Anxious, hypoactive phenotype combined with motor deficits in Gtf2ird1 null mouse model relevant to Williams syndrome.

Williams-Beuren syndrome (WBS) is a rare genetic disorder caused by a hemizygous deletion of around 28 genes on the long arm of chromosome 7 (7q11.23), characterized by a unique spectrum of behavioral impairments, including mental retardation, deficits in visuospatial constructive cognition, hypersociability, anxiety and simple phobias. Physical characteristics include dysmorphic faces, short stature, oculomotor deficits, gross and fine coordination impairments, diminished control of balance and mild extrapyramidal signs as well as gait abnormalities resembling gait hypokinesia. Genes near the distal deletion breakpoint appear to contribute most to the WBS cognitive and behavioral profile and include the GTF family of transcription factors: GTF2I, GTF2IRD1, GTF2IRD2. We have previously shown that heterozygous deletions of GTF2IRD1 in humans and homozygous deletion in mice contributes to craniofacial abnormalities. Here we show an important role of this gene in motor coordination and anxiety ascertained from extensive behavioral mouse phenotyping. Gtf2ird1 null mice showed lower body weight, decreased spontaneous and circadian locomotor activity, diminished motor coordination and strength, gait abnormalities, increased anxiety and an elevated endocrinological response to stress. Gtf2ird1 heterozygous mice displayed lower body weight and decreased circadian activity, but only minor motor coordination and anxiety-related behavioral dysfunctions. Our study strongly supports a role for GTF2IRD1 in the motoric and anxiety-related abnormalities seen in Williams-Beuren syndrome, and suggests basal ganglia and potentially cerebellar abnormalities in Gtf2ird1 mice.

Schneider T ，Skitt Z ，Liu Y ，Deacon RM ，Flint J ，Karmiloff-Smith A ，Rawlins JN ，Tassabehji M ... -  《-》

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

Insufficiency of the transcriptional regulator GTF2IRD1 has become a strong potential explanation for some of the major characteristic features of the neurodevelopmental disorder Williams-Beuren syndrome (WBS). Genotype/phenotype correlations in humans indicate that the hemizygous loss of the GTF2IRD1 gene and an adjacent paralogue, GTF2I, play crucial roles in the neurocognitive and craniofacial aspects of the disease. In order to explore this genetic relationship in greater detail, we have generated a targeted Gtf2ird1 mutation in mice that blocks normal GTF2IRD1 protein production. Detailed analyses of homozygous null Gtf2ird1 mice have revealed a series of phenotypes that share some intriguing parallels with WBS. These include reduced body weight, a facial deformity resulting from localised epidermal hyperplasia, a motor coordination deficit, alterations in exploratory activity and, in response to specific stress-inducing stimuli; a novel audible vocalisation and increased serum corticosterone. Analysis of Gtf2ird1 expression patterns in the brain using a knock-in LacZ reporter and c-fos activity mapping illustrates the regions where these neurological abnormalities may originate. These data provide new mechanistic insight into the clinical genetic findings in WBS patients and indicate that insufficiency of GTF2IRD1 protein contributes to abnormalities of facial development, motor function and specific behavioural disorders that accompany this disease.

Howard ML ，Palmer SJ ，Taylor KM ，Arthurson GJ ，Spitzer MW ，Du X ，Pang TY ，Renoir T ，Hardeman EC ，Hannan AJ ... -  《-》

Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome.

van Hagen JM ，van der Geest JN ，van der Giessen RS ，Lagers-van Haselen GC ，Eussen HJ ，Gille JJ ，Govaerts LC ，Wouters CH ，de Coo IF ，Hoogenraad CC ，Koekkoek SK ，Frens MA ，van Camp N ，van der Linden A ，Jansweijer MC ，Thorgeirsson SS ，De Zeeuw CI ... -  《NEUROBIOLOGY OF DISEASE》

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

Corley SM ，Canales CP ，Carmona-Mora P ，Mendoza-Reinosa V ，Beverdam A ，Hardeman EC ，Wilkins MR ，Palmer SJ ... -  《BMC GENOMICS》

Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile.

Antonell A ，Del Campo M ，Magano LF ，Kaufmann L ，de la Iglesia JM ，Gallastegui F ，Flores R ，Schweigmann U ，Fauth C ，Kotzot D ，Pérez-Jurado LA ... -  《-》