Genomic analysis of the Microphthalmia locus and identification of the MITF-J/Mitf-J isoform

The deafness–pigmentary disorder Waardenburg Syndrome Type 2 is caused by mutations in the human Microphthalmia-associated transcription factor (MITF) gene. Multiple related deafness–pigmentary disorders result from mutations in genes that regulate MITF expression or its activity. Similarly in mouse, homozygous mutations in the Mitf gene disrupt the development of melanocytes as well as retinal pigment epithelial (RPE) cells, osteoclasts, mast cells, and NK cells. Because abnormalities in Mitf/MITF function are associated with numerous inherited disorders of mouse and man, a detailed understanding of its gene structure is important for both diagnostic and structure/function analyses. While at least eight distinct isoforms of MITF/Mitf have been identified to date, each differing in their promoter and initial exon usage, the positions of these exons and their order within the locus have yet to be fully defined. In this study, we provide a detailed description of the MITF/Mitf locus, identify corresponding human and mouse isoforms, and utilize an informatics-based approach to identify a novel ninth MITF/Mitf isoform, MITF-J/Mitf-J, which we show is expressed in multiple cell types. The MITF/Mitf locus is over 200 kb in length, with strong but imperfect exon conservation between human and mouse. MITF/Mitf tissue expression data are presented from multiple datasets, including EST expression patterns and isoform-specific RT-PCR. The majority of isoforms were found to be broadly expressed, with the M- and Mc-isoforms being tissue-restricted to melanocytes and mast cells, respectively. Consequently, a detailed characterization of this complex locus may help to identify additional unknown deafness–pigmentary syndrome mutations in human kindred and permit a better understanding of tissue-regulated expression that likely underlies divergent biological functions of this factor across multiple cell types.