Now I know my ABC's

Reading through a review of risk alleles for cardiovascular disease, I found this section:

ABC Gene Superfamily
The transport of specific molecules against gradients across cellular membranes is a fundamental feature of biological systems. The ABC transporter superfamily encodes proteins that transport a wide variety of substances including sterols, metabolic products, and drugs across both intra- and extracellular membranes. The ABC gene superfamily is highly diverse and is well conserved between species, hinting at the evolutionarily ancient history and critical importance of this gene family (53). ABC transporters are the largest known membrane transporter family, consisting of 49 members in humans (33). The mammalian ABC gene superfamily is divided into seven subfamilies, A through G, based on similarity in gene structure, order of domains, and sequence homology in the nucleotide-binding folds and transmembrane regions. Sixteen of the 49 human ABC genes are known to be associated with genetic disease (shown in Table 1), including cystic fibrosis, Stagardt disease, sistosterolemia, Dubin-Johnson syndrome, and others, underscoring the fundamental importance of this class of transporters in physiological processes.

The cystic fibrosis locus, CFTR is alternatively called ABCC7. There's a whole list of these ABC superfamily genes, all involved in membrane transport of one kind or another. The focus of the cardiovascular review is the first on the list, ABCA1, which is involved in HDL transport.

ABCA1 knockout mutations cause Tangier disease in homozygotes. This is a really intriguing story:

Tangier disease (TD) (Online Mendelian Inheritance in Man no. 2054000) is one such rare disease, affecting approximately 100 patients worldwide. TD was first identified by Donald Fredrickson on Tangier Island in the Chesapeake Bay area of the United States (42). While performing routine tonsil exams, Fredrickson discovered two siblings with massively enlarged orange tonsils and a virtual absence of alpha migrating (HDL) lipoprotein, thus identifying the two salient features of TD: reduced HDL cholesterol and cholesterol accumulation in cells of the reticuloendothelial system. With remarkable foresight, Frederickson noted that "patients with rare genetically determined diseases offer . . . an occasional view of normal processes obtainable in no other way," and that TD may "provide us with just such a view into some now-clouded aspects of fat transport and metabolism" (42).
In 1999, the molecular cause of TD was identified as mutations in both alleles of the ABCA1 gene (12, 14, 74, 93). Soon after, mutations in ABCA1 were also described in familial HDL deficiency, a more common and relatively milder disorder than TD, which results from heterozygous loss of ABCA1 function (79). To date, more than 100 common and rare variants have been described in the ABCA1 gene, with a wide range of biochemical and clinical phenotypes (98). Here we review genetic variation in ABCA1 and how it influences cholesterol transport, HDL metabolism, and risk for atherosclerosis (Brunham et al. 2006:107).

There's really quite a labyrinth of knowledge about these kinds of genetic variants now. "ABC" stands for "ATP-binding cassette" by the way. All of the members of this gene family have common motifs for binding to ATP, with different functional domains in between that are understood to a lesser extent. Knockouts can hit the ATP-binding regions, but more subtle variants that influence the protein activity to a smaller degree can occur within the rest of the functional sequence.


Brunham LR, Singaraya RR, Hayden MR. 2006. Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis. Annu Rev Nutr 26:105-129. doi:10.1146/annurev.nutr.26.061505.111214