Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions

Abstract

TBR1 encodes a transcription factor with critical roles in corticogenesis, including cortical neuron migration and axon pathfinding, establishment of regional and laminar identity of cortical neurons, and control of glutamatergic neuronal cell fate. Based upon TBR1’s role in cortical development, we sought to investigate TBR1 hemizygosity in individuals referred for genetic evaluation of intellectual disability and developmental delay. We describe 4 patients with microdeletions identified by molecular cytogenetic techniques, encompassing TBR1 and spanning 2q24.1q31.1, ranging in size from 2.17 to 12.34 Mb. Only the patient with the largest deletion had a possible cortical malformation. Mild ventriculomegaly is the only common brain anomaly, present in all patients; a Chiari I malformation is seen in 2 patients, and mega cisterna magna is seen in a third. Our findings are consistent with Tbr1 mouse models showing that hemizygosity of the gene requires additional genetic factors for the manifestation of severe structural brain malformations. Other syndromic features are present in these patients, including autism spectrum disorders, ocular colobomas, and craniosynostosis, features that are likely affected by the deletion of genes other than TBR1.

De novo TBR1 mutations in sporadic autism disrupt protein functions

“…Coupled with the observation that the truncated proteins cannot dimerize with WT TBR1, it seems likely that the pathogenic mechanism of these mutations is haploinsufficiency. This hypothesis is supported by the discovery of heterozygous de novo microdeletions encompassing TBR1 in probands with developmental delay, ASD and ID 45–47 . Furthermore, anatomical and behavioural characterization of heterozygous Tbr1 mice revealed that loss of one Tbr1 allele impairs amygdalar axonal projections and results in cognitive abnormalities 48 .…”

Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice

“…25 Human genetic studies have indicated that TBR1 is a high-confidence risk factor for ASD and intellectual disability. [26][27][28][29][30][31] Because interaction with CASK increases the transcriptional activity of TBR1 to upregulate Grin2b expression, 14,24,[32][33][34] the TBR1-GRIN2B pathway is likely involved in the function of CASK in regulating intellectual ability. Our previous study showed that the Thr724 (T724) residue of rat CASK protein is the protein kinase A (PKA) phosphorylation site.…”

TBR1 regulates autism risk genes in the developing neocortex

“…The de novo TBR1 mutations found in ASD patients can cause changes in the transcriptional regulation and cellular localization of TBR1, as well as its interactions with coregulators such as CASK and FOXP2 (Deriziotis et al 2014). In humans, patients with microdeletions of the 2q24 region, which encompasses TBR1, exhibit intellectual disability and developmental delay (Traylor et al 2012). In mice, Tbr1 haploinsufficiency results in defective axonal projections and impairments of social interactions, ultrasonic vocalization, associative memory, and cognitive flexibility .…”