Identification of a Novel ENU-Induced Mutation in Mouse<i> Tbx1</i> Linked to Human DiGeorge Syndrome

Chen, Jiaofeng; Xue, Zhang; Li, Jie; Song, Chi Young; Jia, Yichang; Xiong, Wei

doi:10.1155/2016/5836143

Cited by 16 publications

(9 citation statements)

References 36 publications

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“…In order to identify the mutation responsible for the polydactyly phenotype, we extracted genomic DNA from a G2 affected mouse and performed the whole exome capture and DNA sequencing 21 . One hundred and sixty mutations were identified by the exome capture and 97% of these mutations are located in the gene regions, including exon, intron, and 5′ and 3′ UTR, reflecting our high exome capture efficiency (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

An ENU-induced mutation in Twist1 transactivation domain causes hindlimb polydactyly with complete penetrance and dominant-negatively impairs E2A-dependent transcription

Chen

Cheng

Tan

et al. 2020

Sci Rep

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Twist1 encodes a basic helix-loop-helix transcription factor (TF), which forms homodimer or heterodimer with other TFs, like E2A, to regulate target genes' expression. Mutations in TWIST1 are associated with Saethre-Chotzen syndrome (SCS), a rare congenital disorder characterized with osteogenesis abnormalities. However, how dysfunction of TWIST1 leads to SCS is still largely unknown. Here, using an unbiased ENU-induced mutagenesis screening, we identified a novel Twist1 mutation and the mutant mouse phenocopies some features of SCS in a dominant manner. Physically, our mutation p.F191S lies at the edge of a predicted α-helix in Twist1 transactivation (TA) domain. Adjacent to F191, a consecutive three-residue (AFS) has been hit by 3 human and 2 mouse disease-associated mutations, including ours. Unlike previously reported mouse null and p.S192P alleles that lead to hindlimb polydactyly with incomplete penetrance but a severe craniofacial malformation, our p.F191S causes the polydactyly (84.2% bilateral and 15.8% unilateral) with complete penetrance but a mild craniofacial malformation. Consistent with the higher penetrance, p.F191S has stronger impairment on E2A-dependent transcription than p.S192P. Although human p.A186T and mouse p.S192P disease mutations are adjacent to ours, these three mutations function differently to impair the E2A-dependent transcription. Unlike p.A186T and p.S192S that disturb local protein conformation and unstabilize the mutant proteins, p.F191S keeps the mutant protein stable and its interaction with E2A entire. Therefore, we argue that p.F191S we identified acts in a dominant-negative manner to impair E2Adependent transcription and to cause the biological consequences. In addition, the mutant mouse we provided here could be an additional and valuable model for better understanding the disease mechanisms underlying SCS caused by TWIST1 dysfunction.The function of TWIST1 in osteogenesis has been reflected by the identification of the TWIST1 mutations in Saethre-Chotzen syndrome (SCS), a rare congenital disorder often associated with cone-shaped head, asymmetrical face, hand and foot malformation, and even mental retardation 1-3 . Further studies demonstrated that Twist1 is also involved in epithelial-mesenchymal transition and cell migration during embryonic development and contributes to the invasion of carcinoma cells and tumor metastasis 4-7 .Twist1 encodes a basic helix-loop-helix (bHLH) transcription factor and Twist1 DNA-binding capability essential for its functions has been intensively studied previously [8][9][10][11][12][13] . Twist1 either functions as homodimer or DiscussionIdentification of a novel Twist1 mutation responsible for hindlimb polydactyly. In ENU-induced mutagenesis, mutations that generate stop codon (nonsense), disrupt splicing site, or change amino acid (missense) are most likely disease-causing 22,23 . Among our 160 mutations identified by our exome-sequencing, no stop-gain and splicing site mutation was found. Instead, we identified 16 nonsynonymous mutati...

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Section: Resultsmentioning

confidence: 99%

An ENU-induced mutation in Twist1 transactivation domain causes hindlimb polydactyly with complete penetrance and dominant-negatively impairs E2A-dependent transcription

Chen

Cheng

Tan

et al. 2020

Sci Rep

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“…They participate in various cellular functions and about 30% of congenital hereditary deafness has been reported to be SHL caused by genetic mutations ( Ideura et al, 2019 ). For example, Tbx1 gene mutations are associated with the human DiGeorge syndrome accompanied by a deficiency in hearing function ( Chen et al, 2016 ). Moreover, functional null mutations of Hars2 (encoding mitochondrial histidyl tRNA synthetase) cause Perrault syndrome, which is characterized by ovarian dysgenesis and sensorineural hearing loss ( Pierce et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…More than 120 genes have been associated with NSHL 1 . In contrast, hearing loss is known to occur more frequently in syndromes that affect various other systems of the body, referred to as syndromic hearing loss (SHL) ( Chen et al, 2016 ). Currently, there are over 400 syndromes that result in hearing loss, corresponding to 30% of inherited deafness cases ( Ideura et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Sensorineural Hearing Loss and Mitochondrial Apoptosis of Cochlear Spiral Ganglion Neurons in Fibroblast Growth Factor 13 Knockout Mice

Yang

Luan

et al. 2021

Front. Cell. Neurosci.

