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ized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P=1.04x10(-8)) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P=3.94x10(-7)).

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s of the FOXP2 gene in a monogenic syndrome characterised by impaired sequencing of articulatory gestures, disrupting speech (developmental verbal dyspraxia, DVD), as well as multiple deficits in expressive and receptive language. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerisation. FOXP1, the most closely related member of this subgroup, can directly interact with FOXP2 and is co-expressed in neural structures relevant to speech and language disorders. Moreover, investigations of songbird orthologues indicate that combinatorial actions of the two proteins may play important roles in vocal learning, leading to the suggestion that human FOXP1 should be considered a strong candidate for involvement in DVD. Thus, in this study, we screened the entire coding region of FOXP1 (exons and flanking intronic sequence) for nucleotide changes in a panel of probands used earlier to detect novel mutations in FOXP2. A non-synonymous coding change was identified in a single proband, yielding a proline-to-alanine change (P215A). However, this was also found in a random control sample. Analyses of non-coding SNP changes did not find any correlation with affection status. We conclude that FOXP1 mutations are unlikely to represent a major cause of DVD.

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FOXP1, a gene critical for normal heart development that represses cardiomyocyte proliferation and expression of Nkx2.5. To determine whether FOXP1 mutations are found in patients with CHD, we sequenced FOXP1 in 82 patients with AVSD or hypoplastic left heart syndrome. We discovered two patients who harbored a heterozygous c.1702C>T variant in FOXP1 that predicted a potentially deleterious substitution of a highly conserved proline (p.Pro568Ser). This variant was not found in 287 controls but is present in dbSNP at a 0.2% frequency. The orthologous murine Foxp1 p.Pro596Ser mutant protein displayed deficits in luciferase reporter assays and resulted in increased proliferation and Nkx2.5 expression in cardiomyoblasts. Our data suggest that haploinsufficiency of FOXP1 is associated with human CHD.

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tablish gene expression profile and significance analysis of microarray (SAM) as well as prediction analysis of microarray (PAM) was utilized to screen candidate marker genes in tissue of carcinoma and para-cancerous with cirrhosis from 15 hepatitis B virus (HBV) related HCC patients. RESULT: Total 497 differential genes were selected by microarray (fold change >2; P value<0.01). Then 162 significant genes were determined by SAM (fold change -1.46 to 1.28). A number of 8-genes showing "poor risk signature" was validated with threshold of 6.2, which was associated with cirrhosis progressing to HCC. Only 3 down-regulated and 2 up-regulated predictor genes had statistical difference in HCC and cirrhosis groups by RT-PCR (P value<0.01). Forkhead box protein 1 (FOXP1) and serine protease inhibitor Kazal-type 1 (SPINK1) proteins were found significantly increased in carcinoma tissues than para-cancerous cirrhotic tissues by IH and WB. CONCLUSION: Over-expression of FOXP1 and SPINK1 may participate in the carcinogenesis of HBV related cirrhosis. They could use as potential biomarkers for diagnosing early HCC.

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l development in the midbrain, cerebellum, hindbrain and spinal cord. Using genetic fate-mapping techniques, we show that all En1-lineal cells in the SOC are neurons and that these neurons are glycinergic, cholinergic and GABAergic in neurotransmitter phenotype. En1 deletion does not interfere with specification or neural fate of these cells, but does cause aberrant positioning and subsequent death of all En1-lineal SOC neurons by early postnatal ages. En1-null cells also fail to express the transcription factor FoxP1, suggesting that FoxP1 lies downstream of En1. Our data define important roles for En1 in the development and maturation of a diverse group of brainstem auditory neurons.

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ion remain largely unknown. Recently, we discovered that transcription factors LIM homeobox (LHX) 6 and LHX8, which are key regulators of oral development, repressed the expression of the genes encoding forkhead box transcription factors, Foxp1 and Foxp2, in the oral region. To gain insights into the potential role of the Foxp genes in region-specific development of the face, we examined their expression patterns in the first pharyngeal arch (primordium for the jaw) of mouse embryos at a high spatial and temporal resolution. Foxp1 and Foxp2 were preferentially expressed in the aboral and posterior parts of the first pharyngeal arch, including the developing temporomandibular joint. Through double immunofluorescence and double fluorescent RNA in situ hybridization, we found that Foxp1 was expressed in the progenitor cells for the muscle, bone, and connective tissue. Foxp2 was expressed in subsets of bone and connective tissue progenitors but not in the myoblasts. Neither gene was expressed in the dental mesenchyme nor in the oral half of the palatal shelf undergoing extensive growth and morphogenesis. Together, we demonstrated for the first time that Foxp1 and Foxp2 are expressed during craniofacial development. Our data suggest that the Foxp genes may regulate development of the aboral and posterior regions of the jaw.

