title: Metaxin, a gene contiguous to both thrombospondin 3 and glucocerebrosidase, is required for embryonic development in the mouse: implications for Gaucher disease.
abstract: We have identified a murine gene, metaxin, that spans the 6-kb interval separating the glucocerebrosidase gene (GC) from the thrombospondin 3 gene on chromosome 3E3-F1. Metaxin and GC are transcribed convergently; their major polyadenylylation sites are only 431 bp apart. On the other hand, metaxin and the thrombospondin 3 gene are transcribed divergently and share a common promoter sequence. The cDNA for metaxin encodes a 317-aa protein, without either a signal sequence or consensus for N-linked glycosylation. Metaxin protein is expressed ubiquitously in tissues of the young adult mouse, but no close homologues have been found in the DNA or protein data bases. A targeted mutation (A-->G in exon 9) was introduced into GC by homologous recombination in embryonic stem cells to establish a mouse model for a mild form of Gaucher disease. A phosphoglycerate kinase-neomycin gene cassette was also inserted into the 3'-flanking region of GC as a selectable marker, at a site later identified as the terminal exon of metaxin. Mice homozygous for the combined mutations die early in gestation. Since the same amino acid mutation in humans is associated with mild type 1 Gaucher disease, we suggest that metaxin protein is likely to be essential for embryonic development in mice. Clearly, the contiguous gene organization at this locus limits targeting strategies for the production of murine models of Gaucher disease.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle 98195, USA.
authors.forename: P
authors.initials: P
authors.lastname: Bornstein
authors.forename: C E
authors.initials: CE
authors.lastname: McKinney
authors.forename: M E
authors.initials: ME
authors.lastname: LaMarca
authors.forename: S
authors.initials: S
authors.lastname: Winfield
authors.forename: T
authors.initials: T
authors.lastname: Shingu
authors.forename: S
authors.initials: S
authors.lastname: Devarayalu
authors.forename: H L
authors.initials: HL
authors.lastname: Vos
authors.forename: E I
authors.initials: EI
authors.lastname: Ginns
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005776:Gaucher Disease / Q000235:genetics*; D008040:Genetic Linkage; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice / Q000196:embryology / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D015183:Restriction Mapping; D019699:Thrombospondins
chemical_list: C093550:MTX1 protein, human; D008562:Membrane Glycoproteins; D033681:Mitochondrial Membrane Transport Proteins; C490556:Mtx1 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D019699:Thrombospondins; D005962:Glucosylceramidase