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.

Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children

“…Curiously, 4/16 (25%) patients have very rare variants in ATP-binding cassette (ABC) superfamily genes (Dean et al 2022 ). Patient EXOC 16 exhibited a heterozygous pathogenic missense variant in the ATP-binding cassette subfamily A member 6 ( ABCC6 ) gene and three other patients (EXOC6, EXOC13, and EXOC14) in our cohort exhibit heterozygous missense variants (one pathogenic and two VUS) in the ATP-binding cassette subfamily A member 4 ( ABCA4 ) gene.…”

Transporter-Mediated Drug Delivery

“…Transport proteins are often categorized by their mechanism of transport. ATP-binding cassette (ABC) transporters are primary active transporters that, in higher organisms, use ATP hydrolysis to drive the transport of solutes across the membrane and typically out of cells [ 2 , 3 ]. Secondary active transporters couple solute translocation to the cotransport or counter-transport of either inorganic ions or other solutes; in the latter case, they are often called exchangers.…”

Expression of Chemoresistance-Associated ABC Proteins in Hepatobiliary, Pancreatic and Gastrointestinal Cancers

“…Among them, the efflux of active agents from cancer cells across the plasma membrane through members of the superfamily of ATP-binding cassette (ABC) proteins plays a crucial role in drug resistance mechanisms categorized as MOC-1b. Although there are seven families of ABC proteins in humans (from ABCA to ABCG), only members of the ABCB, ABCC, and ABCG families have been clearly associated with anticancer drug export ( Table 1 ) [ 4 ]. Thus, the first member related to chemoresistance was named multidrug resistance protein 1 (MDR1), also known as P-glycoprotein or P-gp (gene symbol ABCB1 ).…”

“…MDR1 and MRP1-6 are full transporters, whereas ABCG2 is a half-transporter that requires dimerization to become functionally active. In addition to their basal expression in naïve tumors, a common feature in resistance development is their upregulation in response to treatment [ 4 ]. Nevertheless, there is also the possibility of manipulating their expression [ 5 ] and function [ 6 ].…”