Autosomal Recessive Familial Exudative Vitreoretinopathy Is Associated With Mutations in the Carboxy Terminal Domains of LRP5

Abstract

Abstract: : Purpose: To identify the gene causing autosomal recessive familial exudative vitreoretinopathy (FEVR), affecting both the retina and vitreous body, and to correlate the specific LRP5 domains in which mutations occur with the clinical phenotype and inheritance pattern. In addition to adFEVR, mutations in LRP5 previously have been associated with osteoporosis–pseudoglioma syndrome (OPPG). Methods: Isolated autosomal recessive FEVR was diagnosed in individuals from three consanguineous families of European origin. A candidate–oriented genomewide scan was carried out and analyzed using the LINKAGE program package. LRP5 was screened by sequencing PCR amplified exons. Domains in the LRP5 and mutant protein were determined by a template structure search using HMM. Individual domains of LRP5 was modeled using threading methods followed by molecular modeling using the program LOOK, ver. 3.5.2, and then 500 rounds of energy minimization. Results:arFEVR maps to the 22–cM (311–Mb) region of chromosome 11q flanked by markers D11S905 and D11S1314 with a maximum LOD score of 3.6 at = 0 with marker D11S987. This region contains LRP5 but not FZD4: mutations in both of which can cause autosomal dominant FEVR. All three families show homozygous nonconservative mutations in LRP5: R570Q, R752G, and E1367K, not seen in 100 controls tested using PCR amplification and restriction enzyme digestion. These occur in the in the second and third EGF repeat and in the third LDLR ligand–binding domain, respectively. The 4 YWTD/EGF domains and 3 LDL–R–like ligand binding domains were localized in the LRP5 sequence and 3D structures built using homology modeling. Modeling of the mutation R752G suggests that this change might destabilize the YWTD/EGF domain 3 although the other two mutations are predicted to have less severe effect on protein structure. Conclusions: arFEVR maps to chromosome 11q and is associated with mutations in the LRP5 gene, demonstrating that mutations in this gene can cause autosomal recessive as well as autosomal dominant FEVR and osteoporosis–pseudoglioma syndrome. It seems likely that these mutations cause either a loss binding of LRP5 to its modulators, FZD4, Wnt, and Axin, or a loss of function, but do not disrupt signaling by normal LRP5 molecules.

Keywords: gene mapping • protein structure/function • retinal degenerations: hereditary