International Journal of Pediatric Otorhinolaryngology 78 (2014) 926–929
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
De novo dominant mutation of SOX10 gene in a Chinese family with Waardenburg syndrome type II Kaitian Chen 1, Ling Zong 1, Min Liu, Yuan Zhan, Xuan Wu, Wenting Zou, Hongyan Jiang * Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-Sen University and Institute of Otorhinolaryngology, Sun Yat-sen University, Guangzhou 510080, PR China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 December 2013 Received in revised form 11 March 2014 Accepted 14 March 2014 Available online 27 March 2014
Objective: Waardenburg syndrome is a rare genetic disorder, inherited as an autosomal dominant trait. The condition is characterized by sensorineural hearing loss and pigment disturbances of the hair, skin, and iris. The de novo mutation in the SOX10 gene, responsible for Waardenburg syndrome type II, is rarely seen. The present study aimed to identify the genetic causes of Waardenburg syndrome type II in a Chinese family. Methods: Clinical and molecular evaluations were conducted in a Chinese family with Waardenburg syndrome type II. Results: A novel SOX10 heterozygous c.259-260delCT mutation was identified. Heterozygosity was not observed in the parents and sister of the proband, indicating that the mutation has arisen de novo. The novel frameshift mutation, located in exon 3 of the SOX10 gene, disrupted normal amino acid coding from Leu87, leading to premature termination at nucleotide 396 (TGA). The high mobility group domain of SOX10 was inferred to be partially impaired. Conclusion: The novel heterozygous c.259-260delCT mutation in the SOX10 gene was considered to be the cause of Waardenburg syndrome in the proband. The clinical and genetic characterization of this family would help elucidate the genetic heterogeneity of SOX10 in Waardenburg syndrome type II. Moreover, the de novo pattern expanded the mutation data of SOX10. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: De novo SOX10 Waardenburg syndrome
1. Introduction Waardenburg syndrome (WS) is a rare genetic disorder, inherited as an autosomal dominant trait. It is characterized by sensorineural hearing loss and pigment disturbances of the hair, skin, and iris, and has been reported in many ethnic and racial groups [1,2]. Four types of WS have been identified, depending on their clinical characteristics: type I WS (WS1) and type II WS (WS2) are distinguished by the presence or absence of dystopia canthorum, respectively; type III WS (Klein–Waardenburg syndrome, WS3) is similar to type I with additional musculoskeletal abnormalities; type IV WS (Shah–Waardenburg syndrome or Waardenburg–Hirschsprung disease, WS4) is characterized by the presence of an aganglionic megacolon.
* Corresponding author. Tel.: +86 020 87333733; fax: +86 020 87333733. E-mail address: [email protected] (H. Jiang). 1 These authors contributed equally to the study. http://dx.doi.org/10.1016/j.ijporl.2014.03.014 0165-5876/ß 2014 Elsevier Ireland Ltd. All rights reserved.
WS2 is phenotypically well-defined and genetically heterogeneous; its hallmarks are sensorineural hearing loss and iris heterochromia. Other pigmentation disturbances, including white forelock, early graying, and hypo- or hyperpigmented skin patches, are present in relatively low proportions in WS2 patients [3]. It is believed that some WS2 cases are associated with SOX10, MITF, and SNAI2 mutations [4–6]. The WS4 phenotype can also result from a SOX10 mutation [7]. The SOX10 gene is made up of 4/5 exons located on chromosome 22q13.1. It encodes a member of the SOX family of transcription factors, involved in the regulation of embryonic development and the determination of cell fate. Three exons code for a protein composed of 466 amino acids. This protein acts as a nucleocytoplasmic shuttle, important for neural crest and peripheral nervous system development [8]. At present, more than 20 mutations causing WS2/WS4 have been reported in the SOX10 gene. Most WS2 mutations display familial inheritance [5,8]. In contrast, de novo SOX10 mutations are mainly responsible for WS4 [1,7–10]. Moreover, there are very limited reports on SOX10 mutations associated with WS2 in the
K. Chen et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 926–929
