Domain analyses of Usher syndrome causing Clarin-1 and GPR98 protein models

Usher syndrome is an autosomal recessive disorder that causes hearing loss, Retinitis Pigmentosa (RP) and vestibular dysfunction.It is clinically and genetically heterogeneous disorder which is clinically divided into three types i.e. type I, type II and type III. Todate, there are about twelve loci and ten identified genes which are associated with Usher syndrome. A mutation in any of thesegenes e.g. CDH23, CLRN1, GPR98, MYO7A, PCDH15, USH1C, USH1G, USH2A and DFNB31 can result in Usher syndrome ornon-syndromic deafness. These genes provide instructions for making proteins that play important roles in normal hearing,balance and vision. Studies have shown that protein structures of only seven genes have been determined experimentally and thereare still three genes whose structures are unavailable. These genes are Clarin-1, GPR98 and Usherin. In the absence of anexperimentally determined structure, homology modeling and threading often provide a useful 3D model of a protein. Therefore inthe current study Clarin-1 and GPR98 proteins have been analyzed for signal peptide, domains and motifs. Clarin-1 protein wasfound to be without any signal peptide and consists of prokar lipoprotein domain. Clarin-1 is classified within claudin 2 superfamily and consists of twelve motifs. Whereas, GPR98 has a 29 amino acids long signal peptide and classified within GPCR family2 having Concanavalin A-like lectin/glucanase superfamily. It was found to be consists of GPS and G protein receptor F2 domainsand twenty nine motifs. Their 3D structures have been predicted using I-TASSER server. The model of Clarin-1 showed only α-helixbut no beta sheets while model of GPR98 showed both α-helix and β sheets. The predicted structures were then evaluated andvalidated by MolProbity and Ramachandran plot. The evaluation of the predicted structures showed 78.9% residues of Clarin-1and 78.9% residues of GPR98 within favored regions. The findings of present study has resulted in the three dimensional structureprediction and conserved domain analysis which will be quite beneficial in better understanding of molecular components,protein-protein interaction, clinical heterogeneity and pathophysiology of Usher syndrome.