Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene

Abstract

Mutations in the crumbs homologue 1 (CRB1) gene cause a specific form of retinitis pigmentosa (RP) that is designated "RP12" and is characterized by a preserved para-arteriolar retinal pigment epithelium (PPRPE) and by severe loss of vision at age <20 years. Because of the early onset of disease in patients who have RP with PPRPE, we considered CRB1 to be a good candidate gene for Leber congenital amaurosis (LCA). Mutations were detected in 7 (13%) of 52 patients with LCA from the Netherlands, Germany, and the United States. In addition, CRB1 mutations were detected in five of nine patients who had RP with Coats-like exudative vasculopathy, a relatively rare complication of RP that may progress to partial or total retinal detachment. Given that four of five patients had developed the complication in one eye and that not all siblings with RP have the complication, CRB1 mutations should be considered an important risk factor for the Coats-like reaction, although its development may require additional genetic or environmental factors. Although no clear-cut genotype-phenotype correlation could be established, patients with LCA, which is the most severe retinal dystrophy, carry null alleles more frequently than do patients with RP. Our findings suggest that CRB1 mutations are a frequent cause of LCA and are strongly associated with the development of Coats-like exudative vasculopathy in patients with RP.

Figure 1

Cosegregation analysis of CRB1 mutations in (A) one family with LCA and (B) five families with RP and Coats-like exudates. A question mark (?) denotes the unidentified second allele; an asterisk (*) denotes patients with RP who have developed the Coats-like complication. Arrows indicate probands. IVS8 denotes the splice-site mutation of exon 8, 2978+5G→A.

Figure 2

Fundus photograph of the inferior part of the left eye of a patient who had RP with unilateral Coats-like exudative vasculopathy (proband 9439; individual II-4). Note the widespread subretinal yellowish-white deposits between the neural retina and RPE in the lower part. This region of the fundus is out of focus as a result of the elevation of tissue caused by subretinal accumulation of fluid. Triangles (▴) indicate retinal vessels with white sheathing that is indicative of vasculitis. The RPE shows some preservation near retinal arterioles as seen in patients who had RP with PPRPE (arrow).