FOXP2 gene and language impairment in schizophrenia: association and epigenetic studies

Tolosa, A.; Sanjuán, Julio; Dagnall, Adam; Moltó, María Dolores; Herrero, Neus; Frutos, Rosa de

doi:10.1186/1471-2350-11-114

Cited by 92 publications

(61 citation statements)

References 39 publications

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“…The table on the right shows the most frequent haplotypes corresponding to candidate SNPs in high LD with rs6980093. Underlined letters indicate alleles previously associated with a risk low articulation score for rs12533005 (Peter et al, 2010) and schizophrenia for rs2396753 (Sanjuán et al, 2006;Tolosa et al, 2010), and red letters indicate alleles associated with a higher IFG activation in the present study.…”

Section: Discussionmentioning

confidence: 68%

“…In the bottom is displayed the zoom on FOXP2 locus associated with left inferior frontal activity. We reported SNPs from the literature (blue label) that showed a trend of association with the cerebral phenotype ((Ϫlog 10 ( p) Ͼ 2): rs12533005 (Peter et al, 2010), rs2396753 (Sanjuán et al, 2006;Tolosa et al, 2010), and rs1456031 (Sanjuán et al, 2006). Labels of exons covered by the locus are reported below.…”

Section: Discussionmentioning

confidence: 99%

“…Implication of FOXP2 in vocal communication in mice and songbird (Haesler et al, 2004;Shu et al, 2005) and evidence of an accelerated evolution specific to the human lineage (Enard et al, 2002) reinforced the interest for FOXP2 in relation to the evolution of human language. Since then, other point mutations were reported across FOXP2 (MacDermot et al, 2005;Fisher and Scharff, 2009) and recent studies suggest associations between FOXP2 singlenucleotide polymorphisms (SNPs) and speech sound disorders (Zhao et al, 2010), schizophrenia (Sanjuán et al, 2006;Tolosa et al, 2010) or language skills (Peter et al, 2011). Similarly, for developmental reading disabilities, linkage and association studies have pointed to several susceptibility loci (DYX1-9) (Caylak, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Genetic Variants ofFOXP2andKIAA0319/TTRAP/THEM2Locus Are Associated with Altered Brain Activation in Distinct Language-Related Regions

et al. 2012

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Recent advances have been made in the genetics of two human communication skills: speaking and reading. Mutations of the FOXP2 gene cause a severe form of language impairment and orofacial dyspraxia, while single-nucleotide polymorphisms (SNPs) located within a KIAA0319/TTRAP/THEM2 gene cluster and affecting the KIAA0319 gene expression are associated with reading disability. Neuroimaging studies of clinical populations point to partially distinct cerebral bases for language and reading impairments. However, alteration of FOXP2 and KIAA0319/TTRAP/THEM2 polymorphisms on typically developed language networks has never been explored. Here, we genotyped and scanned 94 healthy subjects using fMRI during a reading task. We studied the correlation of genetic polymorphisms with interindividual variability in brain activation and functional asymmetry in frontal and temporal cortices. In FOXP2, SNPs rs6980093 and rs7799109 were associated with variations of activation in the left frontal cortex. In the KIAA0319/TTRAP/THEM2 locus, rs17243157 was associated with asymmetry in functional activation of the superior temporal sulcus (STS). Interestingly, healthy subjects bearing the KIAA0319/TTRAP/THEM2 variants previously identified as enhancing the risk of dyslexia showed a reduced left-hemispheric asymmetry of the STS. Our results confirm that both FOXP2 and KIAA0319/TTRAP/THEM2 genes play an important role in human language development, but probably through different cerebral pathways. The observed cortical effects mirror previous fMRI results in developmental language and reading disorders, and suggest that a continuum may exist between these pathologies and normal interindividual variability.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic Variants ofFOXP2andKIAA0319/TTRAP/THEM2Locus Are Associated with Altered Brain Activation in Distinct Language-Related Regions

et al. 2012

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“…This association is widely supported by Crow 42 , who defends that the same genetic mutation that allowed the emergence of language made Homo sapiens vulnerable to failures in this system, and these failures may be clinically manifested as schizophrenia. Candidates for such schizophrenia vulnerability are the FOXP2 (which is linked to a familial language disorder and autism) and dysbindin 1 genes 43,44 .…”

Section: Formal Thought Disorder -Neurolinguistics Perspectivementioning

confidence: 99%

Formal Thought Disorder and language impairment in schizophrenia

Radanovic

Sousa

Valiengo

et al. 2012

Arq. Neuro-Psiquiatr.

