Alternative titles; symbols
HGNC Approved Gene Symbol: FOXP2
SNOMEDCT: 229703009;
Cytogenetic location: 7q31.1 Genomic coordinates (GRCh38): 7:114,086,327-114,693,765 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q31.1 | Speech-language disorder-1 | 602081 | Autosomal dominant | 3 |
The FOXP2 gene encodes forkhead box P2, a putative transcription factor containing a polyglutamine tract and a forkhead DNA binding domain (Lai et al., 2001).
Because several disorders, most with neuropsychiatric features, had been found to be caused by trinucleotide repeat expansion mutations, Margolis et al. (1997) screened adult and fetal human brain cDNA libraries for clones containing trinucleotide repeats. A partial cDNA clone, designated H44 (CAGH44), encoded a deduced 304-amino acid protein containing a stretch of 40 consecutive glutamine residues from a combination of CAG and CAA codons, such that there were never more than 5 consecutive CAGs. A second polyglutamine stretch, containing only 10 glutamines, encoded by (CAG)7(CAA)(CAG)(CAA), is separated from the first stretch by 8 amino acids.
In a search for the gene responsible for the severe speech and language disorder (602081) in the KE pedigree originally reported by Hurst et al. (1990), Lai et al. (2001) isolated the FOXP2 gene. FOXP2 has an open reading frame (ORF) of 2.1 kb. The carboxy-terminal portion of the predicted protein sequence encoded by the FOXP2 gene contains a segment of 84 amino acids (encoded by exons 12-14) that shows high similarity to the characteristic DNA-binding domains of the forkhead-winged helix (FOX) family of transcription factors. By Northern blot analysis of several human adult tissues, Lai et al. (2001) demonstrated broad expression of a roughly 6.5-kb FOXP2 transcript. This transcript was also observed in fetal tissues, with strong expression in brain. A murine homolog of FOXP2 was expressed in adult and fetal mouse brain.
Haesler et al. (2004) cloned zebra finch Foxp2 and found that the protein sequence of zebra finch Foxp2 was 98% identical with mouse and human FOXP2.
Lai et al. (2001) found 17 exons within the FOXP2 gene. They detected 2 additional exons at the 5-prime end of the gene that are alternatively spliced, and 4 alternatively spliced forms of FOXP2. Form I has an ORF of 2,145 basepairs encoding 715 amino acids beginning with the ATG at the beginning of exon 2. Form II includes alternative splicing of exon 3b and has an ORF of 2,220 basepairs encoding 740 amino acids. Forms III and IV are similar to forms I and II except that the 58-bp exon 3a is included, which shifts the frame such that the ORF begins in exon 4 rather than exon 2; both result in a protein of 623 amino acids. The polyglutamine tract is encoded by exons 5 and 6.
Bruce and Margolis (2002) found evidence of alternate splice variants and 6 previously undetected exons in the FOXP2 gene. Their results suggested that FOXP2 spans at least 603 kb of genomic DNA, more than twice the previously defined region.
Although Margolis et al. (1997) localized the CAGH44 gene to chromosome 6q14-q15 by radiation hybrid mapping, Lai et al. (2000) found that chromosome 7 physical map and sequence data indicated that the gene, designated FOXP2 by the HUGO Nomenclature Committee, resides on chromosome 7q31.
Since mutations in FOXP2 cause developmental speech and language disorders in humans (SPCH1; 602081), it was hypothesized that identification of FOXP2 targets in the developing human brain would provide a unique tool with which to explore the development of human language and speech. Spiteri et al. (2007) defined FOXP2 targets in human basal ganglia and inferior frontal cortex using chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validated the functional regulation of targets in vitro. They identified 285 FOXP2 targets in fetal human brain; statistically significant overlap of targets in basal ganglia and inferior frontal cortex indicated a core set of 34 transcriptional targets of FOXP2. They identified targets specific to one or the other of these 2 areas of the brain that were not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. The data provided the first insight into the functional network of genes directly regulated by FOXP2 in the human brain and by evolutionary comparisons, highlighting genes likely to be involved in the development of human higher-order cognitive processes.
Vernes et al. (2007) used ChIP-chip to identify genomic sites that are directly bound by FOXP2 protein in native chromatin of human neuron-like cells. They focused on a subset of downstream targets identified by this approach, showing that altered FOXP2 levels yield significant changes in expression of cell-based models and that FOXP2 binds in a specific manner to consensus sites within the relevant promoters. Moreover, they demonstrated significant quantitative differences in target expression in embryonic brains of mutant mice, mediated by specific in vivo Foxp2-chromatin interactions. This work represented the first identification and in vivo verification of neural targets regulated by FOXP2. The data indicated that FOXP2 has dual functionality, acting either to repress or activate gene expression at occupied promoters.
Vernes et al. (2008) showed that FOXP2 directly regulates expression of the CNTNAP2 gene (604569), encoding a neurexin expressed in developing human cortex, by binding to a regulatory sequence in intron 1. Both FOXP2 and CNTNAP2 are involved in developmental speech and language disorders.
Konopka et al. (2009) demonstrated that the 2 human-specific amino acid alterations in FOXP2 (see EVOLUTION) function by conferring differential transcriptional regulation in vitro. They extended these observations in vivo to human and chimpanzee brain, and used network analysis to identify novel relationships among the differentially expressed genes. Their data provided experimental support for the functional relevance of changes in FOXP2 that occur on the human lineage, highlighting specific pathways with direct consequences for human brain development and disease in the CNS. Because FOXP2 has an important role in speech and language in humans, the identified targets may have a critical function in the development and evolution of language circuitry in humans.
