Abstract
Abstract: :
Purpose: MFRP is a member of the frizzled-related protein family and contains a cysteine-rich domain essential for Wnt binding and signaling. MFRP is highly expressed in the retinal pigment epithelial cells of the eye. A splice donor mutation in the mouse homolog of Mfrp is responsible for photoreceptor degeneration in the rd6 mouse, whose fundus is characterized by discrete dots distributed across the retina. We investigated MFRP as a candidate gene for a variety of retinal degenerations. Methods: To date, a partial screen (11 of 13 exons) for mutations in 47 unrelated patients with Stargardt’s macular dystrophy, 44 unrelated patients with Retinitis Pigmentosa (RP), and 22 unrelated patients with Leber Congentital Amaurosis (LCA) has been performed using exon-by-exon SSCP. Variant bands detected by SSCP were further analyzed by direct genomic sequencing. Results: Three missense sequence changes (Arg54Gly, Ile119Val, and Val136Met) were identified in MFRP. Arg54Gly was identified in one autosomal dominant Stargardt’s patient and Ile119Val was identified in one simplex Stargardt’s patient. The Val136Met missense change and three isocoding changes (Asp238Asp, Leu318Leu and Ala545Ala) were found in patients with all three retinal degenerations. An intronic change (IVS11+3G→A) was also identified in one Stargardt’s patient. None of the isocoding changes or the intron change alters a splice site. Cosegregation is pending to determine whether the observed missense sequence anomalies are pathogenic in Stargardt’s macular dystrophy. Conclusions: We report 7 sequence changes in MFRP in patients with inherited retinal degenerations. The possible pathogenic role of these changes is under further investigation. We are proceeding with an evaluation of the remaining exons in these patients and an evaluation of all exons in additional patients with allied diseases.
Keywords: candidate gene analysis • retinal degenerations: hereditary • genetics