Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12

Abstract

Several years ago, we initiated a long-term project of cloning new human ATP-binding cassette (ABC) transporters and linking them to various disease phenotypes. As one of the results of this project, we present two new members of the human ABCC subfamily, ABCC11 and ABCC12. These two new human ABC transporters were fully characterized and mapped to the human chromosome 16q12. With the addition of these two genes, the complete human ABCC subfamily has 12 identified members (ABCC1–12), nine from the multidrug resistance-like subgroup, two from the sulfonylurea receptor subgroup, and the CFTR gene. Phylogenetic analysis determined that ABCC11 and ABCC12 are derived by duplication, and are most closely related to the ABCC5 gene. Genetic variation in some ABCC subfamily members is associated with human inherited diseases, including cystic fibrosis (CFTR/ABCC7), Dubin–Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6) and familial persistent hyperinsulinemic hypoglycemia of infancy (ABCC8). Since ABCC11 and ABCC12 were mapped to a region harboring gene(s) for paroxysmal kinesigenic choreoathetosis, the two genes represent positional candidates for this disorder.

Introduction

The ATP-binding cassette (ABC) transporter superfamily is one of the largest gene families and encodes a functionally diverse group of membrane proteins involved in energy-dependent transport of a wide variety of substrates across membranes (Dean and Allikmets, 1995). Phylogenetic analysis further divides human ABC transporters into seven subfamilies: ABCA (ABC1 subfamily), ABCB (MDR/TAP subfamily), ABCC (CFTR/MRP subfamily), ABCD (ALD subfamily), ABCE (OABP subfamily), ABCF (GCN20 subfamily), and ABCG (white subfamily) (Allikmets et al., 1996; http://www.gene.ucl.ac.uk/users/hester/abc.html). Most ABC proteins from eukaryotes encode so-called ‘full transporters’, each consisting of two ATP-binding domains and two transmembrane domains (Hyde et al., 1990).

The human ABCC subfamily currently has ten identified members (ABCC1–10), seven from the multidrug resistance-like (MRP) subgroup, two from the sulfonylurea receptor (SUR) subgroup, and the CFTR gene. MRP-like proteins are organic anion transporters, i.e. they transport anionic drugs, exemplified by methotrexate (MTX), as well as neutral drugs conjugated to acidic ligands, such as glutathione (GSH), glucuronate, or sulfate, and play a role in resistance to nucleoside analogs (Cui et al., 1999, Kool et al., 1999, Schuetz et al., 1999, Wijnholds et al., 2000). Genetic variation in some ABCC subfamily members is associated with human inherited diseases, including cystic fibrosis (CFTR/ABCC7) (Riordan et al., 1989), Dubin–Johnson syndrome (ABCC2) (Wada et al., 1998), pseudoxanthoma elasticum (ABCC6) (Bergen et al., 2000, Le Saux et al., 2000) and familial persistent hyperinsulinemic hypoglycemia of infancy (ABCC8) (Thomas et al., 1995).

Paroxysmal kinesigenic choreoathetosis (PKC; MIM# 128200), the most frequent type of paroxysmal dyskinesia, is a disorder characterized by recurrent, frequent attacks of involuntary movements and postures, including chorea and dystonia, induced by sudden voluntary movements, stress, or excitement (for a detailed description of clinical and genetic features, see Swoboda et al., 2000). In most families it is inherited as an autosomal dominant trait with incomplete penetrance. The gene locus has been mapped to human chromosome 16q11-q12 (Tomita et al., 1999, Bennett et al., 2000).

We initiated a long-term project of cloning new human ABC transporters and linking them to various disease phenotypes (Allikmets et al., 1996, Allikmets et al., 1997, Allikmets et al., 1999). As one of the results of this project, we present here two new members of the human ABCC subfamily, ABCC11 and ABCC12.