title: Impaired routing of wild type FXYD2 after oligomerisation with FXYD2-G41R might explain the dominant nature of renal hypomagnesemia.
abstract: Autosomal dominant renal hypomagnesemia, associated with hypocalciurea, has been linked to a G to A mutation at nucleotide position 121 in the FXYD2 gene, resulting in the substitution of Gly with Arg at residue 41 of the protein. FXYD2, also called the Na,K-ATPase gamma-subunit, binds to Na,K-ATPase and influences its cation affinities. In this paper, we provide evidence for the molecular mechanism underlying the dominant character of the disorder. Co-immunoprecipitation experiments using tagged FXYD2 proteins demonstrated that wild type FXYD2 proteins oligomerise. Moreover, FXYD2-G41R also shows oligomerisation with itself and with the wild type protein. In the case of FXYD2-G41R, however, formation of homo-oligomers was prevented by addition of DTT or introduction of the C52A mutation. Finally, we demonstrated that artificial glycosylation of the wild type FXYD2 is reduced when co-expressed with FXYD2-G41R. These data indicate that binding of FXYD2-G41R to wild type FXYD2 subunit might abrogate the routing of wild type FXYD2 to the plasma membrane thus causing the dominant nature of this mutation.
authors.affiliation: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Edinio R
authors.initials: ER
authors.lastname: Cairo
authors.forename: Thomas
authors.initials: T
authors.lastname: Friedrich
authors.forename: Herman G P
authors.initials: HG
authors.lastname: Swarts
authors.forename: Nine V
authors.initials: NV
authors.lastname: Knoers
authors.forename: René J M
authors.initials: RJ
authors.lastname: Bindels
authors.forename: Leo A
authors.initials: LA
authors.lastname: Monnens
authors.forename: Peter H G M
authors.initials: PH
authors.lastname: Willems
authors.forename: Jan Joep H H M
authors.initials: JJ
authors.lastname: De Pont
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001704:Biopolymers / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D008274:Magnesium / Q000097:blood*; D016297:Mutagenesis, Site-Directed; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D001704:Biopolymers; C416502:FXYD2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium