Functional difference of the SOX10 mutant proteins responsible for the phenotypic variability in auditory-pigmentary disorders.

Waardenburg syndrome (WS) is an inherited disorder, characterized by auditory-pigmentary abnormalities. SOX10 transcription factor and endothelin receptor type B (EDNRB) are responsible for WS type 4 (WS4), which also exhibits megacolon, while microphthalmia-associated transcription factor (MITF) is responsible for WS2, which is not associated with megacolon. Here, we investigated the functions of SOX10 mutant proteins using the target promoters, EDNRB and MITF. The SOX10 mutations chosen were E189X, Q377X, and 482ins6, which are associated with WS4, and S135T that is associated with Yemenite deaf-blind hypopigmentation syndrome (YDBS), which does not manifest megacolon. These SOX10 mutant proteins showed impaired transactivation activity on the MITF promoter. In contrast, E189X and Q377X proteins, each of which lacks its C-terminal portion, activated the EDNRB promoter, whereas no activation was detected with the SOX10 proteins mutated at the DNA-binding domain, 482ins6 and S135T. However, unlike 482ins6 protein, S135T protein synergistically activated EDNRB promoter with a transcription factor Sp1, indicating that Sp1 could compensate the impaired function of a SOX10 mutant protein. We suggest that the variability in transactivation ability of SOX10 mutant proteins may account for the different phenotypes between WS4 and YDBS and that Sp1 is a potential modifier gene of WS4.