title: Mouse strain-specific coding polymorphism in the Slc4a2/Ae2 gene encodes Ae2c2 variants differing in isoform-specific dominant negative activity.
abstract: The Slc4a2/Ae2 gene encodes multiple polypeptides arising from alternate promoter usage. The Ae2c promoter gives rise to only one Ae2c transcript from the human Ae2 gene, but to two, alternatively spliced, Ae2c1 and Ae2c2 transcripts from the mouse and rat genes. Unlike in the rat, the mouse Ae2c2 transcript encodes a novel Ae2c2 polypeptide. Here we report that the Ae2c2 residue 9 can be either proline or serine in a mouse strain-specific manner. Both Ae2c2 polypeptides express low function in Xenopus oocytes secondary to reduced or absent surface expression. Ae2c2S, but not Ae2c2P, exerts a dominant negative effect when coexpressed with Ae2a polypeptide, has a less prominent effect when coexpressed with Ae2b1 or Ae2c1 polypeptides, but has no effect on the function of coexpressed Ae2b2 polypeptide. Coexpression of Ae2c2P does not reduce activity of any Ae2 polypeptide variant. Ae2c2S and Ae2c2P also express low functional activity in HEK-293 cells. Knowledge of strain-specific coding polymorphisms with potential functional consequences such as that of Ae2c2 should aid in interpretation of strain-specific phenotypes investigated in the mouse phenome project.
authors.affiliation: Molecular and Vascular Medicine and Renal Units, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Kurschat
authors.forename: Boris E
authors.initials: BE
authors.lastname: Shmukler
authors.forename: Lianwei
authors.initials: L
authors.lastname: Jiang
authors.forename: Sarah
authors.initials: S
authors.lastname: Hevi
authors.forename: Edward H
authors.initials: EH
authors.lastname: Kim
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Stewart
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides / Q000378:metabolism; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009865:Oocytes; D010641:Phenotype; D011110:Polymorphism, Genetic; D011392:Proline; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D064606:SLC4A Proteins; D012694:Serine; D013045:Species Specificity; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D064606:SLC4A Proteins; C579496:SLC4A2 protein, human; C579495:Slc4a2 protein, mouse; C579494:Slc4a2 protein, rat; D012694:Serine; D011392:Proline