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83rd Annual Meeting of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery

German Society of Oto-Rhino-Laryngology, Head and Neck Surgery

16.05. - 20.05.2012, Mainz

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Functional analysis of Waardenburg Syndrome-associated mutations

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  • corresponding author Yong Feng - Xiangya Hospital, Central South University, Changsha, P.R. China
  • Hua Zhang - Xiangya Hospital, Central South University, Changsha, P.R. China
  • Hongsheng Chen - Xiangya Hospital, Central South University, Changsha, P.R. China

Deutsche Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie. 83. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie. Mainz, 16.-20.05.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12hnod395

doi: 10.3205/12hnod395, urn:nbn:de:0183-12hnod3958

Published: April 4, 2012

© 2012 Feng et al.
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Outline

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Objective: To investigate effect of mutations of MITF, PAX3, and SOX10 causing Waardenburg Syndrome (WS) on their wild type (WT) protein and further study molecular mechanism of WS.

Methods: we performed studies of the nine mutations (H80D and H186fs in PAX3 with WS1, R217I and T192fs in MITF with WS2, G38fs,R43X,E248fs, G37fs, and W85X in SOX10 with WS2) which we have reported before in WS of Chinese and analyzed the subcellular distribution, expression, and in vitro activities of these mutations in 293T or NIH3T3 cells in a series of transfection experiments.

Results: Except R217I MITF and H80D PAX3, which retained partial activity, the other mutants were unable to activate tyrosinase or MITF promoter. The R217I MITF, H80D PAX3, and E248fsX30 SOX10 were localized in the nucleus as WT proteins, whereas the other mutant proteins were distributed in both cytoplasm and nucleus except T192fs MITF only in cytoplasm. Furthermore, E248fs SOX10 protein retained the DNA-binding activity and showed dominant negative effect on WT SOX10. However, E248fs SOX10 protein seems decay faster than the WT one, which may underlie the mild WS2 phenotype caused by this mutation.

Conclusion: The nine mutations ultimately downregulate the expression of tyrosinase or MITF as a result of haploinsufficiency which is most possible mechanism to explain their leading to mild phenotypes of WS1 or WS2 rather than severe phenotypes of WS3 or WS4.