A de novo 2.3Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl

Belengeanu, Valerica; Gamage, Thilini H; Farcas, Simona; Stoian, Monica; Andreescu, Nicoleta; Belengeanu, Alina; Frengen, Eirik; Misceo, Doriana

doi:10.1016/j.gene.2014.01.060

Cited by 24 publications

(15 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 .…”

Section: Discussionmentioning

confidence: 87%

De novo TBR1 mutations in sporadic autism disrupt protein functions

et al. 2014

View full text Add to dashboard Cite

Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

show abstract

Section: Discussionmentioning

confidence: 87%

De novo TBR1 mutations in sporadic autism disrupt protein functions

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Although DPP4 had never been directly associated with autism, some findings link it to autistic features. Recent studies show that a decrease in the gene expression or activity of DPP4 would result in possible neurological consequences and exacerbation of autism symptoms23. Moreover, a deletion encompassing DPP4 among other genes was found in a patient presenting with hypotonia, delayed motor development, severe language impairment, and behavior consistent with ASD24.…”

Section: Discussionmentioning

confidence: 99%

Candidate Genes for Inherited Autism Susceptibility in the Lebanese Population

Kourtian

Soueid

Makhoul

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is characterized by ritualistic-repetitive behaviors and impaired verbal/non-verbal communication. Many ASD susceptibility genes implicated in neuronal pathways/brain development have been identified. The Lebanese population is ideal for uncovering recessive genes because of shared ancestry and a high rate of consanguineous marriages. Aims here are to analyze for published ASD genes and uncover novel inherited ASD susceptibility genes specific to the Lebanese. We recruited 36 ASD families (ASD: 37, unaffected parents: 36, unaffected siblings: 33) and 100 unaffected Lebanese controls. Cytogenetics 2.7 M Microarrays/CytoScan™ HD arrays allowed mapping of homozygous regions of the genome. The CNTNAP2 gene was screened by Sanger sequencing. Homozygosity mapping uncovered DPP4, TRHR, and MLF1 as novel candidate susceptibility genes for ASD in the Lebanese. Sequencing of hot spot exons in CNTNAP2 led to discovery of a 5 bp insertion in 23/37 ASD patients. This mutation was present in unaffected family members and unaffected Lebanese controls. Although a slight increase in number was observed in ASD patients and family members compared to controls, there were no significant differences in allele frequencies between affecteds and controls (C/TTCTG: γ2 value = 0.014; p = 0.904). The CNTNAP2 polymorphism identified in this population, hence, is not linked to the ASD phenotype.

show abstract

“…In light of the evidence that bicarbonate transporters of the SLC4A family including SLC4A10 are involved in seizure disorders (Gurnett et al, 2008; Krepischi et al, 2010; Belengeanu et al, 2014), a better understanding of their role for synaptic transmission is desirable to get a more comprehensive view of neuronal excitability and the pathophysiology of epilepsy (Chesler, 2003; Leniger et al, 2004). …”

Section: Discussionmentioning

confidence: 99%

“…The latter is most likely owed to a compromised production of the cerebrospinal fluid, because Slc4a10 is prominently expressed in choroid plexus epithelial cells (Praetorius et al, 2004). Surprisingly, different neurological disorders including idiopathic epilepsy have been associated with heterozygous deletions of large genomic regions spanning the human SLC4A10 (Gurnett et al, 2008; Krepischi et al, 2010; Belengeanu et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Disruption of Slc4a10 augments neuronal excitability and modulates synaptic short-term plasticity

Sinning

Liebmann

Hübner

2015

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. Slc4a10 knockout (KO) mice have collapsed brain ventricles and display an increased seizure threshold, while heterozygous deletions in man have been associated with idiopathic epilepsy and other neurological symptoms. To further characterize the role of Slc4a10 for network excitability, we compared input-output relations as well as short and long term changes of evoked field potentials in Slc4a10 KO and wildtype (WT) mice. While responses of CA1 pyramidal neurons to stimulation of Schaffer collaterals were increased in Slc4a10 KO mice, evoked field potentials did not differ between genotypes in the stratum radiatum or the neocortical areas analyzed. Paired pulse facilitation was diminished in the hippocampus upon disruption of Slc4a10. In the neocortex paired pulse depression was increased. Though short term plasticity is modulated via Slc4a10, long term potentiation appears independent of Slc4a10. Our data support that Slc4a10 dampens neuronal excitability and thus sheds light on the pathophysiology of SLC4A10 associated pathologies.

show abstract

A de novo 2.3Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl

Cited by 24 publications

References 24 publications

De novo TBR1 mutations in sporadic autism disrupt protein functions

De novo TBR1 mutations in sporadic autism disrupt protein functions

Candidate Genes for Inherited Autism Susceptibility in the Lebanese Population

Disruption of Slc4a10 augments neuronal excitability and modulates synaptic short-term plasticity

Contact Info

Product

Resources

About