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ically the function of FOXP1 in neuronal development. Here, we report that suppression of Foxp1 expression in mouse cerebral cortex led to a neuronal migration defect, which was rescued by overexpression of Foxp1. Mice with Foxp1 knockdown exhibited ectopic neurons in deep layers of the cortex postnatally. The neuronal differentiation of Foxp1-downregulated cells was normal. However, morphological analysis showed that the neurons with Foxp1 deficiency had an inhibited axonal growth in vitro and a weakened transition from multipolar to bipolar in vivo. Moreover, we found that the expression of Foxp1 modulated the dendritic maturation of neurons at a late postnatal date. Our results demonstrate critical roles of Foxp1 in the radial migration and morphogenesis of cortical neurons during development. This study may shed light on the complex relationship between neuronal development and the related cognitive disorders.

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. The discovery of FOXP2 has added an additional avenue for exploring the origins of language and animal communication. The FOXP2 gene is a member of the forkhead box P (FOXP) family of transcription factors. Prior to the prenatal androgen surge in male fetuses, we observed no sex difference for Foxp2 protein levels in cultured cells. In contrast, 24 hours after the onset of the androgen surge, we found a sex difference for Foxp2 protein levels in cultured cortical cells with males having higher levels than females. Furthermore, we observed the potent nonaromatizable androgen dihydrotestosterone altered not only Foxp2 mRNA and protein levels but also Foxp1. Androgen effects on both Foxp2 and Foxp1 were found to occur in the striatum, cerebellar vermis, and cortex. Immunofluorescence microscopy and coimmunoprecipitation demonstrate Foxp2 and the androgen receptor protein interact. Databases for transcription factor binding sites predict a consensus binding motif for androgen receptor on the Foxp2 promoter regions. We also observed a sex difference in rat pup vocalization with males vocalizing more than females and treatment of females with dihydrotestosterone eliminated the sex difference. We propose that androgens might be an upstream regulator of both Foxp2 and Foxp1 expression and signaling. This has important implications for language and communication as well as neuropsychiatric developmental disorders involving impairments in communication.

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oxp1, a transcriptional factor, was dynamically relocated from the nucleus to the cytoplasm of HFSCs in phase transitions from anagen to catagen, coupled with the rise of oxidative stress. Mass spectrum analyses revealed that the S468 phosphorylation of Foxp1 protein was responsive to oxidative stress and affected its nucleocytoplasmic translocation. Foxp1 deficiency in hair follicles led to compromised ROS accrual and increased HFSC proliferation. And more, NAC treatment profoundly elongated the anagen duration and HFSC proliferation in Foxp1-deficient background. Molecularly, Foxp1 augmented ROS levels through suppression of Trx1-mediated reductive function, thereafter imposing the cell cycle arrest by modulating the activity of p19/p53 pathway. Our findings identify a novel role for Foxp1 in controlling HFSC proliferation with cellular dynamic location in response to oxidative stress during hair cycling.

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le-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.

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ng cancer (NSCLC).
METHODS: Our study evaluated the associations of 14,400 (1,599 genotyped and 12,801 imputed) single-nucleotide polymorphisms (SNPs) in 176 lymphocyte activation pathway-related genes with survival of 1,185 NSCLC patients in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 984 NSCLC patients from the Harvard Lung Cancer Susceptibility (HLCS) trial.
RESULTS: Multivariable Cox proportional hazards regression analyses identified two distinct and possibly functional variants in forkhead box P1 (FOXP1; rs2568847 G>C) and RAR-related orphan receptor A (RORA; rs922782 T>G) that were significantly and independently associated with overall survival (OS) [adjusted hazards ratios (HRs) of 1.21 and 0.82, respectively; 95% confidence intervals (CI), 1.11 to 1.32 and 0.76 to 0.88, respectively; P=5.38×10-6 and 2.68×10-2, respectively]. Combined analysis of the unfavorable genotypes showed a significant correlation with both OS and disease-specific survival (DSS) in patients with NSCLC patients from PLCO trial (both Ptrend<0.0001). Further expression quantitative trait loci (eQTL) analysis using RORA mRNA expression and genotype data in the 1000 Genomes Project demonstrated that the RORA rs922782 G allele predicted mRNA expression levels.
CONCLUSIONS: Genetic variants in FOXP1 and RORA of the lymphocyte activation pathway may be promising predictors of NSCLC survival. The RORA rs922782 G allele may predict NSCLC survival, possibly by controlling RORA mRNA expression.

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t:700;'>FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett's esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P < 10(-4) in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P < 10(-5) ) although not genome-wide significantly associated with the BEACON GWAS. Therefore, both variants and corresponding genes represent promising candidates for future EAC association studies on independent samples.

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lls, which resulted in substantially enhanced GC and antibody responses. We found that Foxp1 used both constitutive Foxp1A and Foxp1D induced by stimulation of the T cell antigen receptor (TCR) to inhibit the generation of T(FH) cells. Mechanistically, Foxp1 directly and negatively regulated interleukin 21 (IL-21); Foxp1 also dampened expression of the costimulatory molecule ICOS and its downstream signaling at early stages of T cell activation, which rendered Foxp1-deficient CD4(+) T cells partially resistant to blockade of the ICOS ligand (ICOSL) during T(FH) cell development. Our findings demonstrate that Foxp1 is a critical negative regulator of T(FH) cell differentiation.