Chinese population. Chen et al. only detected three SOX10 mutants among 18 WS2/WS1 patients [11]. Yang et al. screened 20 WS2 patients and did not identify any mutations in the SOX10 gene [12]. In addition, Sham et al. found two SOX10 mutations in two Chinese WS4 patients [13], while no SOX10 mutations were reported in Chinese WS2 patients. In this study, we describe a novel mutation in the SOX10 gene, associated with WS2 in a Chinese family. The de novo mutation in WS2 challenges traditional prenatal genetic counseling. 2. Patients and methods A six year old boy (II-1) from the Guangdong Province in China was referred to our center for molecular diagnosis, with his parents and sister, who had normal hearing, eyes, and skin (Fig. 1). A complete medical history was taken, and physical examinations were performed for all subjects, to exclude the possibility of environmental causes. There was no family history of malformations, hearing impairment, constipation, and/or mental retardation. Pregnancy and delivery of the proband were uneventful. The boy did not pass the newborn hearing screening at 24 h and 42 days old, and his speech was delayed after birth. He was diagnosed with bilateral congenital profound deafness at two years old, using the auditory brainstem response (ABR) and the auditory steadystate evoked response (ASSR). In addition, his right iris was blue
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and he had gray hair. Other signs, such as dystopia canthorum, musculoskeletal abnormalities, or aganglionic megacolon were absent. The W index was less than 1.85. No vision loss was present. Mental and physical development were normal. Temporal computed tomography (CT) and magnetic resonance imaging (MRI) identified bilateral posterior semicircular canal aplasia and an enlarged lateral semicircular canal in the left ear (Fig. 2). He received left ear cochlear implantation at three years old and achieved nearly normal hearing and speech after language rehabilitation. The study was approved by the institutional review board of the First Affiliated Hospital, Sun Yat-sen University. Informed consent was obtained from his parents. Blood samples were collected from all four subjects, and DNA isolation was performed using a standard chloroform extraction method. The primers to amplify all coding regions and intron/exon boundaries of target genes were designed using PRIMER5 software. All coding exons of SOX10, MITF, PAX3, and SNAI2 were subsequently PCR amplified and directly sequenced using an ABI 3730 Genetic Sequencer. All sequences were aligned and compared with published sequences from the NCBI (SOX10: NM_006941.3; MITF: NM_000248.3; PAX3: NM_000438.5; SNAI2: NM_003068.4). Amino acid conservation alignments were applied across different mammalian and human SOX gene families. Three dimensional modeling of the high mobility group (HMG) domain of the human SOX10 protein, which
[(Fig._1)TD$IG]
Fig. 1. Pedigree of the family showing the de novo heterozygous SOX10 c.259-260delCT mutation.
[(Fig._2)TD$IG]
Fig. 2. Clinical features of the proband included iris heterochromia in the right eye (a), gray hair (b), and bilateral posterior semicircular canal aplasia and an enlarged lateral semicircular canal in the left ear (c–d). Both ABR (e) and ASSR (f) confirmed bilateral profound deafness.
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K. Chen et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 926–929
resembles a known SOX9 at 2.77 A˚ resolution, was performed using SWISS-MODEL (http://swissmodel.expasy.org/workspace/). 3. Results The boy was diagnosed with WS type II based on clinical manifestations, according to the international criteria proposed by the Waardenburg Consortium [14]. Molecular evaluation identified a novel dominant SOX10 heterozygous c.259-260delCT (p.L87del) mutation (Fig. 1). Both his parents and sister were negative for this substitution, suggesting a de novo mutation. This variant was also absent in 50 normal control individuals. No MITF, PAX3, or SNAI2 gene mutations were found. The novel mutation c.259-260delCT was located in SOX10 gene exon 3. In wild type SOX10, the 259-260CT nucleotides encode Leu87 at the dimerization domain (from Gly52 to Val94) upstream of the HMG DNA binding domain (from His103 to Tyr173). The frameshift mutation disrupted normal amino acid coding from Leu87, resulting in premature termination at nucleotide 396 (TGA). The HMG domain was inferred to be partially impaired. In addition, amino acids around the targeted regions were highly conserved across different mammalian species and the human SRY-related HMG-box gene family (Fig. 3). The pathogenicity of this alteration was further confirmed by online MutationTaster prediction (http://www.mutationtaster.org/) [15].
