Identification of Tspan12 as a New Gene Mutated in FEVR

Abstract

Purpose: : Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Although mutations in three genes (LRP5, FZD4 & NDP) are known to cause FEVR, these account for only a fraction of FEVR cases. The proteins encoded by these FEVR genes form part of a signaling complex which activates the Norrin/β-catenin signaling pathway. Recently through a large scale reverse genetic screen in mice, an additional member of this signaling complex was identified - TSPAN12. The purpose of this study was to screen this gene in a cohort of FEVR patients to see if TSPAN12 mutations cause FEVR.

Methods: : PCR products were generated from genomic DNA with primers designed to amplify the coding and flanking intronic sequences of TSPAN12. The PCR products were screened for mutations by direct sequencing.

Results: : Mutations screening was undertaken in a cohort of over 100 FEVR patients in whom we had already excluded the known FEVR genes. To date we have identified seven heterozygous mutations in TSPAN12. These include insertions, deletions, splice mutations, nonsense and missense mutations. The eye phenotype observed in these FEVR patients was highly variable and similar to those reported in other forms of FEVR.

Conclusions: : We have identified mutations in TSPAN12 in FEVR patients. This is the fourth FEVR gene to be identified. Our results suggest that more FEVR genes remain to be identified and further underlines the significance of the Norrin/β-catenin signaling pathway in the vascularization of the eye and FEVR. [e-mail]

Keywords: genetics • retinal degenerations: hereditary • retinal neovascularization