Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12
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.
Section snippets
Sequence analysis
Searches of the GenBank HTGS database were performed with the TBLASTN and TBLASTP programs on the NCBI file server (http://www.ncbi.nlm.nih.gov) with the known ABC transporter nucleotide and protein sequences as queries. Potential transmembrane spanning segments were predicted with the TMAP program (http://bioweb.pasteur.fr/seqanal/interfaces/tmap.html). Amino acid alignments were generated with the PILEUP program included in the Genetics Computer Group (GCG) Package. The GRAIL and GeneScan
Cloning and genomic structure of ABCC11 and ABCC12
Two new human ABC transporter gene sequences were detected on the bacterial artificial chromosome (BAC) clone #AC007600 from the GenBank HTGS database. cDNA sequencing, genomic structure prediction programs, and computer searches determined the sequence and genomic structure of both new genes belonging to the ABCC (MRP) subfamily. Only the combination of all these methods allowed for the correct assembly of these genes which are closely related and highly conserved in evolution.
The human ABCC11
Acknowledgements
We wish to thank Laurent Naudin, Catherine Devaud and Carole Lafargue for their skilled scientific contribution to this collaborative work. The assistance of Delphine Debono, Karine Nadal and Gilles Haussy in the sequencing group is also acknowledged.
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