4. Discussion In this study, we presented a Chinese family with WS2 and detected a novel heterozygous SOX10 mutation. Only the proband patient carried the mutation, suggesting that it had arisen de novo. No MITF, PAX3, or SNAI2 gene mutations were found. The heterozygosity observed in SOX10 supported the hereditary heterogeneity of WS and expanded the limited data regarding Chinese patients with WS2, since the SOX10 mutation is rare among the Chinese population [11–13]. SOX10, a member of the group E SOX genes, contains a central HMG domain and a C-terminal transactivation domain [16]. This gene encodes a member of the SOX family of transcription factors, involved in the regulation of embryonic development and the determination of cell fate. The protein acts as a nucleocytoplasmic shuttle protein, important for neural crest and peripheral nervous system development. More than 20 mutations have been reported in the SOX10 gene, most of which generate premature stop codons resulting in WS4 or the more severe PCWH (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease) [9,10]. In China, Chen et al. found three SOX10 mutations, c.113delG, c.110_219del110, and c.126_127delinsTT among 18 WS1/WS2 patients [11]. In a recent study conducted on 20 Chinese WS2 patients, no SOX10
[(Fig._3)TD$IG]
Fig. 3. The mutation alters the amino acids coding for the dimerization domain and impairs the HMG domain (a–c). The amino acids were highly conserved (d). D, dimerization domain; HMG, HMG domain; E, conserved domain of SOX8/9/10; TA, transactivation domain.
K. Chen et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 926–929
mutations were detected [12]. The present study is the first to report on mutation c.259-260delCT in the SOX10 gene, which is associated with WS2 in a Chinese boy. In this family, the typical signs of WS were present in the proband, such as prelingual sensorineural deafness and iris heterochromia. In addition, the patient presented with gray hair and semicircular canal abnormalities, supporting the multiple involvement of SOX10 protein dysfunction in the body. The c.259260delCT mutation is a truncating mutation, which removes only part of the HMG domain. This may explain the less severe phenotype than that seen in WS4, which is caused by SOX10 mutations involving the whole HMG domain. 5. Conclusion The novel heterozygous c.259-260delCT mutation in the SOX10 gene was considered to be the cause of WS in the proband. The clinical and genetic characterization of this family would help understand the genetic heterozygosity of SOX10 in WS type II. Moreover, the de novo pattern also expanded mutation data on SOX10. Conflict of interest None. Acknowledgements The authors thank all participants in this study for their cooperation. We thank Elixigen Corporation (Huntington Beach, California, USA) for helping in proofreading and editing the English of final manuscript. The study was supported by grants from the National Basic Research Program of China (2011CB504502), the National Natural Science Fund of China (81271076), the National Natural Science Fund of China (81200748) and the Minster of Health of China (No. 201202005).
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References [1] M. Morı´n, A. Vin˜uela, T. Rivera, M. Villamar, M.A. Moreno-Pelayo, F. Moreno, et al., A de novo missense mutation in the gene encoding the SOX10 transcription factor in a Spanish sporadic case of Waardenburg syndrome type IV, Am. J. Med. Genet. A 146A (8) (2008) 1032–1037. [2] S.G. Otman, N.I. Abdelhamid, Waardenburg syndrome type 2 in an African patient, Indian J. Dermatol. Venereol. Leprol. 71 (6) (2005) 426–427. [3] X.Z. Liu, V.E. Newton, A.P. Read, Waardenburg syndrome type II: phenotypic findings and diagnostic criteria, Am. J. Med. Genet. 55 (1) (1995) 95–100. [4] M. Tassabehji, V.E. Newton, A.P. Read, Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene, Nat. Genet. 8 (3) (1994) 251–255. [5] N. Bondurand, F. Dastot-Le Moal, L. Stanchina, N. Collot, V. Baral, S. Marlin, et al., Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4, Am. J. Hum. Genet. 81 (6) (2007) 1169–1185. [6] M. Sa´nchez-Martı´n, A. Rodrı´guez-Garcı´a, J. Pe´rez-Losada, A. Sagrera, A.P. Read, I.S.L.U.G. Sa´nchez-Garcı´a, (SNAI2) deletions in patients with Waardenburg disease, Hum. Mol. Genet. 11 (25) (2002) 3231–3236. [7] V. Pingault, N. Bondurand, K. Kuhlbrodt, D.E. Goerich, M.O. Prehu, A. Puliti, et al., SOX10 mutations in patients with Waardenburg–Hirschsprung disease, Nat. Genet. 