Mutation of Gtf2ird1 from the Williams–Beuren syndrome critical region results in facial dysplasia, motor dysfunction, and altered vocalisations

Howard, Monique L.; Palmer, Steve; Taylor, Kylie M.; Arthurson, Geoffrey J.; Spitzer, M.; Du, Xin; Pang, Terence Y; Renoir, Thibault; Hardeman, Edna C.; Hannan, Anthony J.

doi:10.1016/j.nbd.2011.12.010

Cited by 32 publications

(28 citation statements)

References 44 publications

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“…Mice haploinsufficient for both Gtf2ird1 and Gtf2i are often growth retarded, and show hyploplasia of the mandible as well as other craniofacial defects resembling the anomalies and dental problems of WBS individuals [Enkhmandakh et al, 2009]. Finally, haploinsufficiency of GTF2IRD1 protein contributes to abnormalities of facial development, motor function and specific behavioral disorders that accompany WBS disease [Young et al, 2008;Howard et al, 2012;Schneider et al, 2012]. The phenotype of the patient reported here is in accordance with Dai et al [2009], who described a patient carrying a full deletion of GTF2IRD1 gene but preserving the GTF2I gene.…”

Section: Resultsmentioning

confidence: 99%

A 1.3-Mb 7q11.23 Atypical Deletion Identified in a Cohort of Patients with Williams-Beuren Syndrome

et al. 2013

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Williams-Beuren syndrome is a rare multisystem neurodevelopmental disorder caused by a 1.55-1.84-Mb hemizygous deletion on chromosome 7q11.23. The classical phenotype consists of characteristic facial features, supravalvular aortic stenosis, intellectual disability, overfriendliness, and visuospatial impairment. So far, 26-28 genes have been shown to contribute to the multisystem phenotype associated with Williams-Beuren syndrome. Among them, haploinsufficiency of the ELN gene has been shown to cause the cardiovascular anomalies. Identification of patients with atypical deletions has provided valuable information for genotype-phenotype correlation, in which other genes such as LIMK1,CLIP2, GTF2IRD1, or GTF2I have been correlated with specific cognitive profiles or craniofacial features. Here, we report the clinical and molecular characteristics of a patient with an atypical deletion that does not include the GTF2I gene and only partially includes the GTF2IRD1 gene.

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Section: Resultsmentioning

confidence: 99%

A 1.3-Mb 7q11.23 Atypical Deletion Identified in a Cohort of Patients with Williams-Beuren Syndrome

et al. 2013

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“…Gtf2ird1 is expressed strongly during skeletal muscle development, but is downregulated in mature muscle (Palmer et al, 2007). Studies on Gtf2ird1 knockout mice (Palmer et al, 2010;Howard et al, 2012) have so far failed to reveal fiber type changes, which may reflect very low levels of adult expression. By contrast, Gtf2i mRNA is relatively abundant in adult skeletal muscle tissue (Roy et al, 1997) and therefore TFII-I is the best candidate for such a role.…”

Section: Subcellular Localization Of Gtf2ird2 Gtf2ird1 and Tfii-imentioning

confidence: 99%

“…Careful analysis of the features of patients carrying atypical deletions of the region has led to the conclusion that loss of GTF2IRD1 and GTF2I can explain most of the other principal features including craniofacial dysmorphology, hypersociability and visuospatial deficits (Antonell et al, 2010). Recent work studying mice with mutations of the orthologous Gtf2ird1 and Gtf2i genes supports this conclusion and phenotypes of craniofacial dysmorphology (Tassabehji et al, 2005;Lucena et al, 2010;Howard et al, 2012), reduced fear and aggression (Young et al, 2008) and increased social interactions (Sakurai et al, 2011) have been reported.…”

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confidence: 99%

GTF2IRD2from the Williams-Beuren critical region encodes a mobile element-derived fusion protein that antagonizes the action of its related family members

