Mutations in TBR1 gene leads to cortical malformations and intellectual disability

A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice

“…TBR1 is a high-risk ASD gene and has been shown to affect the expression of many other ASD-risk genes (Neale et al, 2012; O’Roak et al, 2012, 2014; Traylor et al, 2012; De Rubeis et al, 2014; Deriziotis et al, 2014; Hamdan et al, 2014; Palumbo et al, 2014; Chuang et al, 2015; Sanders et al, 2015; Notwell et al, 2016; Bowling et al, 2017; Geisheker et al, 2017; Fazel Darbandi et al, 2018; McDermott et al, 2018; Vegas et al, 2018). We thus tested whether the Tbr1 +/K228E and Tbr1 K228E/K228E transcriptomes are enriched for ASD-related gene sets (Werling et al, 2016).…”

“…Reflecting this critical role of TBR1 in brain and cortical development, TBR1 has been strongly associated with brain disorders, including ASD and intellectual disability (Neale et al, 2012; O’Roak et al, 2012, 2014; Traylor et al, 2012; De Rubeis et al, 2014; Deriziotis et al, 2014; Hamdan et al, 2014; Palumbo et al, 2014; Chuang et al, 2015; Sanders et al, 2015; Bowling et al, 2017; Geisheker et al, 2017; McDermott et al, 2018; Vegas et al, 2018); among the many other genes on the SFARI (Simons Foundation Autism Research Initiative) list, it is considered a category 1 high-confidence ASD-risk gene (Abrahams et al, 2013). In addition, TBR1 has been shown to regulate the expression of various ASD-risk genes (Chuang et al, 2014, 2015; Huang et al, 2014; Notwell et al, 2016; Fazel Darbandi et al, 2018), likely as part of a large network of genes involved in ASD.…”

A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability

“…Given the major role of the TBR1 gene in brain development and the early frameshift pathogenic variant identified in the patient, we could expect a more severe phenotype. Indeed, a recent study showed that a de novo frameshift pathogenic variant in TBR1 was associated with developmental encephalopathy [48], whereas here, the whole-brain MRI of the patient appeared to be typical. A reinitiation of translation could potentially account for the absence of visible brain abnormalities.…”

“…TBR1 binds to CASK, which is a membrane-associated guanylate kinase playing a key role in intellectual disability [30,53]. Heterozygous loss-of-function mutations in the X-linked CASK gene have been associated with severe intellectual disability and with ASD [48,54,55]. The TBR1-CASK complex regulates the expression of genes involved in brain development [56] and of several candidate genes for ASD and intellectual disability.…”

Caracterização genótipo-fenótipo em novas síndromes associadas ao Transtorno do Espectro Autista

“…Um modelo de estudo de lesão cerebral sugere que a expressão de PAX6 estaria associada a geração de novos neurônios em áreas de dano, presentes em doenças neurodegenerativas(Thomas et al 2016). Desta forma, a expressão aumentada de PAX6 durante o período de maturação neural pode estar diretamente relacionada ao fenótipo clínico de neurodegeneração encontrado nas pacientes Tbr1 foi recentemente relacionado a deficiência intelectual, autismo e atraso no desenvolvimento, por regular a expressão de genes que são críticos para o desenvolvimento cortical(Notwell et al 2016;Mihalas and Hevner 2017;Vegas et al 2018;den Hoed et al 2018;Kwan 2013). No desenvolvimento do córtex, Tbr1 atua tanto como ativador (caso dos genes RELN e BCL11B) e repressor (em Fezf2), e a expressão alterada de genes regulados por Tbr1 refletem a importância de seus níveis de atividade nas camadas corticais(Mihalas and Hevner 2017).…”