Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II

Chen, Hongsheng; Luo, Hunjin; An, Jing; Sun, Lin; Mei, Lingyun; He, Chufeng; Jiang, Lu; Jiang, Wen; Xia, Kun; Li, Jia‐Da; Feng, Yong

doi:10.1007/s00439-011-1098-2

Cited by 41 publications

(31 citation statements)

References 35 publications

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“…Transcription factor SOX10 contained a highly conserved HMG domain that could bind to the target gene to regulate its transcription (Southard-Smith et al, 1999 ; Pingault et al, 2010 ). Hypothetically, mutations in SOX10 located upstream of the HMG domain may result in haploinsufficiency (Bondurand et al, 2007 ; Ruiz-Maldonado, 2007 ; Zhang et al, 2012 ). In this study, most of the down-regulated genes and lncRNAs appeared to be a result of the mutation site located at the beginning of HMG domain.…”

Section: Discussionmentioning

confidence: 99%

Key Genes and Pathways Associated With Inner Ear Malformation in SOX10 p.R109W Mutation Pigs

Chen

et al. 2018

Front. Mol. Neurosci.

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SRY-box 10 (SOX10) mutation may lead to inner ear deformities. However, its molecular mechanisms on inner ear development are not clear. In this work, the inner ear morphology was investigated at different embryonic stages of the SOX10 mutation miniature porcine model with sensorineural hearing loss, and high-throughput RNA-seq and bioinformatics analyses were applied. Our results indicated that the SOX10 mutation in the miniature pigs led to an incomplete partition (IP) of the cochlea, a cystic apex caused by fusion from middle and apical turns, cochlear modiolar defects and a shortened cochlear duct. The model demonstrated 173 differentially expressed genes (DEGs) and 185 differentially expressed long non-coding RNAs (lncRNAs). The down-regulated DEGs most significantly enriched the inflammatory mediator regulation of the TRP channels, arachidonic acid metabolism, and the salivary secretion pathways, while the up-regulated DEGs most significantly enriched the systemic lupus erythematosus and alcoholism pathways. Based on gene cluster analysis, we selected four gene groups: WNT1, KCNQ4, STRC and PAX6.

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Section: Discussionmentioning

confidence: 99%

Key Genes and Pathways Associated With Inner Ear Malformation in SOX10 p.R109W Mutation Pigs

Chen

et al. 2018

Front. Mol. Neurosci.

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“…Dominant negative, monoallelic Sox10 mutations in humans are associated with Waardenburg syndrome which is characterized by abnormal pigmentation, intestinal aganglionosis (megacolon), and hearing loss (Pingault et al 1998(Pingault et al , 2014Bondurand et al 1999;Britsch et al 2001;Paratore et al 2002;Zhang et al 2012;Watanabe et al 2013;Jelena et al 2014). While it has been shown that Sox10 heterozygous knockout or mutant mice can exhibit intestinal and pigmentation phenotypes similar to those seen in Waardenburg syndrome, the presence of these phenotypes appears to depend upon the genetic background (i.e., strain) of the mice (Southard-Smith et al 1999a, b;Britsch et al 2001;Cantrell et al 2004).…”

Section: Sox10 Rtta/+ Mice Do Not Exhibit Gross Morphological or Audimentioning

confidence: 99%

A Sox10rtTA/+ Mouse Line Allows for Inducible Gene Expression in the Auditory and Balance Organs of the Inner Ear

Walters

Zuo

2015

JARO

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Genetic mouse models provide invaluable tools for discerning gene function in vivo. Tetracycline-inducible systems (Tet-On/Off) provide temporal and cell-type specific control of gene expression, offering an alternative or even complementary approach to existing Cre/LoxP systems. Here we characterized a Sox10(rtTA/+) knock-in mouse line which demonstrates inducible reverse tetracycline trans-activator (rtTA) activity and Tet-On transgene expression in the inner ear following induction with the tetracycline derivative doxycycline (Dox). These Sox10(rtTA/+) mice do not exhibit any readily observable developmental or hearing phenotypes, and actively drive Tet-On transgene expression in Sox10 expressing cells in the inner ear. Sox10(rtTA/+) activity was revealed by multiple Tet-On reporters to be nearly ubiquitous throughout the membranous labyrinth of the developing inner ear, and notably absent from hair cells, tympanic border cells, and ganglion neurons following postnatal Dox inductions. Interestingly, Dox-induced Sox10(rtTA/+) activity declined with induction age, where Tet-On reporters became uninducible in adult cochlear epithelium. Co-administration of the loop diuretic furosemide was able to rescue Dox-induced reporter expression, though this method also caused significant cochlear hair cell loss. Surprisingly, Sox10(rtTA/+) driven reporter expression in the cochlea persists for at least 54 days after cessation of neonatal induction, presumably due to the persistence of Dox within inner ear tissues. These findings highlight the utility of the Sox10(rtTA/+) mouse line as a powerful tool for functional genetic studies of the auditory and balance organs in vivo, but also reveal some important considerations that must be adequately controlled for in future studies that rely upon Tet-On/Off systems.