18 (1998) 171–173. [8] V. Pingault, D. Ente, F. Dastot-Le Moal, M. Goossens, S. Marlin, N. Bondurand, Review and update of mutations causing Waardenburg syndrome, Hum. Mutat. 31 (4) (2010) 391–406. [9] V. Pingault, M. Girard, N. Bondurand, H. Dorkins, L. Van Maldergem, D. Mowat, et al., SOX10 mutations in chronic intestinal pseudo-obstruction suggest a complex physiopathological mechanism, Hum. Genet. 111 (2) (2002) 198–206. [10] J.B. Verheij, D.A. Sival, J.H. van der Hoeven, Y.J. Vos, L.C. Meiners, O.F. Brouwer, et al., Shah–Waardenburg syndrome and PCWH associated with SOX10 mutations: a case report and review of the literature, Eur. J. Paediatr. Neurol. 10 (1) (2006) 11–17. [11] H. Chen, L. Jiang, Z. Xie, L. Mei, C. He, Z. Hu, et al., Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome, Biochem. Biophys. Res. Commun. 397 (1) (2010) 70–74. [12] S. Yang, P. Dai, X. Liu, D. Kang, X. Zhang, W. Yang, et al., Genetic and phenotypic heterogeneity in Chinese patients with Waardenburg syndrome type II, PLoS ONE 8 (10) (2013) e77149. [13] M.H. Sham, V.C. Lui, B.L. Chen, M. Fu, P.K. Tam, Novel mutations of SOX10 suggest a dominant negative role in Waardenburg–Shah syndrome, J. Med. Genet. 38 (9) (2001) E30. [14] X.Z. Liu, V.E. Newton, A.P. Read, Waardenburg syndrome type II: phenotypic finding and diagnostic criteria, Am. J. Med. Genet. 55 (1) (1995) 95–100. [15] J.M. Schwarz, C. Ro¨delsperger, M. Schuelke, D. Seelow, MutationTaster evaluates disease-causing potential of sequence alterations, Nat. Methods 7 (8) (2010) 575– 576. [16] K.K. Chan, C.K. Wong, V.C. Lui, P.K. Tam, M.H. Sham, Analysis of SOX10 mutations identified in Waardenburg–Hirschsprung patients: differential effects on target gene regulation, J. Cell Biochem. 90 (3) (2003) 573–585.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
De novo dominant mutation of SOX10 gene in a Chinese family with Waardenburg syndrome type II Kaitian Chen 1, Ling Zong 1, Min Liu, Yuan Zhan, Xuan Wu, Wenting Zou, Hongyan Jiang * Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-Sen University and Institute of Otorhinolaryngology, Sun Yat-sen University, Guangzhou 510080, PR China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 December 2013 Received in revised form 11 March 2014 Accepted 14 March 2014 Available online 27 March 2014
Objective: Waardenburg syndrome is a rare genetic disorder, inherited as an autosomal dominant trait. The condition is characterized by sensorineural hearing loss and pigment disturbances of the hair, skin, and iris. The de novo mutation in the SOX10 gene, responsible for Waardenburg syndrome type II, is rarely seen. The present study aimed to identify the genetic causes of Waardenburg syndrome type II in a Chinese family. Methods: Clinical and molecular evaluations were conducted in a Chinese family with Waardenburg syndrome type II. Results: A novel SOX10 heterozygous c.259-260delCT mutation was identified. Heterozygosity was not observed in the parents and sister of the proband, indicating that the mutation has arisen de novo. The novel frameshift mutation, located in exon 3 of the SOX10 gene, disrupted normal amino acid coding from Leu87, leading to premature termination at nucleotide 396 (TGA). The high mobility group domain of SOX10 was inferred to be partially impaired. Conclusion: The novel heterozygous c.259-260delCT mutation in the SOX10 gene was considered to be the cause of Waardenburg syndrome in the proband. The clinical and genetic characterization of this family would help elucidate the genetic heterogeneity of SOX10 in Waardenburg syndrome type II. Moreover, the de novo pattern expanded the mutation data of SOX10. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: De novo SOX10 Waardenburg syndrome
1. Introduction Waardenburg syndrome (WS) is a rare genetic disorder, inherited as an autosomal dominant trait. It is characterized by sensorineural hearing loss and pigment disturbances of the hair, skin, and iris, and has been reported in many ethnic and racial groups [1,2]. Four types of WS have been identified, depending on their clinical characteristics: type I WS (WS1) and type II WS (WS2) are distinguished by the presence or absence of dystopia canthorum, respectively; type III WS (Klein–Waardenburg syndrome, WS3) is similar to type I with additional musculoskeletal abnormalities; type IV WS (Shah–Waardenburg syndrome or Waardenburg–Hirschsprung disease, WS4) is characterized by the presence of an aganglionic megacolon.
