Epistatic relationship between Waardenburg Syndrome genes MITF and PAX3 (original) (raw)

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• Published: 01 March 1998

Nature Genetics volume 18, pages 283–286 (1998)Cite this article

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Abstract

Waardenburg syndrome (WS) is a hereditary disorder that causes hypopigmentation and hearing impairment. Depending on additional symptoms, WS is classified into four types1: WS1, WS2, WS3 and WS4. Mutations in MITF (mi crophthalmia-associated t ranscription f actor) and PAX3, encoding transcription factors, are responsible for WS2 and WS1/WS3, respectively1. We have previously shown that MITF transactivates the gene for tyrosinase, a key enzyme for melanogenesis, and is critically involved in melanocyte differentiation2. Absence of melanocytes affects pigmentation in the skin, hair and eyes, and hearing function in the cochlea3. Therefore, hypopigmentation and hearing loss in WS2 are likely to be the results of an anomaly of melanocyte differentiation caused by MITF mutations4,5. However, the molecular mechanism by which PAX3 mutations cause the auditory-pigmentary symptoms in WS1/WS3 remains 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 paired domain or the homeodomain fail to recognize and transactivate the MITF promoter. These results provide evidence that PAX3 directly regulates MITF, and suggest that the failure of this regulation due to PAX3 mutations causes the auditory-pigmentary symptoms in at least some individuals with WS1.

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Author notes

1. Atsushi Watanabe
   Present address: Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan
2. Kazuhisa Takeda
   Present address: Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Sendai, 980-8575, Japan

Authors and Affiliations

1. Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rm 2A31, Rockville, Maryland, 20850, USA
   Atsushi Watanabe, Kazuhisa Takeda, Barbara Ploplis & Masayoshi Tachibana

Authors

1. Atsushi Watanabe
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2. Kazuhisa Takeda
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3. Barbara Ploplis
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4. Masayoshi Tachibana
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Correspondence toMasayoshi Tachibana.

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Watanabe, A., Takeda, K., Ploplis, B. et al. Epistatic relationship between Waardenburg Syndrome genes MITF and PAX3.Nat Genet 18, 283–286 (1998). https://doi.org/10.1038/ng0398-283

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• Received: 24 November 1997
• Accepted: 23 January 1998
• Issue Date: 01 March 1998
• DOI: https://doi.org/10.1038/ng0398-283

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