Identification and functional analysis of a novel mutation in the SOX10 gene associated with Waardenburg syndrome type IV.
Waardenburg syndrome type IV (WS4) is a rare genetic disorder, characterized by auditory-pigmentary abnormalities and Hirschsprung disease. Mutations of the EDNRB gene, EDN3 gene, or SOX10 gene are responsible for WS4. In the present study, we reported a case of a Chinese patient with clinical features of WS4. 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.1063C>T (p.Q355*), in the last coding exon of SOX10. 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 SOX10 p.Q355* 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 SOX10.
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Department of Head and Neck Surgery, Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Province Key Laboratory of Otolaryngology Critical Diseases, Changsha 410008, Hunan, China.
Hong-Han
HH
Wang
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Province Key Laboratory of Otolaryngology Critical Diseases, Changsha 410008, Hunan, China.
Hong-Sheng
HS
Chen
State Key Laboratory of Medical Genetics of China, Changsha 410078, Hunan, China.
Hai-Bo
HB
Li
Department of Otolaryngology, Head and Neck Surgery, First Affiliated Hospital, Xinjiang Medical University, Urumqi 830054, Xinjiang, China.
Hua
H
Zhang
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Province Key Laboratory of Otolaryngology Critical Diseases, Changsha 410008, Hunan, China.
Ling-Yun
LY
Mei
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Province Key Laboratory of Otolaryngology Critical Diseases, Changsha 410008, Hunan, China.
Chu-Feng
CF
He
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Province Key Laboratory of Otolaryngology Critical Diseases, Changsha 410008, Hunan, China.
Xing-Wei
XW
Wang
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
Mei-Chao
MC
Men
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Province Key Laboratory of Otolaryngology Critical Diseases, Changsha 410008, Hunan, China.
Lu
L
Jiang
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
Xin-Bin
XB
Liao
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
Hong
H
Wu
Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; State Key Laboratory of Medical Genetics of China, Changsha 410078, Hunan, China; Province Key Laboratory of Otolaryngology Critical Diseases, Changsha 410008, Hunan, China. Electronic address: fyong@xysm.net.
Yong
Y
Feng
D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism; D002675:Child, Preschool; D018389:Codon, Nonsense; D005091:Exons; D006627:Hirschsprung Disease; D006801:Humans; D008297:Male; D010375:Pedigree; D011485:Protein Binding; D055757:SOXE Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014849:Waardenburg Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism
D018389:Codon, Nonsense; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors
Hirschsprung disease; Mutation; SOX10; Sensorineural hearing loss; Waardenburg syndrome