Disease relevance of FOXP2

• A point mutation in the forkhead domain of FOXP2 (R553H) is responsible for a severe speech and language disorder, while a series of missense mutations distributed over the forkhead domain of FOXP3 cause a fatal disorder called IPEX, characterized by immune dysregulation, polyendocrinopathy, and enteropathy [1].
• We detected little polymorphism and no expansions in the FOXP2 CAG/CAA repeat in 142 individuals with progressive movement disorders [2].

Psychiatry related information on FOXP2

• Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia [3].
• FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition [3].
• Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants [3].
• Association between the FOXP2 gene and autistic disorder in Chinese population [4].
• METHODS: Two FOXP2 polymorphisms, Intron3a and SNP 923875, and the G-->A transition in exon 14 were analysed in 149 patients with schizophrenia and schizoaffective disorders according to DSM-IV, as well as in 137 controls [5].

High impact information on FOXP2

• Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification [6].
• Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language [6].
• Investigations of a unique three-generation family showing monogenic inheritance of speech and language deficits led to the isolation of the first such gene on chromosome 7, which encodes a transcription factor known as FOXP2 [7].
• Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS [8].
• Half the members of the KE family suffer from a speech and language disorder caused by a mutation in the FOXP2 gene [9].

Biological context of FOXP2

• FOXP2 is located on chromosome 7q31, and studies of other disorders with speech and language impairment, including autism, have found linkage to this region [10].
• A mutation in the FOXP2 forkhead domain cosegregates with a severe speech disorder, whereas several mutations in the FOXP3 forkhead domain are linked to the IPEX syndrome in human and a similar autoimmune phenotype in mice [11].
• The missense mutations R553H in FOXP2 and R397W in FOXP3 dramatically alter the electrostatic potentials of the molecular surface of their respective forkhead domains [1].
• Our results suggest that FOXP2 spans at least 603 kb of genomic DNA, more than twice the previously defined region, and provide evidence of a promoter region flanking exon s1 [2].
• FOXP2 is a transcription factor containing a polyglutamine tract, a zinc-finger motif, and a forkhead DNA-binding domain [2].

Anatomical context of FOXP2

• Here we report the first direct functional genetic investigation of missense and nonsense mutations in FOXP2 using human cell-lines, including a well-established neuronal model system [12].
• In the avian and crocodilian forebrain, FoxP2 was expressed predominantly in the striatum, a basal ganglia brain region affected in patients with FOXP2 mutations [13].
• Expression of Foxp2 mRNA was detected in the ventral telencephalon as early as embryonic day 13 [14].
• Foxp1 and Foxp2 are expressed at high levels in the lung as early as E12.5 of mouse development with Foxp2 expression restricted to the airway epithelium [15].

Associations of FOXP2 with chemical compounds

• The FOXP2 gene, located on human 7q31 (at the SPCH1 locus), encodes a transcription factor containing a polyglutamine tract and a forkhead domain [16].
• Our studies also reveal that the FOXP2 forkhead domain can form a domain-swapped dimer, made possible by a strategic substitution of a highly conserved proline in conventional FOX proteins with alanine in the P subfamily [11].

Other interactions of FOXP2

• Disease-causing mutations in FOXP2 and FOXP3 map either to the DNA binding surface or the domain-swapping dimer interface, functionally corroborating the crystal structure [11].
• In support of this idea, we find that FOXP1 and FOXP2 expression patterns in human fetal brain are strikingly similar to those in the songbird, including localization to subcortical structures that function in sensorimotor integration and the control of skilled, coordinated movement [17].
• We conclude that coding-region variants in FOXP2 do not underlie the AUTS1 linkage and that the gene is unlikely to play a role in autism or more common forms of language impairment [16].
• Importantly, these results can also be applied to predict the consequences of the molecular effects of mutations of other FOX genes that have analogous missense mutations, including FOXP2, FOXE3 and FOXC2 [18].
• FOXP2: novel exons, splice variants, and CAG repeat length stability [2].

Analytical, diagnostic and therapeutic context of FOXP2

• Language fMRI abnormalities associated with FOXP2 gene mutation [9].
• Furthermore, we demonstrated the expression of FOXP2 in human fetal brain by RT-PCR, in the perisylvian area of the left and right cerebral hemispheres, as well as in the frontal and occipital cortices [19].
• We screened all of the exons of FOXP2 for causative mutations in 53 Japanese autistic patients using denaturing high-performance liquid chromatography and direct sequencing [20].
• Fluorescence in situ hybridization analyses with BACs/PACs from the sequence map localized the t(5;7)(q22;q31.2) breakpoint in the first patient (CS) to a single clone within the newly refined SPCH1 interval [21].

References