Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.
Bottom Line: We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS.The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population.Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.
Affiliation: Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Sevilla, Spain.Show MeSH
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Mentions: We present here the identification of a putative coiled-coil structure, which is an interesting novel feature, in the central portion of the protein coincident with a region of Alpha helix overrepresentation (Fig. 1, Supp. Figure S1). The insight into the functional repercussion of both the already known signal peptide domain and the novel coiled-coil domain reported here supports a structural role for this new protein, which would be secreted and polymerize into a scaffolding that would contribute to the human retinal architecture. This is consistent with the function of Eys in Drosophila, where it is secreted by photoreceptor cells [Husain et al., 2006] and is essential for the formation of the matrix-filled interrhabdomeral space. The signal peptide and its cleavage site consensus sequence located in the N-terminal region of EYS (Fig. 1, Fig. 2) may confer a secretory nature to the protein or result in an intracellular or cytoplasmatic location of the mature protein [Jarjanazi et al., 2008]. Remarkably, we have identified the consensus sequence for this feature in EYS homologues in a number of species such as orangutan, dog, horse, marmoset, monkey and chimpanzee (data available on request). Accordingly, Drosophila Spacemaker and other proteins which share several of EYS domains have been found to be secreted and to have a structural function, such as SCUBE [Yang et al., 2002] or CMG-2 [Bell et al., 2001]. The members of SCUBE gene family contain both a signal peptide domain and multiple EGF-like repeats. Interestingly, both EYS and SCUBE1 share homology with the same protein families, such as members of the fibrillin and Notch families among others. SCUBE1 and 2 are known to form oligomers and manifest a stable association with the cell surface in vascular endothelial cells [Yang et al., 2002]. CMG-2, containing a potential signal peptide, targets to the endoplasmic reticulum and shows affinity for the basement membrane matrix proteins, collagen type IV and laminin. Similarly, CMG-1, which encodes a protein with coiled-coil domains, was observed to target to an intracellular vesicular compartment and may play as well a structural role since it has been postulated that this gene may be implicated in the regulation of capillary formation in an in-vitro model of endothelial cell morphogenesis [Bell et al., 2001].
Affiliation: Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Sevilla, Spain.