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Deafness is known to occur in more than 400 syndromes and accounts for almost 30% of hereditary hearing loss. The molecular mechanisms underlying such syndromic deafness remain unclear. Furthermore, deafness has been a common feature in patients with three main syndromes, the BÖrjeson-Forssman-Lehmann syndrome, Wildervanck syndrome, and Congenital Generalized Hirsutism, all of which are characterized by loss-of-function mutations in the Fgf13 gene. Whether the pathogenesis of deafness in these syndromes is associated with the Fgf13 mutation is not known. To elucidate its role in auditory function, we generated a mouse line with conditional knockout of the Fgf13 gene in the inner ear (Fgf13 cKO). FGF13 is expressed predominantly in the organ of Corti, spiral ganglion neurons (SGNs), stria vascularis, and the supporting cells. Conditional knockout of the gene in the inner ear led to sensorineural deafness with low amplitude and increased latency of wave I in the auditory brainstem response test but had a normal distortion product otoacoustic emission threshold. Fgf13 deficiency resulted in decreased SGN density from the apical to the basal region without significant morphological changes and those in the number of hair cells. TUNEL and caspase-3 immunocytochemistry assays showed that apoptotic cell death mediated the loss of SGNs. Further detection of apoptotic factors through qRT-PCR suggested the activation of the mitochondrial apoptotic pathway in SGNs. Together, this study reveals a novel role for Fgf13 in auditory function, and indicates that the gene could be a potential candidate for understanding deafness. These findings may provide new perspectives on the molecular mechanisms and novel therapeutic targets for treatment deafness.

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“…The adult mice were tested to evaluate hearing threshold by click auditory brainstem response (click ABR) as described previously (Chen et al, 2016 ). Before measurement, the mouse was anesthetized by i.p.…”

Section: Methodsmentioning

confidence: 99%

Deletion of Kncn Does Not Affect Kinocilium and Stereocilia Bundle Morphogenesis and Mechanotransduction in Cochlear Hair Cells

et al. 2018

Front. Mol. Neurosci.

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Auditory hair cells possess stunning cilia structure that composes of a bundle of stereocilia for mechano-electrical transduction and a single kinocilium for guiding the polarity of hair bundle towards maturation. However, the molecules underlying kinocilium function have not yet been fully understood. Hence, the proteins involved in hair bundle development and function are of a large interest. From a fine microarray analysis, we found that kinocilin (Kncn) was enriched in hair cell specific expression profile. Consistently, it has been reported that KNCN was a protein mainly located in the kinocilium of hair cells in the inner ear. However, the hypothesis that KNCN is a kinocilium protein has not been validated in mice with Kncn gene perturbed. In this study, we generated Kncn knockout mouse lines by CRISPR/Cas9 technique and further examined the morphology and function of cochlear hair cells. Our results showed that there was no obvious hearing loss in the knockout mice, determined by audiometry. Histological study demonstrated that the inner ear and hair cell structure were intact. Especially, there was no deficit of mechanotransduction (MET) in cochlear outer hair cells (OHCs). In summary, our work suggests that KNCN is not essential for kinocilium-oriented hair bundle function in cochlear hair cells.

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Identification of a Novel ENU-Induced Mutation in Mouse Tbx1 Linked to Human DiGeorge Syndrome

Cited by 16 publications

References 36 publications

An ENU-induced mutation in Twist1 transactivation domain causes hindlimb polydactyly with complete penetrance and dominant-negatively impairs E2A-dependent transcription

An ENU-induced mutation in Twist1 transactivation domain causes hindlimb polydactyly with complete penetrance and dominant-negatively impairs E2A-dependent transcription

Sensorineural Hearing Loss and Mitochondrial Apoptosis of Cochlear Spiral Ganglion Neurons in Fibroblast Growth Factor 13 Knockout Mice

Deletion of Kncn Does Not Affect Kinocilium and Stereocilia Bundle Morphogenesis and Mechanotransduction in Cochlear Hair Cells

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