Functions of <i>Gtf2i</i> and <i>Gtf2ird1</i> in the developing brain: transcription, DNA-binding, and long term behavioral consequences

Kopp, Nathan; Nygaard, Kayla R; McCullough, Katherine; Maloney, Susan E.; Gabel, Harrison W.; Dougherty, Joseph D.

doi:10.1101/854851

Cited by 5 publications

(11 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S3A ), suggesting a more complex picture. Of note, SYN1 and NLGN1 are found among GTF2I targets (Kopp et al, 2020; McCleary-Wheeler et al, 2020). We next compared the iNeurons transcriptomes to a single-cell RNAseq time-course of Ngn2 differentiation (Lin et al, 2021), which revealed a slight differentiation delay of WBS lines ( Fig.…”

Section: Resultsmentioning

confidence: 95%

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

Mihailovich

Germain

Shyti

et al. 2022

Preprint

View full text Add to dashboard Cite

Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and excitability. Genes related to neuronal transmission chiefly followed 7q11.23 dosage and appeared transcriptionally controlled, while translation and ribosomal protein genes followed the opposite trend and were post-transcriptionally buffered. Mechanistically, we uncovered REST regulon as a key mediator of observed phenotypes and rescued transcriptional and excitability alterations through REST inhibition. We identified downregulation of global protein synthesis, mGLUR5 and ERK-mTOR pathways activity in steady-state in both WBS and 7Dup, whereas BDNF stimulation rescued them specifically in 7Dup. Overall, we show that 7q11.23 CNVs alter protein synthesis and neuronal firing-established molecular and cellular phenotypes of neurodevelopmental disorders.

show abstract

Section: Resultsmentioning

confidence: 95%

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

Mihailovich

Germain

Shyti

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…USV recordings were performed as described in ref. 75 to assess early communicative behaviors. Pup vocalizations were recorded on postnatal days 5, 7, and 9 in the home colony room of the pups.…”

Section: Methodsmentioning

confidence: 99%

“…Pups were recorded for 3 min, after which their weight was taken and they were returned to their home cage within the warming box. MATLAB software was used to prepare sonograms of the recordings (frequency range = frequency range = 25-120 kHz, fast Fourier transform size = 512, overlap = 50%, time resolution = 1.024 ms, frequency resolution = 488.2 Hz) using a previously published protocol 75 .…”

Section: Methodsmentioning

confidence: 99%

Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis

et al. 2021

Self Cite

View full text Add to dashboard Cite

The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders.

show abstract

“…Mouse models in which GTF2IRD1 specifically has been disrupted, in both a heterozygous and biallelic fashion, have variably recapitulated portions of the WBS neurocognitive profile, including increased anxiety, increased sociability, and impaired motor coordination depending on the model utilized (Howard et al, 2012; Schneider et al, 2012; Young et al, 2008). Most recently, Kopp et al generated mice with homozygous GTF2IRD1 variants, alone or in combination with disruption of GTF2I , and interestingly demonstrated that disruption of GTF2IRD1 alone was sufficient to generate significant behavioral anomalies in mice, with the addition of GTF2I disruption only marginally altering the phenotype (Kopp et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Biallelic GTF2IRD1 variants in brothers with profound neurodevelopmental disorder: A possible novel disorder involving a critical gene for Williams syndrome

Cummings

Starr

2022

American J of Med Genetics Pt A

View full text Add to dashboard Cite

GTF2IRD1, a gene on chromosome 7 which encodes a transcription factor, is of significant clinical interest due to its heterozygous loss as part of the classical deletion associated with Williams–Beuren syndrome (WBS). However, biallelic variants in GTF2IRD1 alone as part of an autosomal recessive disease have not been previously reported. Here, we present two full brothers with variants in trans of GTF2IRD1 at c.1231C > T (p.Arg411Trp) and c.2632C > G (p.Leu878Val). A detailed clinical phenotype is described, which includes severe neurodevelopmental disability, facial dysmorphology, and pectus excavatum. Importantly, out of eight full siblings, only these two brothers harboring both variants in trans present with the profound described phenotype. We present the possibility that these brothers represent the identification of a new syndrome characterized by biallelic variants in GTF2IRD1, which may also have important implications for the molecular etiology of WBS.

show abstract

Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences

Cited by 5 publications

References 68 publications

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis

Biallelic GTF2IRD1 variants in brothers with profound neurodevelopmental disorder: A possible novel disorder involving a critical gene for Williams syndrome

Contact Info

Product

Resources

About