrix. Over time, the misfolded protein forms insoluble deposits—histologically composed of amyloid and non-amyloid material—that disrupt corneal transparency and regularity. Disease onset is usually in childhood or early adolescence, with symptoms such as glare, photophobia, recurrent corneal erosions, and gradually declining visual acuity. Clinical progression is variable but often accelerates in the third to fourth decade of life.

Importantly, GCD is not triggered by environmental factors, infection, or systemic disease—it arises solely from germline genetic alterations passed through families. Genetic testing for *TGFBI* mutations confirms diagnosis and enables accurate counseling regarding inheritance risk (50% chance of transmission to offspring) and prognosis. Corneal transplantation may be required in advanced cases, though recurrence in grafts remains a well-documented concern due to persistence of mutant protein expression by host keratocytes.