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A. H. Child, D. Ahnood, P. Comeglio, L. Ocaka, D. Charteris, G. Arno; The Role of Fibrillin-1 Mutations in Families With Dominantly Inherited Ectopia Lentis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4115.
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Ectopia lentis affects 40% patients with Marfan syndrome, explained by fibrillin-1 mutations in 92% of classical Marfan syndrome patients. However only 50% of patients presenting primarily with ectopia lentis have a demonstrable mutation in fibrillin-1. Our purpose was to restudy ectopia lentis patients using dHPLC to increase the yield of fibrillin-1 mutations, obtaining the true percentage with mutations. This prepares the way to study the remaining patients for other possible causative genes, since heterogeneity in ectopia lentis is a distinct possibility.
A consecutive series of 38 patients referred primarily for ectopia lentis and demonstrating no, or very mild, heart involvement on echocardiogram were selected. Of these, 19 demonstrated a fibrillin-1 mutation on screening using SSCP or dHPLC. To date, 11 of 17 patients found negative by SSCA have been re-examined by dHPLC. Mutations were detected in four.
Four of the eleven patients were demonstrated to have fibrillin-1 mutations, increasing the mutation yield in our total group of EL patients to 60%. The four mutations discovered were c.2210C>G (p.Gly737Val), c.2415T>G (p.Cys805Trp), c.2670C>G (p.Cys890Trp) and c.5918-1G>A (intronic). None of the mutations were found in exons 1-15 commonly associated with EL. Two out four were cysteine mutations which have been associated with major ocular involvement in Marfan syndrome (Comeglio et al 2007).Clinical presentation of most of the ectopia lentis patients indicated marfanoid build, suggesting systemic involvement. Candidate genes for production pathways of proteins known to be components of the ciliary zonular filaments includes Chondroitin sulphate, fibrillin-2, microfibrillar associated proteins 1, 3 and 4, Fibulin 1 and 2, Emilin, latent TGFß binding proteins 1,2 and 3, as well as enzymes involved in cross linkage such as lysyl oxidase and transglutaminase. Further work will explore families with ectopia lentis who do not demonstrate fibrillin-1 mutations, for linkage to known genetic loci for the above fibrillin-1 associated proteins in the zonular fibres. Mutations will then be sought in prioritized candidate genes.
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