* Corresponding author. Tel.: +86 020 87333733; fax: +86 020 87333733. E-mail address: [email protected] (H. Jiang). 1 These authors contributed equally to the study. http://dx.doi.org/10.1016/j.ijporl.2014.03.014 0165-5876/ß 2014 Elsevier Ireland Ltd. All rights reserved.
WS2 is phenotypically well-defined and genetically heterogeneous; its hallmarks are sensorineural hearing loss and iris heterochromia. Other pigmentation disturbances, including white forelock, early graying, and hypo- or hyperpigmented skin patches, are present in relatively low proportions in WS2 patients [3]. It is believed that some WS2 cases are associated with SOX10, MITF, and SNAI2 mutations [4–6]. The WS4 phenotype can also result from a SOX10 mutation [7]. The SOX10 gene is made up of 4/5 exons located on chromosome 22q13.1. It encodes a member of the SOX family of transcription factors, involved in the regulation of embryonic development and the determination of cell fate. Three exons code for a protein composed of 466 amino acids. This protein acts as a nucleocytoplasmic shuttle, important for neural crest and peripheral nervous system development [8]. At present, more than 20 mutations causing WS2/WS4 have been reported in the SOX10 gene. Most WS2 mutations display familial inheritance [5,8]. In contrast, de novo SOX10 mutations are mainly responsible for WS4 [1,7–10]. Moreover, there are very limited reports on SOX10 mutations associated with WS2 in the
K. Chen et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 926–929
Chinese population. Chen et al. only detected three SOX10 mutants among 18 WS2/WS1 patients [11]. Yang et al. screened 20 WS2 patients and did not identify any mutations in the SOX10 gene [12]. In addition, Sham et al. found two SOX10 mutations in two Chinese WS4 patients [13], while no SOX10 mutations were reported in Chinese WS2 patients. In this study, we describe a novel mutation in the SOX10 gene, associated with WS2 in a Chinese family. The de novo mutation in WS2 challenges traditional prenatal genetic counseling. 2. Patients and methods A six year old boy (II-1) from the Guangdong Province in China was referred to our center for molecular diagnosis, with his parents and sister, who had normal hearing, eyes, and skin (Fig. 1). A complete medical history was taken, and physical examinations were performed for all subjects, to exclude the possibility of environmental causes. There was no family history of malformations, hearing impairment, constipation, and/or mental retardation. Pregnancy and delivery of the proband were uneventful. The boy did not pass the newborn hearing screening at 24 h and 42 days old, and his speech was delayed after birth. He was diagnosed with bilateral congenital profound deafness at two years old, using the auditory brainstem response (ABR) and the auditory steadystate evoked response (ASSR). In addition, his right iris was blue
927
and he had gray hair. Other signs, such as dystopia canthorum, musculoskeletal abnormalities, or aganglionic megacolon were absent. The W index was less than 1.85. No vision loss was present. Mental and physical development were normal. Temporal computed tomography (CT) and magnetic resonance imaging (MRI) identified bilateral posterior semicircular canal aplasia and an enlarged lateral semicircular canal in the left ear (Fig. 2). He received left ear cochlear implantation at three years old and achieved nearly normal hearing and speech after language rehabilitation. The study was approved by the institutional review board of the First Affiliated Hospital, Sun Yat-sen University. Informed consent was obtained from his parents. Blood samples were collected from all four subjects, and DNA isolation was performed using a standard chloroform extraction method. The primers to amplify all coding regions and intron/exon boundaries of target genes were designed using PRIMER5 software. All coding exons of SOX10, MITF, PAX3, and SNAI2 were subsequently PCR amplified and directly sequenced using an ABI 3730 Genetic Sequencer. All sequences were aligned and compared with published sequences from the NCBI (SOX10: NM_006941.3; MITF: NM_000248.3; PAX3: NM_000438.5; SNAI2: NM_003068.4). Amino acid conservation alignments were applied across different mammalian and human SOX gene families. Three dimensional modeling of the high mobility group (HMG) domain of the human SOX10 protein, which
[(Fig._1)TD$IG]
Fig. 1. Pedigree of the family showing the de novo heterozygous SOX10 c.259-260delCT mutation.
