The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between FOXP2 genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in FOXP2 and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, CNTNAP2, Contactin-associated protein-like 2 and PRNP, prion protein genes. Overall, 27 SNPs were selected by a tagging approach. FOXP2-rs17213159-C/T resulted associated with disease risk (OR = 2.16, P = 0.0004), as well as with age at onset and severity of dementia. Other FOXP2 markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with CNTNAP2 and PRNP genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.

Parkinson\'s disease (PD) can dramatically change cortical neurophysiology. The molecular basis for PD-related cortical changes is unclear because gene expression data are usually derived from postmortem tissue collected at the end of a complex disease and they profoundly change in the minutes after death. Here, we studied cortical changes in tissue from the prefrontal cortex of living PD patients undergoing deep-brain stimulation implantation surgery. We examined 780 genes using the NanoString nCounter platform and found that 40 genes were differentially expressed between PD (n = 12) and essential tremor (ET; n = 9) patients. One of these 40 genes, STAT1, correlated with intraoperative 4-Hz rhythms and intraoperative performance of an oddball reaction-time task. Using a pre-designed custom panel of 780 targets, we compared these intraoperative data with those from a separate cohort of fresh-frozen tissue from the same frontal region in postmortem human PD donors (n = 6) and age-matched neurotypical controls (n = 6). This cohort revealed 279 differentially expressed genes. Fifteen of the 40 intraoperative PD-specific genes overlapped with postmortem PD-specific genes, including CALB2 and FOXP2. Transcriptomic analyses identified pathway changes in PD that had not been previously observed in postmortem cases. These molecular signatures of cortical function and dysfunction may help us better understand cognitive and neuropsychiatric aspects of PD.

UNASSIGNED: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by language impairment, and challenges with social interaction, communication, and repetitive behaviors. Although genetics are a primary cause of ASD, the exact genes and molecular mechanisms involved in its pathogenesis are not completely clear. The FOXP2 gene encodes a transcription factor that is known for its major role in language development and severe speech problems. The present study aimed to evaluate the role of FOXP2 in ASD etiology, executive functions, and brain activities.
UNASSIGNED: In the present study, we recruited 450 children with ASD and 490 neurotypical control children. Three domains of executive functions (working memory, response inhibition, and vigilance) were assessed. In addition, five-minute eyes closed electroencephalography was obtained from some of the children with ASD and neurotypical children. DNA sequence and expression level of FOXP2 in blood samples of children with ASD and the control group were evaluated by using sequencing and Real-time PCR, respectively.
UNASSIGNED: The results showed no mutations but a significant down expression of FOXP2 genes in children with ASD vs. neurotypical children. Several cognitive and executive function deficiencies were detected in children with ASD. Low alpha and gamma bands in the frontal lobe and high theta bands in the occipital lobe were revealed in children with ASD. We also found several correlations between FOXP2 expression levels and clinical assessments.
UNASSIGNED: Our finding revealed the down expression of FOXP2, which could be considered as a biomarker for ASD as well as cognitive and executive dysfunction. Based on brain mapping data, FOXP2 may be related to the theta wave abnormality of children with ASD. FOXP2 may be considered a target of novel treatment to improve memory and executive functions.
UNASSIGNED: Our findings highlight the role of FOXP2 mRNA level in ASD etiology, executive functions, and brain wave frequencies.

Comparative animal studies of complex behavioural traits, and their neurobiological underpinnings, can increase our understanding of their evolution, including in humans. Vocal learning, a potential precursor to human speech, is one such trait. Mammalian vocal learning is under-studied: most research has either focused on vocal learning in songbirds or its absence in non-human primates. Here, we focus on a highly promising model species for the neurobiology of vocal learning: grey seals (Halichoerus grypus). We provide a neuroanatomical atlas (based on dissected brain slices and magnetic resonance images), a labelled MRI template, a three-dimensional model with volumetric measurements of brain regions, and histological cortical stainings. Four main features of the grey seal brain stand out: (i) it is relatively big and highly convoluted; (ii) it hosts a relatively large temporal lobe and cerebellum; (iii) the cortex is similar to that of humans in thickness and shows the expected six-layered mammalian structure; (iv) there is expression of FoxP2 present in deeper layers of the cortex; FoxP2 is a gene involved in motor learning, vocal learning, and spoken language. Our results could facilitate future studies targeting the neural and genetic underpinnings of mammalian vocal learning, thus bridging the research gap from songbirds to humans and non-human primates. Our findings are relevant not only to vocal learning research but also to the study of mammalian neurobiology and cognition more in general. This article is part of the theme issue \'Vocal learning in animals and humans\'.

FOXP2 is a transcription factor expressed in multiple tissues during embryonic development. FOXP2 regulates transcription by binding to DNA at its DNA binding domain, the forkhead domain (FHD) through the recognition helix. Ser557 is a residue located within the recognition helix that has the potential to become phosphorylated posttranslationally. In this study we investigated whether phosphorylation of Ser557 can influence the structure and DNA binding of the FOXP2 FHD. We did this by constructing S557E, a phosphomimetic mutant, and comparing its behaviour to the wild type. The mutation did not affect the secondary or tertiary structure of the protein although it did decrease the propensity of the FOXP2 FHD to form dimers. Most notably, the mutation showed significantly reduced DNA binding compared to the wild type as detected using electrophoretic mobility shift assays. Molecular docking was also performed in which the wild type, phosphomimetic mutant and phosphorylated wild-type were docked to DNA and their interactions with DNA were compared. These results indicated that the wild type forms more interactions with the DNA and that the phosphomimetic mutant as well as the phosphorylated wild type did not associate as favourably with the DNA. This indicates that phosphorylation of Ser557 could disrupt DNA binding likely due to electrostatic and steric hindrance. This suggests that phosphorylation of Ser557 in the FOXP2 FHD could act as a control mechanism for FOXP2 and ultimately could be involved in regulation of transcription.

A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p=0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p=0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI.