Abstract
The ATP-binding cassette transporter 6 (ABCC6) gene encodes a cellular transmembrane protein transporter (MRP6) that is involved in the regulation of tissue calcification in mammals. Mutations in ABCC6 are associated with human ectopic calcification disorders. To gain insight into its evolution and involvement in tissue calcification we conducted a comparative analysis of the ABCC6 gene and the related gene ABCC1 from invertebrates to vertebrates where a bony endoskeleton first evolved. Taking into consideration the role of ABCC6 in ectopic calcification of human skin we analysed the involvement of both genes in the regeneration of scales, mineralized structures that develop in fish skin. The ABCC6 gene was only found in bony vertebrate genomes and was absent from Elasmobranchs, Agnatha and from invertebrates. In teleost fish the abcc6 gene duplicated but the two genes persisted only in some teleost genomes. Six disease causing amino acid mutations in human MRP6 are a normal feature of abcc6 in fish, suggesting they do not have a deleterious effect on the protein. After scale removal the abcc6 (5 and 10 days) and abcc1 (10 days) gene expression was up-regulated relative to the intact control skin and this coincided with a time of intense scale mineralization.
Highlights
The ATP-Binding Cassette (ABC) transporters are a large and ancient family of active transporter proteins present in a broad spectrum of organisms from bacteria to vertebrates[1,2]
The results indicate that abcc[1] and abcc[6] genes are involved in skin regeneration and scale formation in teleosts
Orthologues of the human ABCC6 gene were explored in several vertebrate genomes and phylogenetic analysis revealed that human and other vertebrate ABCC6 genes shared common ancestry and emerged early in the course of the vertebrate radiation
Summary
The ATP-Binding Cassette (ABC) transporters are a large and ancient family of active transporter proteins present in a broad spectrum of organisms from bacteria to vertebrates[1,2]. The ABCC6 gene encodes the multidrug resistance protein 6 (MRP6), which arose in genomes by tandem gene duplication, a process that produced the ABCC1 (MRP1) gene[11], which in humans prevents soft tissue calcification[18]. Homologues of the human ABCC6 gene occur in other vertebrates but their role in tissue calcification remains poorly understood. In contrast to humans where the ABCC6 gene is mostly detected in the liver, in zebrafish expression of abcc6a was strongly linked with tissues actively involved in mineralization suggesting that in fish abcc6a functions locally and that ligand transport is not liver derived[39]. Enpp[1] mutants exhibited ectopic calcification in soft tissues, including the skin, cartilage elements, heart, intracranial space and notochord sheet[35]
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