title: Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus.
abstract: Mouse microphthalmia transcription factor (Mitf) mutations affect the development of four cell types: melanocytes, mast cells, osteoclasts, and pigmented epithelial cells of the eye. The mutations are phenotypically diverse and can be arranged in an allelic series. In humans, MITF mutations cause Waardenburg syndrome type 2A (WS2A) and Tietz syndrome, autosomal dominant disorders resulting in deafness and hypopigmentation. Mitf mice thus represent an important model system for the study of human disease. Here we report the complete exon/intron structure of the mouse Mitf gene and show it to be similar to the human gene. We also found that the mouse gene is transcriptionally complex and is capable of generating at least 13 different Mitf isoforms. Some of these isoforms are missing important functional domains of the protein, suggesting that they might play an inhibitory role in Mitf function and signal transduction. In addition, we determined the molecular basis for six microphthalmia mutations. Two of the mutations are reported for the first time here (Mitf(mi-enu198) and Mitf(mi-x39)), while the others (Mitf(mi-ws), Mitf(mi-bws), Mitf(mi-ew), and Mitf(mi-di)) have been described but the molecular basis for the mutation not determined. When analyzed in terms of the genomic and transcriptional data presented here, it is apparent that these mutations result from RNA processing or transcriptional defects. Interestingly, three of the mutations (Mitf(mi-x39), Mitf(mi-bws), and Mitf(mi-ws)) produce proteins that are missing important functional domains of the protein identified in in vitro studies, further confirming a biological role for these domains in the whole animal.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Iceland, 101 Reykjavík, Iceland.
authors.forename: J H
authors.initials: JH
authors.lastname: Hallsson
authors.forename: J
authors.initials: J
authors.lastname: Favor
authors.forename: C
authors.initials: C
authors.lastname: Hodgkinson
authors.forename: T
authors.initials: T
authors.lastname: Glaser
authors.forename: M L
authors.initials: ML
authors.lastname: Lamoreux
authors.forename: R
authors.initials: R
authors.lastname: Magnúsdóttir
authors.forename: G J
authors.initials: GJ
authors.lastname: Gunnarsson
authors.forename: H O
authors.initials: HO
authors.lastname: Sweet
authors.forename: N G
authors.initials: NG
authors.lastname: Copeland
authors.forename: N A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: E
authors.initials: E
authors.lastname: Steingrímsson
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D005807:Genes, Overlapping; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D016296:Mutagenesis; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D014157:Transcription Factors