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A.N. Yatsenko, W. Wiszniewski, R.A. Lewis, J.R. Lupski; An evolutionary comparative analysis of abcr proteins in vertebrates’ species. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4713.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Defects of human ABCR (ABCA4) are known to be responsible for a number of autosomal recessive macular degenerations, such as Stargardt disease, recessive Con–rod dystrophy, Retinitis pigmentosa and predisposition to Age–related macular degeneration. However, little is known about the protein transporter function. It has been suggested that ABCR functions as an outwardly directed flippase for a retinoid N–retinylidene–PE. Genotype/phenotype studies have indicated that the position and type of ABCR mutations can influence retinal disease phenotype, suggesting a diverse impact of mutations on ABCR domains. One tool to evaluate protein domains employs an evolutionary comparison of human ABCR with homologous proteins of other vertebrates. Methods: To clone frog abcr genes we have used a method combining RT–PCR with degenerative and homologous vertebrate primers with 5’–/3’–RACE. Sequencing data of each clone was confirmed on both strands by multiple sequence analyses. Sequences were aligned and the proteins predicted by conceptual translation compared with protein databases using blastx. Multiple alignments of translated proteins were performed with program ClustalW. Results: We have cloned two abcr genes from African frogs, X. laevis and X. tropicalis. We have annotated the abcr gene from the Japanese puffer fish, Fugu rubripes. Using sequences of the cloned and known mammalian genes, we have made multiple alignments and examined evolutionary relationships. All predicted functional domains were highly conserved and showed high identity (>90%). Nonconserved regions were observed in the intradiscal loops and linker segments between transmembrne and ATP–binding domains. Two linker segments in frog and fish proteins were larger than mammalian ABCR proteins, and C–terminal abcr portion was the same or larger in mammals. Conclusions: We have performed the first evolutionary comparative study for six vertebrate abcr proteins and identified conserved regions of the human protein. The high identity of predicted functional domains supports a hypothesis of conservation of protein domains with important essential function. Based on our observation that nonconserved regions showed a difference of size, we suggest that during evolution certain segments of abcr protein have been transformed by the single amino acid change as well as segmental indels. We hypothesize that abcr protein becomes more specific during evolution in course of efficient utilization of visual cycle products due to higher organization of the mammalian central retina that require higher speed of retinoids metabolism.
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