An in vivo study of GTF2IRD1 function and its contribution to the physical features of Williams Beuren Syndrome

Williams-Beuren Syndrome (WBS) is a complex neurodevelopmental genetic disorder caused by a hemizygous deletion involving up to 28 genes on chromosome 7q11.23. Amongst the spectrum of physical and neurological defects of WBS, it is common to find sensorineural hearing loss (SNHL) and a characteristic set of facial features. The gene GTF2IRD1, first discovered in our laboratory, and the adjacent, homologous gene GTF2I, both fall within the WBS deletion region. Haploinsufficiency of the transcriptional regulators they encode is thought to account for the major neurological and craniofacial aspects of the disease. The aim of the work presented here is to drill deeper into the function of GTF2IRD1 by investigating the impact of a targeted Gtf2ird1 mouse deletion on neurological and craniofacial phenotypes using direct physiological and cellular analysis methods. A detailed analysis of Gtf2ird1 expression in the inner ear and the skin was conducted. A comprehensive analysis of hearing capacity in Gtf2ird1 knockout mice was carried out by examining the auditory brainstem response (ABR) and the distortion product of otoacoustic emissions (DPOAE). The role of GTF2IRD1 in the development of facial skin was examined by a detailed investigation of the control of epidermal proliferation, differentiation and barrier function, followed by an RNA-Seq analysis, to identify the molecular mechanisms that underpin the facial abnormalities observed in these mice. The hearing analyses revealed that Gtf2ird1 knockout mice have hypoacusis (a higher hearing threshold) in both assessments, indicating that the principal hearing deficit in the mice can be traced to impairments in the cochlear amplifier. We suggest that similar mechanisms may underpin the SNHL experienced by WBS patients. Analysis of the facial skin in knockout mice revealed that keratinocyte proliferation was augmented, keratinized epidermal layers were disorganized and the barrier function was compromised in facial regions where Gtf2ird1 is normally expressed during development. The RNA-Seq analysis demonstrated that these abnormalities correlate with dysregulated expression of several key factors, including FGF7. These data suggest that GTF2IRD1 is a crucial component of the transcriptional regulation machinery controlling facial skin patterning and differentiation and supports a role for its involvement in the causation of the facial characteristics of WBS.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2015

Author dc:creator

• Canales Martinez, Cesar

• Hearing
• GTF2IRD1
• Williams Beuren Syndrome
• Skin
• Mouse model
• Phenotype Characterisation
• RNA Seq
• DPOAE
• ABR

Statement dc:rights

• open access
• CC BY-NC-ND 3.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by-nc-nd/3.0/au/

Language dc:language

EN

Identifier

https://doi.org/10.26190/unsworks/18876

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/55786