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Williams–Beuren Syndrome
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Hui Zhang, Barbara Pober, Cheryl Klaiman, Robert Schultz
GTF2I is the most telomeric gene in the WBS critical region and codes for TFII-I, which functions as part of the basal transcription machinery, as well as an inducible transcription factor that regulates the expression of other genes (174). TFII-I is involved in histone deacetylation and chromatin structure remodeling (175,185,186). Although TFII-I is expressed ubiquitously (186), its function may be dosage sensitive only in certain tissues such as the brain. The multifaceted ability of TFII-I with effects on multiple down-steam target genes makes it a likely candidate responsible for some aspects of the WBS phenotype.
Thymoma and Thymic Carcinoma
Published in Dongyou Liu, Tumors and Cancers, 2017
Francesco Facciolo, Mirella Marino, Maria Teresa Ramieri
The tendency of THY to recur after R0 (no residual tumor tissue) resection is probably related to thymic nests/remnants in the mediastinum; hence, the adequate surgical management is based on total thymectomy even for relatively limited tumors. Moreover, the possibility of new clones emerging cannot be excluded. A molecular classification of TET would contribute to identify prognostic as well as predictive biomarkers and to promote personalized treatment approaches. Use of next-generation sequencing (NGS) led to the identification in a series of 274 TET of a GTF2I gene mutation in 82% of type A and 74% of type AB thymomas (two relatively indolent thymoma subtypes) but rarely in the aggressive subtypes [5]. The GTF2I gene, situated on chromosome 7, encodes a phosphoprotein functioning as a regulator of transcription. The missense mutation in GTF2I (in chromosome 7 c.74146970T>A) correlated with better survival. Moreover, a higher number of mutations in TC than in THY and recurrent mutations of known cancer genes, such as TP53, CYLD, CDKN2A, BAP1, and PBRM1 were identified [5].
Investigational drugs for the treatment of thymic cancer: a focus on phase 1 and 2 clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Fabio Conforti, Laura Pala, Tommaso De Pas, Yongfeng He, Giuseppe Giaccone
The knowledge of TETs genetic alterations has significantly improved in the past 10 years; however, this has hardly translated into new potential therapeutic options. This is in large part due to the poor understanding of the pathogenesis of this heterogeneous group of tumors. The lack of preclinical models that are representative of human TETs is a major hindrance to understanding the biology of these tumors and also to study potential novel therapies. Although the most common unique recurrent mutation in TETs in the transcription factor GTF2I gene was first described in 2014, the role played by GTF2I gene mutation in the pathogenesis of TETs is still largely unknown[60]. The genetics of TMs is clearly distinct from that of TCs, where the GFT2I mutation is rare, whereas mutations in common tumor suppressor genes (e.g. TP53) or oncogenes (e.g. HRAS) is relatively common. This finding together with the different biology of TMs vs TCs, support the development of separate strategies for the therapy of these two main groups of tumors.
The Prenatal Diagnosis of Seven Fetuses with 7q11.23 Microdeletion or Microduplication
Published in Fetal and Pediatric Pathology, 2020
Yinghui Dang, Shanning Wan, Yunyun Zheng, Tingting Song, Chunyan Li, Yu Li, Jianfang Zhang
BoBs and CMA indicated an approximately 1.5-Mb heterozygous microdeletion/microduplication of 7q11.23 in seven fetuses. This region contains 23 OMIM genes, including LIMK1, ELN, GTF2I, etc. There are also many studies on related genes in this region. The dosage-sensitive pathways of the ELN and LIMK1 genes may play a role in reciprocal fashion, resulting in converse phenotypes in deletion and duplication patients. ELN haploinsufficiency is unequivocally responsible for supravalvular aortic stenosis (SVAS) and the other connective tissue abnormalities of WBS patients [13]. One study found that the ELN gene in skin fibroblasts from WBS patients had highly variable expression with values overlapping those of non-affected patients [14]. LIMK1 is markedly expressed in the central nervous system, especially in mature synapses, suggesting that it may be involved in synapse formation or maintenance [15]. GTF2I is associated with the hyper-sociability in WBS patients [16], and in contrast, to separation anxiety. Many factors may play a key role in determining the variable expressivity of the WBS phenotype [17].
Convergent neurobiological predictors of mood and anxiety symptoms and treatment response
Published in Expert Review of Neurotherapeutics, 2019
Mbemba Jabbi, Charles B. Nemeroff
The general transcription factor 2I (GTF2i) gene is implicated in RNA polymerase II transcription initiation, promotor clearance, and translational control [23]. GTF2i is a transcriptional co-activator with the functional ability to bind to promotor elements of many genes [23]. CNVs of GTF2i [24] and sequence variations [25] have been implicated in anxiety phenotypes [24]. Hemizygosity for transcriptional activators and related DNA-binding proteins have functionally relevant dose-sensitive effects on social and anxiety phenotypes in human multi-system disorders such as the chromosome 7q11.23 hemideletion that causes Williams syndrome (WS) [26]. Remarkably, this genetic CNV is marked by over 70% prevalence of anxiety and abnormal insular pathway structure and function [26,27].