Four polymorphic variations in the PEDF gene identified during the mutation screening of patients with Leber congenital amaurosis.

Correspondence to: Dr. Robert Koenekoop, Ophthalmology Department, Montreal Children’s Hospital, 2300 Tupper, Montreal, Quebec H3H 1P3, Canada; Phone: (514) 934-4400 ext. 2891; FAX: (514) 934-4443; email: rkoeoph@mch.mcgill.ca Leber congenital amaurosis (LCA) is the earliest form of retinitis pigmentosa (RP) and is characterized by autosomal recessive inheritance, visual impairment at birth, nystagmus, and an abolished electroretinogram (ERG). Finding the cause of LCA commands considerable interest because it is a common cause of retinal blindness in children [1-4], and its gene identification will allow study of the molecular developmental biology of the human eye. Genetic heterogeneity of LCA has been suspected since Waardenburg’s report [5] of normal children born to two affected parents, and rare reports of autosomal dominant inheritance [6]. Patients with LCA might maintain visual function, despite progressive retinal changes supporting the hypothesis that some forms of LCA are an aplasia and not a degeneration with impaired development of rod and cone photoreceptors [7,8]. Other pathological findings ranging from diffuse retinal atrophy [6], to ganglion cell abnormalities [9] absent rods [10], or cones [11], immature [12], or normal rods and cones [13], also support the aplasia hypothesis. Recently, the genetic heterogeneity of this disease has been confirmed, when mutations in three genes were found to be associated with the LCA phenotype: the guanylate cyclase gene [14], RPE65 [15] and CRX [16]. Also a recent linkage study reported a new LCA locus on chromosome 14q24, but the gene remains to be identified [17]. Of these genes, guanylate cyclase is located in 17p13.1, the first locus for LCA described [18,19]. Until now, only LCA patients of Maghrebian origin from North Africa have been linked to 17p13.1 [14]. However, in the same report, it was demonstrated that from eight families linked to 17p13.1, only four show mutations in RetGC. Another candidate gene, Pigment Epithelium-Derived Factor (PEDF), also localizes to 17p13.1 [20]. PEDF is a serine protease inhibitor (serpin) expressed in fetal retinal pigment epithelial cells. In vitro studies [21] show, that in PEDF-treated retinoblastoma cells (which represent primitive photoreceptor cells), neurite like projections develop, and neuron specific enolase including neurofilament NF-200 are expressed, unlike untreated cells. Based on linkage data and a compelling physiological profile, PEDF is still, an obvious and intriguing candidate gene for photoreceptor degenerations, particularly LCA.