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

Abstract

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.

RNA-Seq analysis of Gtf2ird1 knockout epidermal tissue provides potential insights into molecular mechanisms underpinning Williams-Beuren syndrome

“…In the developing head, many of the hard and soft tissue components express Gtf2ird1 . In the transition to maturity, many of these sites are shut down and expression in the adult becomes mainly confined to sensory organs, neurons of the peripheral and central nervous system, smooth muscle, cardiac muscle, cells in the testis and brown adipose tissue [ 9 , 10 ].…”

Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I

“…Disruption of TFII-I-mediated transcriptional activation and/or TRPC3-mediated calcium transport may, however, still underlie some of the cognitive and behavioral deficits in WBS individuals and Src mutant mice. A closely related protein, GTF2IRD1, is also deleted in WBS and has been linked to increased social interaction in mice, as well as deficits in cued fear conditioning, growth delay, hearing loss, and craniofacial abnormalities ( Tassabehji et al, 2005 ; Young et al, 2008 ; Canales et al, 2014 ). It is possible that these two proteins both play a role in WBS, perhaps in a combinatorial manner, and that both are regulated by Src and have dual cellular functions.…”

Sensogenomics and the Biological Background Underlying Musical Stimuli: Perspectives for a New Era of Musical Research

“…In the field of genetics, Canales et al [ 71 ] investigated the 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. This work suggests that GTF2IRD1 insufficiency is not enough to explain all the hypoacusis.…”