Implications of isoform multiplicity of microphthalmia-associated transcription factor in the pathogenesis of auditory-pigmentary syndromes.

Microphthalmia-associated transcription factor (MITF) is the human homolog of a basic helix-loop-helix-leucine zipper protein (Mitf), encoded by the mouse microphthalmia locus. Mutations in the MITF gene have been identified in some patients with Waardenburg syndrome type 2 (WS2), which is a dominantly inherited disorder, characterized by varying combinations of sensorineural hearing loss and pigmentary disturbances. Furthermore, mice with mutations at the Mitf locus are associated with various phenotypes, such as white coat color, small eyes, a deficiency in mast cells, and osteopetrosis. Thus, MITF/Mitf may play an important role in differentiation of melanocytes and some other cell types. Recently we have identified two MITF isoforms with extended amino-termini, MITF-A and MITF-H. Both isoforms possess unique amino-termini that are different from the amino-terminus of the originally identified melanocyte-specific MITF (MITF-M). MITF-M mRNA is exclusively expressed in melanocytes and pigmented melanoma cells, whereas MITF-A and MITF-H mRNA are widely expressed in many cell types, including retinal pigment epithelium. Transient transfection assays suggested that these isoforms possess differential transactivation capacity. It is therefore conceivable that the previously identified mutations may alter the functions of not only MITF-M but also MITF-A and MITF-H. Possible implications of the MITF isoform multiplicity in the pathogenesis of auditory-pigmentary disorders are discussed.