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E. T. Tsilou, N. Smaoui, C. Toomes, M. Meltzer, Y. V. Sergeev; Functional Impact of Missense Mutations in Low-Density-Lipoprotein Receptor-Related Protein 5 (LRP5) Associated With Familial Exudative Vitreoretinopathy (FEVR). Invest. Ophthalmol. Vis. Sci. 2010;51(13):3093.
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Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder characterized by incomplete vascularization of the peripheral retina. It is a genetically and phenotypically heterogeneous disease; autosomal dominant, autosomal recessive and X-linked inheritance has been described. The purpose of this study is to describe the clinical data from two FEVR families with identified novel mutations in the low-density-lipoprotein receptor-related protein 5, LRP5,and implicate molecular modeling to analyze the structure-function of mutant proteins and their correlation with the disease phenotype.
Affected and unaffected family members from two families with FEVR underwent a complete ophthalmic examination that included fluorescein angiography when age and patient’s cooperation permitted. Blood samples were obtained. Genomic DNA was extracted and the entire coding region of the LRP5 gene was PCR-amplified with primers located in introns. Exons including coding sequence and intron-exon boundaries were sequenced , analyzed.and compared to the published gene sequence. LRP5 protein structure and mutation severity were obtained using molecular modeling.
Missense mutations were identified in each family. The first mutation is a heterozygous change in exon 6 (c.1135G>A, D379N) The second mutation is a heterozygous change in exon 9 (c.1828G>C, G610R), it has been previously reported. These mutations appear in structurally conserved positions located in the second blade and EGF motifs of the 2-d YWTD-EGF domain pair, respectively, suggesting a variable effect on protein stability. Disease phenotype ranged from complete absence of signs and symptoms to very severe disease in both families.
The absence of an association between genetic changes and disease phenotype is not uncommon in FEVR and indicates a possible existence of genetic disease modifiers. Moreover, intragenic, exon-spanning deletions within LRP5 are another possibility in these two families and further investigations are under way.
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