Evolution of ABCA4 Proteins in Vertebrates

Abstract

The ABCA4 (ABCR) gene encodes a retinal-specific ATP-binding cassette transporter. Mutations in ABCA4 are responsible for several recessive macular dystrophies and susceptibility to age related macular degeneration (AMD). The protein appears to function as a flippase of all-trans-retinaldehyde and/or its derivatives across the membrane of outer segment disks and is a potentially important element in recycling visual cycle metabolites. However, the understanding of ABCA4's role in the visual cycle is limited due to the lack of a direct functional assay. An evolutionary analysis of ABCA4 may aid in the identification of conserved elements, the preservation of which implies functional importance. To date, only human, murine, and bovine ABCA4 genes are described. We have identified ABCA4 genes from African (Xenopus laevis) and Western (Silurana tropicalis) clawed frogs. A comparative analysis describing the evolutionary relationships between the frog ABCA4s, annotated T. rubripes ABCA4, and mammalian ABCA4 proteins was carried out. Several segments are conserved in both intradiscal loop (IL) domains, in addition to the transmembrane and ATP-binding domains. Nonconserved segments were found in the IL and cytoplasmic linker domains. Maximum likelihood analyses of the aligned sequences strongly suggest that ABCA4 was subject to purifying selection. Collectively, these data corroborate the current evolutionary model where two distinct ABCA half-transporter progenitors were combined to form a full ABCA4 progenitor in ancestral chordates. We speculate that evolutionary alterations may increase the retinoid metabolite recycling capacity of ABCA4 and may improve dark adaptation.

A genotype-phenotype correlation matrix for ABCA4 disease based on long-term prognostic outcomes

“…)p.(Arg2030Gln),(27,28) p.(Pro1486Leu),(29) p.(Thre1526Met)(27,28,30) and p.(Ile1562Thr)(30,31) alleles in the literature are also consistent with milder disease in general and with specific hypomorphic features.These and other mild ABCA4 alleles, including p.(Gly1961Glu) and the frequent hypomorph p.(Asn1868Ile), also exhibit some collective characteristics that are inconsistent with most autosomal recessive diseases. Under an additive pathogenicity model which has been proposed for ABCA4,(32) patient phenotypes are expected to vary according to the combined effects of both ABCA4 alleles and indeed, the phenotypic outcome of Moderate and Severe/PVS1 alleles vary widely depending on the allele in trans (Figure5D-5F).…”

Interaction of Extracellular Domain 2 of the Human Retina-specific ATP-binding Cassette Transporter (ABCA4) with All-trans-retinal

“…The extracellular loops project from TMD1 for ECD1 and from TMD7 for ECD2; they represent significantly large polypeptide domains, with 603 residues for ECD1 (amino acids and 285 residues for ECD2 (amino acids 1395-1680). The high degree of sequence conservation observed in the ECDs of vertebrate ABCA4 proteins suggests an important physiological significance (20,25).…”

Multidrug resistance-associated ABC transporters – too much of one thing, good for nothing

“…The comparison of multiple variants of ABC B5 gene, however, revealed that those full-transporters could later lose some sequences, and in the end, they remind more the structure of half-transporters (21) . The study in bacteria also showed that the typical structure of ABC transporters was probably formed when ATPase non-covalently associated with some membrane proteins became involved in transport -usually import of nutrients (5,22) . The ABC transporters are one of the most conserved proteins even though their genes are extremely fl exible as they adapted to an extensive number of substrates during evolution and till now are able to effl ux even the man-made compounds.…”