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“…In all, 293T cells growing in a 100-mm plate were transfected at approximately 80% confluency with 6 µg of pcDNA-LEF-1-HA and 6 µg of pCMV-MITF-Flag or its mutants using Lipofectamine 2000 (Invitrogen Life Technologies, Carlsbad, CA, USA). At 36–48 h after transfection, the co-immunoprecipitation were performed as reported previously [ 32 ]. The immunoprecipitation (IP) samples were incubated with 1 µg anti-Flag M2 monoclonal antibody (Sigma, St. Louis, WA, USA, F1804), and the negative control was incubated with 1 µg normal mouse IgG as a negative control.…”

Section: Methodsmentioning

confidence: 99%

“…The LEF-1-binding oligonucleotide derived from the promoter of the MITF gene, F: 5′-TTGGCCTTGATCTGACAGTGAGTTTGACTTTATAGCTCGTC-3′, was synthesized, biotinylated at the 5-terminus, and then annealed with its complementary strand to generate double-stranded oligonucleotides. The assays were performed as previously described [ 32 ]. In all, 293T cells were used with anti-HA rabbit antibody (1:1000 dilution, Cell Signaling Technology, Boston, MA, USA, 3724s).…”

Section: Methodsmentioning

confidence: 99%

Wnt signaling pathway involvement in genotypic and phenotypic variations in Waardenburg syndrome type 2 with MITF mutations

Wang

Mei

et al. 2018

J Hum Genet

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Mutation in the gene encoding microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome 2 (WS2), an autosomal dominantly inherited syndrome with auditory-pigmentary abnormalities, which is clinically and genetically heterogeneous. Haploinsufficiency may be the underlying mechanism for WS2. However, the mechanisms explaining the genotypic and phenotypic variations in WS2 caused by MITF mutations are unclear. A previous study revealed that MITF interacts with LEF-1, an important factor in the Wnt signaling pathway, to regulate its own transcription through LEF-1-binding sites on the MITF promoter. In this study, four different WS2-associated MITF mutations (p.R217I, p.R217G, p.R255X, p.R217del) that are associated with highly variable clinical features were chosen. According to the results, LEF-1 can activate the expression of MITF on its own, but MITF proteins inhibited the activation. This inhibition weakens when the dosage of MITF is reduced. Except for p.R217I, p.R255X, p.R217G, and p.R217del lose the ability to activate TYR completely and do not inhibit the LEF-1-mediated activation of the MITF-M promoter, and the haploinsufficiency created by mutant MITF can be overcome; correspondingly, the mutants’ associated phenotypes are less severe than that of p.R217I. The dominant negative of p.R217del made it have a second-most severe phenotype. This study’s data imply that MITF has a negative feedback loop of regulation to stabilize MITF gene dosage that involves the Wnt signaling pathway and that the interaction of MITF mutants with this pathway drives the genotypic and phenotypic differences observed in Waardenburg syndrome type 2 associated with MITF mutations.

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Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II

Cited by 41 publications

References 35 publications

Key Genes and Pathways Associated With Inner Ear Malformation in SOX10 p.R109W Mutation Pigs

Key Genes and Pathways Associated With Inner Ear Malformation in SOX10 p.R109W Mutation Pigs

A Sox10rtTA/+ Mouse Line Allows for Inducible Gene Expression in the Auditory and Balance Organs of the Inner Ear

Wnt signaling pathway involvement in genotypic and phenotypic variations in Waardenburg syndrome type 2 with MITF mutations

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