title: The novel mouse microphthalmia mutations Mitfmi-enu5 and Mitfmi-bcc2 produce dominant negative Mitf proteins.
abstract: Mutations in the microphthalmia-associated transcription factor (Mitf) gene affect the development of different cell types, including melanocytes, osteoclasts, and retinal pigmented epithelial cells of the eye. Many different mutations at the locus are known and since they affect the phenotype to different extents they form an allelic series. The Mitf protein is a member of the Mitf-Tfe subfamily of basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factors and binds the 6-bp canonical CAC/TGTG sequence (E box) as either a homodimer or a heterodimer with related proteins. The many Mitf mutations have provided important insights into the in vivo behavior of a bHLH-Zip protein. Here we describe the phenotype of two new semidominant Mitf mutations recovered in recent mutagenic screens, Mitf(mi-enu5) and Mitf(mi-bcc2); determine the molecular lesions involved; and show that the mutant proteins act in a dominant negative fashion in vitro. The novel mutations are phenotypically distinct from previously known Mitf mutations.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Iceland, 101 Reykjavík, Iceland.
authors.forename: Adalheidur Gígja
authors.initials: AG
authors.lastname: Hansdottir
authors.forename: Karen
authors.initials: K
authors.lastname: Pálsdóttir
authors.forename: John
authors.initials: J
authors.lastname: Favor
authors.forename: Angelika
authors.initials: A
authors.lastname: Neuhäuser-Klaus
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Eiríkur
authors.initials: E
authors.lastname: Steingrímsson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005799:Genes, Dominant / Q000235:genetics*; D005838:Genotype; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D014157:Transcription Factors