Palmer

Taylor

Santucci

et al. 2012

Journal of Cell Science

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Summary GTF2IRD2 belongs to a family of transcriptional regulators (including TFII-I and GTF2IRD1) that are responsible for many of the key features of Williams-Beuren syndrome (WBS). Sequence evidence suggests that GTF2IRD2 arose in eutherian mammals by duplication and divergence from the gene encoding TFII-I. However, in GTF2IRD2, most of the C-terminal domain has been lost and replaced by the domesticated remnant of an in-frame hAT-transposon mobile element. In this first experimental analysis of function, we show that transgenic expression of each of the three family members in skeletal muscle causes significant fiber type shifts, but the GTF2IRD2 protein causes an extreme shift in the opposite direction to the two other family members. Mating of GTF2IRD1 and GTF2IRD2 mice restores the fiber type balance, indicating an antagonistic relationship between these two paralogs. In cells, GTF2IRD2 localizes to cytoplasmic microtubules and discrete speckles in the nuclear periphery. We show that it can interact directly with TFII-Ib and GTF2IRD1, and upon co-transfection changes the normal distribution of these two proteins into a punctate nuclear pattern typical of GTF2IRD2. These data suggest that GTF2IRD2 has evolved as a regulator of GTF2IRD1 and TFII-I; inhibiting their function by direct interaction and sequestration into inactive nuclear zones.

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“…In particular, homozygous null Gtf2ird1 mouse mutant lines show abnormal craniofacial development, altered anxiety responses in social and non-social contexts, altered exploratory drive and increased vocalisation in response to stressful stimuli and impaired motor coordination. [8][9][10][11] One of the typical features of WBS is an abnormal hearing response, classically described as 'hyperacusis'. This term aims to describe the extreme adverse behavioural reactions of WBS patients to sounds that are not normally regarded as loud or aversive and are generally acceptable to others.…”

Section: Introductionmentioning

confidence: 99%

“…However, acoustic tests in mice usually rely on behavioural responses, such as noise-evoked freezing time, and could be confounded by the altered anxiety responses previously reported in Gtf2ird1 knockouts. 8,11 In heterozygous Gtf2i mutant mice, 'hyperacusis' was reported on the basis of a mild increase in freezing response time. In addition, the mice also showed increased anxiety in the elevated plus maze and light-dark box tests.…”

Section: Introductionmentioning

confidence: 99%

The role of GTF2IRD1 in the auditory pathology of Williams–Beuren Syndrome

et al. 2014

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Williams-Beuren Syndrome (WBS) is a rare genetic condition caused by a hemizygous deletion involving up to 28 genes within chromosome 7q11.23. Among the spectrum of physical and neurological defects in WBS, it is common to find a distinctive response to sound stimuli that includes extreme adverse reactions to loud, or sudden sounds and a fascination with certain sounds that may manifest as strengths in musical ability. However, hearing tests indicate that sensorineural hearing loss (SNHL) is frequently found in WBS patients. The functional and genetic basis of this unusual auditory phenotype is currently unknown. Here, we investigated the potential involvement of GTF2IRD1, a transcription factor encoded by a gene located within the WBS deletion that has been implicated as a contributor to the WBS assorted neurocognitive profile and craniofacial abnormalities. Using Gtf2ird1 knockout mice, we have analysed the expression of the gene in the inner ear and examined hearing capacity by evaluating the auditory brainstem response (ABR) and the distortion product of otoacoustic emissions (DPOAE). Our results show that Gtf2ird1 is expressed in a number of cell types within the cochlea, and Gtf2ird1 null mice showed higher auditory thresholds (hypoacusis) in both ABR and DPOAE hearing assessments. These data indicate that the principal hearing deficit in the mice can be traced to impairments in the amplification process mediated by the outer hair cells and suggests that similar mechanisms may underpin the SNHL experienced by WBS patients.

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Mutation of Gtf2ird1 from the Williams–Beuren syndrome critical region results in facial dysplasia, motor dysfunction, and altered vocalisations

Cited by 32 publications

References 44 publications

A 1.3-Mb 7q11.23 Atypical Deletion Identified in a Cohort of Patients with Williams-Beuren Syndrome

A 1.3-Mb 7q11.23 Atypical Deletion Identified in a Cohort of Patients with Williams-Beuren Syndrome

GTF2IRD2from the Williams-Beuren critical region encodes a mobile element-derived fusion protein that antagonizes the action of its related family members

The role of GTF2IRD1 in the auditory pathology of Williams–Beuren Syndrome

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