EPISTATIC RELATIONSHIP BETWEEN WAARDENBURG SYNDROME GENES MITF AND PAX3

Waardenburg syndrome (WS) is a hereditary disorder that causes hypopig mentation and hearing impairment. Depending on additional symptoms, WS is classified into four types(1): WS1, WS2, WS3 and WS4. Mutations in MITF (microphthalmia-associated transcription factor) and PAX3, encod ing transcription factors, are responsible for WS2 and WS1/WS3, respec tively(1). We have previously shown that MITF transactivates the gene for tyrosinase, a key enzyme for melanogenesis, and is critically invo lved in melanocyte differentiation(2). Absence of melanocytes affects pigmentation in the skin, hair and eyes, and hearing function in the c ochlea(3). Therefore, hypopigmentation and hearing loss in WS2 are lik ely to be the results of an anomaly of melanocyte differentiation caus ed by MITF mutations(4,5). However, the molecular mechanism by which P AX3 mutations cause the auditory-pigmentary symptoms in WS1/WS3 remain s to be explained. Here we show that PAX3, a transcription factor with a paired domain and a homeodomain, transactivates the MITF promoter. We further show that PAX3 proteins associated with WS1 in either the p aired domain or the homeodomain fail to recognize and transactivate th e MITF promoter. These results provide evidence that PAX3 directly reg ulates MITF, and suggest that the failure of this regulation due to PA X3 mutations causes the auditory-pigmentary symptoms in at least some individuals with WS1.