Identification and functional analysis of a novel mutation in the SOX10 gene associated with Waardenburg syndrome type IV.

[hirschsprung disease]

Waardenburg syndrome type IV (WS 4 ) is a rare genetic disorder , characterized by auditory-pigmentary abnormalities and Hirschsprung disease . Mutations of the EDNRB gene , EDN 3 gene , or SOX 10 gene are responsible for WS 4 . In the present study , we reported a case of a Chinese patient with clinical features of WS 4 . In addition , the three genes mentioned above were sequenced in order to identify whether mutations are responsible for the case . We revealed a novel nonsense mutation , c .1063 C >T (p .Q 355 *), in the last coding exon of SOX 10 . The same mutation was not found in three unaffected family members or 100 unrelated controls . Then , the function and mechanism of the mutation were investigated in vitro . We found both wild-type (WT ) and mutant SOX 10 p .Q 355 * were detected at the expected size and their expression levels are equivalent . The mutant protein also localized in the nucleus and retained the DNA-binding activity as WT counterpart ; however , it lost its transactivation capability on the MITF promoter and acted as a dominant-negative repressor impairing function of the WT SOX 10 .