title: Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.
abstract: Waardenburg syndrome (WS) is an auditory-pigmentary disorder resulting from melanocyte defects, with varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1-WS4) based on additional symptoms. PAX3 and SOX10 are two transcription factors that can activate the expression of microphthalmia-associated transcription factor (MITF), a critical transcription factor for melanocyte development. Mutations of PAX3 are associated with WS1 and WS3, while mutations of SOX10 cause WS2 and WS4. Recently, we identified some novel WS-associated mutations in PAX3 and SOX10 in a cohort of Chinese WS patients. Here, we further identified an E248fsX30 SOX10 mutation in a family of WS2. We analyzed the subcellular distribution, expression and in vitro activity of two PAX3 mutations (p.H80D, p.H186fsX5) and four SOX10 mutations (p.E248fsX30, p.G37fsX58, p.G38fsX69 and p.R43X). Except H80D PAX3, which retained partial activity, the other mutants were unable to activate MITF promoter. The H80D PAX3 and E248fsX30 SOX10 were localized in the nucleus as wild type (WT) proteins, whereas the other mutant proteins were distributed in both cytoplasm and nucleus. Furthermore, E248fsX30 SOX10 protein retained the DNA-binding activity and showed dominant-negative effect on WT SOX10. However, E248fsX30 SOX10 protein seems to decay faster than the WT one, which may underlie the mild WS2 phenotype caused by this mutation.
authors.affiliation: Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Chen
authors.forename: Hunjin
authors.initials: H
authors.lastname: Luo
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Lingyun
authors.initials: L
authors.lastname: Mei
authors.forename: Chufeng
authors.initials: C
authors.lastname: He
authors.forename: Lu
authors.initials: L
authors.lastname: Jiang
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.forename: Jia-Da
authors.initials: JD
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000293:Adolescent; D005260:Female; D015870:Gene Expression; D006801:Humans; D009154:Mutation; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010375:Pedigree; D055757:SOXE Transcription Factors / Q000235:genetics*; D014018:Tissue Distribution; D014162:Transfection; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors