The human ATP-binding cassette (ABC) transporter superfamily

Abstract

The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intracellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. To provide tools to study the function of human ABC transporters we compiled data from multiple genomics databases. We analyzed ABC gene conservation within human populations and across vertebrates and surveyed phenotypes of ABC gene mutations in mice. Most mouse ABC gene disruption mutations have a phenotype that mimics human disease, indicating they are applicable models. Interestingly, several ABCA family genes, whose human function is unknown, have cholesterol level phenotypes in the mouse. Genome-wide association studies confirm and extend ABC traits and suggest several new functions to investigate. Whole-exome sequencing of tumors from diverse cancer types demonstrates that mutations in ABC genes are not common in cancer, but specific genes are overexpressed in select tumor types. Finally, an analysis of the frequency of loss-of-function mutations demonstrates that many human ABC genes are essential with a low level of variants, while others have a higher level of genetic diversity.

Keywords: ATP-binding cassette transporter; evolution; human disease; lipid transport.

Figure 1.. Rate of loss-of-function mutations.

The number of loss-of-function mutations in the gnomAD database of exome and whole-genome sequences is shown. The values are adjusted for gene size. The ABCB7 and ABCD1 genes are on the X-chromosome.

Figure 2.. Genes with individuals homozygous for loss-of-function mutations.

The number of full-transporters (FT) with at least one individual with loss-of-function mutations is shown to that of other genes (half-transporters and cytoplasmic). * P-value less than 0.05 (Actual P-value 0.012).