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Schizophrenia is a psychiatric illness in which disorders of thought content are a prominent feature. The disruption of normal flow of thought, or “Formal Thought Disorder” (FTD), has been traditionally assessed through the content and form of patients’ speech, and speech abnormalities in schizophrenia were considered as a by-product of the disruption in conceptual structures and associative processes related to psychosis. This view has been changed due to increasing evidence that language per se is impaired in schizophrenia, especially its semantic, discursive, and pragmatic aspects. Schizophrenia is currently considered by some authors as a “language related human specific disease” or “logopathy”, and the neuroanatomical and genetic correlates of the language impairment in these patients are under investigation. Such efforts may lead to a better understanding about the pathophysiology of this devastating mental disease. We present some current concepts related to FTD as opposed to primary neurolinguistic abnormalities in schizophrenia.

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“…Hence, FOXP2 is likely to be a good candidate gene since its mutation has been reported to be associated with speech and language deficits [46,47,48]. FOXP2 has also been reported to be associated with schizophrenia [49,50,51,52] and autism [53,54,55,56]. FOXP2 may therefore directly cause the disease or affect its downstream targets that lead to the development of such disorders.…”

Section: Over-represented Gene Ontologies and Kegg Pathways Of Commonmentioning

confidence: 99%

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

Islam¹

2017

JABB

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MicroRNAs (miRNAs) are approximately 22-nucleotide-long, non-coding RNAs that bind to complementary mRNAs with inhibitory effect. An intronic miRNA is embedded in a particular gene called its host gene. Our study focuses on the Homo sapiens intronic miRNA-host gene pair, hsa-miR-3666 and FOXP2. Previous report of coexpression of miR-3666 and FOXP2 indicates possible regulation of FOXP2 functions by miR-3666. However, direct correlation has not been shown yet. Therefore, we took a computational approach to determine if and how such modulation occurs. ChIP-seq identified FOXP2 targets and putative miR-3666 targets showed a significant overlap of 574 common target genes. Functional enrichment analysis of common targets revealed over-representation of KEGG pathways and Gene Ontology modules associated with neurodevelopment. These modules, along with further literature mining and proteinprotein interaction analysis of FOXP2 and miR-3666 identified several specific genes associated with neurodevelopment and finally integration of transcriptomic expressions data lead to the selection of four models depicting the mechanisms by which miR-3666 can modulate FOXP2 functions. Model 1 illustrates that during neurodevelopment, miR-3666 can directly modulate the functions of FOXP2 through regulation of common targets, such as IGF1 and EFNB2, whereas model 2 shows miR-3666 can also indirectly modulate FOXP2 functions by considering targets that are not common for the intronic miRNA-host gene pair, for example CDH2 and LMO4. This direct and indirect regulation is necessary for precise spatial and temporal expression of genes during neurodevelopment. Models 3 and 4 exhibit mechanisms in which the interactions of miR-3666 and FOXP2 with target genes contribute to the pathogenesis of schizophrenia and autism respectively. a role in transcriptional activation [7]. FOXP2 hosts the intronic miRNA, miR-3666. Though not much work has been done on miR-3666, its targets have been predicted and deposited in various databases. A few recent experiments have shown the repression activity of miR-3666 on targets such as MET and ZEB1 in thyroid carcinoma and cervical carcinoma cells, respectively [9,10].

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FOXP2 gene and language impairment in schizophrenia: association and epigenetic studies

Cited by 92 publications

References 39 publications

Genetic Variants ofFOXP2andKIAA0319/TTRAP/THEM2Locus Are Associated with Altered Brain Activation in Distinct Language-Related Regions

Genetic Variants ofFOXP2andKIAA0319/TTRAP/THEM2Locus Are Associated with Altered Brain Activation in Distinct Language-Related Regions

Formal Thought Disorder and language impairment in schizophrenia

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

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