<i>GTF2IRD2</i>from the Williams-Beuren critical region encodes a mobile element-derived fusion protein that antagonizes the action of its related family members

Palmer, Steve; Taylor, Kylie M.; Santucci, Nicole; Widagdo, Jocelyn; Chan, Yee-Ka Agnes; Yeo, Jen-Li; Adams, Merritt; Gunning, Peter W.; Hardeman, Edna C.

doi:10.1242/jcs.102798

Cited by 12 publications

(8 citation statements)

References 53 publications

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“…The functional bases for cognitive-behavioral effects from GTF2I remains largely unknown. GTF2I codes for the transcription factor TFII-I that is highly expressed in the brain [ 33 ], and it belongs to a small paralogous gene family of transcriptional regulators that includes two other genes in the Williams-syndrome region, GTF2IRD1 and GTF2IRD2 [ 4 ] that interact with one another in their effects [ 15 ]. Of particular interest with regard to the cognitive-behavioral effects of GTF2I is the finding that this gene shows evidence of genomic imprinting effects, with higher expression from the maternally-inherited allele [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Genes mediating cognitive-behavioral phenotypes in 7q11.23 deletions and duplications have been identified in several ways. First, the cognitive-behavioral profiles of individuals with small, atypical deletions in this region have implicated the GTF2I gene in hypersociality [ 14 , 15 ]. Variable-sized deletions have also been generated in mouse models, which have implicated the region including GTF2I, GTF2IRD1, LIMK1, and intervening genes, in sociality and anxiety phenotypes [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Cognitive-behavioral phenotypes of Williams syndrome are associated with genetic variation in the GTF2I gene, in a healthy population

Crespi

Hurd

2014

BMC Neurosci

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BackgroundIndividuals with Williams syndrome, a neurogenetic condition caused by deletion of a set of genes at chromosomal location 7q11.23, exhibit a remarkable suite of traits including hypersociality with high, nonselective friendliness and low social anxiety, expressive language relatively well-developed but under-developed social-communication skills overall, and reduced visual-spatial abilities. Deletions and duplications of the Williams-syndrome region have also been associated with autism, and with schizophrenia, two disorders centrally involving social cognition. Several lines of evidence have linked the gene GTF2I (General Transcription Factor IIi) with the social phenotypes of Williams syndrome, but a role for this gene in sociality within healthy populations has yet to be investigated.ResultsWe genotyped a large set of healthy individuals for two single-nucleotide polymorphisms in the GTF2I gene that have recently been significantly associated with autism, and thus apparently exhibit functional effects on autism-related social phenotypes. GTF2I genotypes for these SNPs showed highly significant association with low social anxiety combined with reduced social-communication abilities, which represents a metric of the Williams-syndrome cognitive profile as described from previous studies.ConclusionsThese findings implicate the GTF2I gene in the neurogenetic basis of social communication and social anxiety, both in Williams syndrome and among individuals in healthy populations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cognitive-behavioral phenotypes of Williams syndrome are associated with genetic variation in the GTF2I gene, in a healthy population

Crespi

Hurd

2014

BMC Neurosci

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“…If CYP27C1 has a similar function in Cottus , increased gene dosage could be beneficial for enhanced vision in more turbid environments (Fain, ) such as the larger streams inhabited by invasive Cottus . Finally, GTF2IRD2 might affect the development of skeletal muscle during the growth period of juvenile stages, with increased gene dosage leading to a higher proportion of slow‐type muscle fibres (Palmer et al., ). Changed proportions of muscle fibre types could be involved in the acclimation to different temperature regimes by invasive Cottus , resembling what has been reported for other teleost fishes (e.g., Woytanowski & Coughlin, ).…”

Section: Discussionmentioning

confidence: 99%

Copy number increases of transposable elements and protein‐coding genes in an invasive fish of hybrid origin

et al. 2017

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Evolutionary dynamics of structural genetic variation in lineages of hybrid origin is not well explored, although structural mutations may increase in controlled hybrid crosses. We therefore tested whether structural variants accumulate in a fish of recent hybrid origin, invasive Cottus, relative to both parental species Cottus rhenanus and Cottus perifretum. Copy‐number variation in exons of 10,979 genes was assessed using comparative genome hybridization arrays. Twelve genes showed significantly higher copy numbers in invasive Cottus compared to both parents. This coincided with increased expression for three genes related to vision, detoxification and muscle development, suggesting possible gene dosage effects. Copy number increases of putative transposons were assessed by comparative mapping of genomic DNA reads against a de novo assembly of 1,005 repetitive elements. In contrast to exons, copy number increases of repetitive elements were common (20.7%) in invasive Cottus, whereas decrease was very rare (0.01%). Among the increased repetitive elements, 53.8% occurred at higher numbers in C. perifretum compared to C. rhenanus, while only 1.4% were more abundant in C. rhenanus. This implies a biased mutational process that amplifies genetic material from one ancestor. To assess the frequency of de novo mutations through hybridization, we screened 64 laboratory‐bred F2 offspring between the parental species for copy‐number changes at five candidate loci. We found no evidence for new structural variants, indicating that they are too rare to be detected given our sampling scheme. Instead, they must have accumulated over more generations than we observed in a controlled cross.

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“…Evidence indicates that TFII-I and GTF2IRD1 have overlapping properties, can physically interact with each other and share a similar range of target genes. [5][6][7] In addition, work on mice carrying mutations of the orthologous genes Gtf2i and Gtf2ird1 supports a role for these genes in the craniofacial and neurological features of WBS. 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.…”

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

Cited by 12 publications

References 53 publications

Cognitive-behavioral phenotypes of Williams syndrome are associated with genetic variation in the GTF2I gene, in a healthy population

Cognitive-behavioral phenotypes of Williams syndrome are associated with genetic variation in the GTF2I gene, in a healthy population

Copy number increases of transposable elements and protein‐coding genes in an invasive fish of hybrid origin

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

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