[(Fig._2)TD$IG]
Fig. 2. Clinical features of the proband included iris heterochromia in the right eye (a), gray hair (b), and bilateral posterior semicircular canal aplasia and an enlarged lateral semicircular canal in the left ear (c–d). Both ABR (e) and ASSR (f) confirmed bilateral profound deafness.
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K. Chen et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 926–929
resembles a known SOX9 at 2.77 A˚ resolution, was performed using SWISS-MODEL (http://swissmodel.expasy.org/workspace/). 3. Results The boy was diagnosed with WS type II based on clinical manifestations, according to the international criteria proposed by the Waardenburg Consortium [14]. Molecular evaluation identified a novel dominant SOX10 heterozygous c.259-260delCT (p.L87del) mutation (Fig. 1). Both his parents and sister were negative for this substitution, suggesting a de novo mutation. This variant was also absent in 50 normal control individuals. No MITF, PAX3, or SNAI2 gene mutations were found. The novel mutation c.259-260delCT was located in SOX10 gene exon 3. In wild type SOX10, the 259-260CT nucleotides encode Leu87 at the dimerization domain (from Gly52 to Val94) upstream of the HMG DNA binding domain (from His103 to Tyr173). The frameshift mutation disrupted normal amino acid coding from Leu87, resulting in premature termination at nucleotide 396 (TGA). The HMG domain was inferred to be partially impaired. In addition, amino acids around the targeted regions were highly conserved across different mammalian species and the human SRY-related HMG-box gene family (Fig. 3). The pathogenicity of this alteration was further confirmed by online MutationTaster prediction (http://www.mutationtaster.org/) [15].
4. Discussion In this study, we presented a Chinese family with WS2 and detected a novel heterozygous SOX10 mutation. Only the proband patient carried the mutation, suggesting that it had arisen de novo. No MITF, PAX3, or SNAI2 gene mutations were found. The heterozygosity observed in SOX10 supported the hereditary heterogeneity of WS and expanded the limited data regarding Chinese patients with WS2, since the SOX10 mutation is rare among the Chinese population [11–13]. SOX10, a member of the group E SOX genes, contains a central HMG domain and a C-terminal transactivation domain [16]. This gene encodes a member of the SOX family of transcription factors, involved in the regulation of embryonic development and the determination of cell fate. The protein acts as a nucleocytoplasmic shuttle protein, important for neural crest and peripheral nervous system development. More than 20 mutations have been reported in the SOX10 gene, most of which generate premature stop codons resulting in WS4 or the more severe PCWH (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease) [9,10]. In China, Chen et al. found three SOX10 mutations, c.113delG, c.110_219del110, and c.126_127delinsTT among 18 WS1/WS2 patients [11]. In a recent study conducted on 20 Chinese WS2 patients, no SOX10
[(Fig._3)TD$IG]
Fig. 3. The mutation alters the amino acids coding for the dimerization domain and impairs the HMG domain (a–c). The amino acids were highly conserved (d). D, dimerization domain; HMG, HMG domain; E, conserved domain of SOX8/9/10; TA, transactivation domain.
K. Chen et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 926–929
mutations were detected [12]. The present study is the first to report on mutation c.259-260delCT in the SOX10 gene, which is associated with WS2 in a Chinese boy. In this family, the typical signs of WS were present in the proband, such as prelingual sensorineural deafness and iris heterochromia. In addition, the patient presented with gray hair and semicircular canal abnormalities, supporting the multiple involvement of SOX10 protein dysfunction in the body. The c.259260delCT mutation is a truncating mutation, which removes only part of the HMG domain. This may explain the less severe phenotype than that seen in WS4, which is caused by SOX10 mutations involving the whole HMG domain. 5. Conclusion The novel heterozygous c.259-260delCT mutation in the SOX10 gene was considered to be the cause of WS in the proband. The clinical and genetic characterization of this family would help understand the genetic heterozygosity of SOX10 in WS type II. Moreover, the de novo pattern also expanded mutation data on SOX10. Conflict of interest None. Acknowledgements The authors thank all participants in this study for their cooperation. We thank Elixigen Corporation (Huntington Beach, California, USA) for helping in proofreading and editing the English of final manuscript. The study was supported by grants from the National Basic Research Program of China (2011CB504502), the National Natural Science Fund of China (81271076), the National Natural Science Fund of China (81200748) and the Minster of Health of China (No. 201202005).
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