Using gel retardation, quantitative RT-PCR, and reporter gene assays, Roll et al. (2010) found that human FOXP2 bound the promoter regions of SRPX2 (300642) and its binding partner UPAR (PLAUR; 173391) and downregulated their expression. Foxp2-binding sites were conserved in the promoter regions of chimpanzee and mouse Srpx2 and in chimpanzee Upar, but Foxp2-binding sites were not conserved in mouse Upar.
Using transfected HEK293 cells, Walker et al. (2012) found that expression of FOXP2 downregulated expression of DISC1 (605210), which is involved in various neurodevelopmental processes and diseases.
Sia et al. (2013) showed that the SRPX2 gene encodes a protein that promotes synaptogenesis in the cerebral cortex. In humans, SRPX2 is an epilepsy- and language-associated gene that is a target of the FOXP2 transcription factor. Sia et al. (2013) showed that FOXP2 modulates synapse formation through regulating SRPX2 levels and that SRPX2 reduction impairs development of ultrasonic vocalization in mice. The results of Sia et al. (2013) suggested that FOXP2 modulates the development of neural circuits through regulating synaptogenesis and that SRPX2 is a synaptogenic factor that plays a role in the pathogenesis of language disorders.
The FOXP2 gene is mutated in a severe monogenic form of speech and language impairment known as developmental verbal dyspraxia (SPCH1; 602081). Lai et al. (2000) reported a boy with language impairment and verbal dyspraxia associated with de novo balanced translocation t(5;7)(q22;q31.2). The disrupted region at 7q31.2 was found to map within the SPCH1 locus identified in a family (KE) with developmental verbal dyspraxia. Lai et al. (2000) characterized this interval and found that the translocation breakpoint occurred in the intron between exons 3b and 4 of the FOXP2 gene, suggesting that this gene is relevant to the etiology of the speech and language disorder. However, sequencing of the partial FOXP2 coding region known at the time did not reveal any variant cosegregating with the disorder in family KE.
After complete characterization of the entire coding region of the FOXP2 gene, Lai et al. (2001) identified a mutation (R553H; 605317.0001) in affected members of the KE family with developmental verbal dyspraxia mapping to 7q31.
O'Brien et al. (2003) used samples from children with specific language impairment (SLI) and their family members to study linkage and association of SLI to markers within and around the FOXP2 gene, and samples from 96 probands with SLI were directly sequenced for the mutation in exon 14 of the FOXP2 gene (R553H). No mutations were found in exon 14 of FOXP2, but strong association was found to a marker within the cystic fibrosis gene, CFTR (602421), and another marker on 7q31, D7S3052, both adjacent to FOXP2, suggesting that genetic factors for regulation of common language impairment reside in the vicinity of FOXP2.
Feuk et al. (2006) characterized 13 patients with developmental verbal dyspraxia (DVD; 602081): 5 with hemizygous paternal deletions spanning the FOXP2 gene; 1 with a translocation interrupting FOXP2; and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7) who were also given a diagnosis of Silver-Russell syndrome (SRS2; 618905). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. The authors also described 5 other individuals with deletions of paternally inherited FOXP2 with incomplete clinical information or phenotypes too complex to properly assess. Four of the patients with DVD also met criteria for autism spectrum disorder (see 209850). Using quantitative real-time PCR, Feuk et al. (2006) showed maternally inherited FOXP2 to be comparatively underexpressed. The results indicated that absence of paternal FOXP2 was the cause of DVD in patients with SRS with maternal UPD7. The data also pointed to a role for differential parent-of-origin expression of FOXP2 in human speech development.
Exclusion in Autism 9
Several studies of autistic disorder have demonstrated linkage to a similar region of 7q (AUTS9; 611015), leading to the proposal that a single genetic factor on 7q31 contributes to both autism and language disorders. However, using association and mutation screening analyses, Newbury et al. (2002) concluded that the coding region variants in FOXP2 do not underlie the AUTS9 linkage and that the gene is unlikely to play a role in autism or more common forms of language impairment.
Rice et al. (2012) reported a mother and son with FOXP2 haploinsufficiency due to a 1.57-Mb deletion on chromosome 7q31, which included 2 other genes, MDFIC (614511) and PPP1R3A (600917). The boy had severe childhood apraxia of speech, with poor expressive speech, severely delayed speech acquisition, and inability to laugh, sneeze or cough spontaneously. He showed mildly impaired cognition, which may have been due to the speech limitations. He also lacked fine motor control. His 24-year-old mother was similarly, if slightly less, affected. She had a similar early developmental history, with speech apraxia and mild developmental delay. Neither patient had autistic features.
Zilina et al. (2012) reported 2 unrelated families with speech and language disorders and other neurologic deficits associated with deletions of chromosome 7q31 involving the FOXP2 gene. A mother and daughter in the first family were affected. Both had problems chewing and swallowing food, showed pronounced drooling, and had delayed onset of the cough reflex in early life, as well as an inability to sneeze. The daughter showed failure to thrive, developmental delay, dysmorphic features, nystagmus, and myopia. Brain MRI showed mild brain atrophy and mild white matter hyperintensities. At age 3 years, she had some autistic features, low vocalization, poor vocabulary, and mild hand tremor. The mother had some autistic features, moderate speech delay, below average intelligence (IQ 88), poor social skills, emotional lability, and developmental verbal dyspraxia with difficulty in speech expression. Microarray analysis identified an 8.3-Mb deletion on chromosome 7q31.1-q31.31 including the FOXP2 gene in both the mother and the daughter. The mother's deletion was on the paternally derived chromosome. In the second family, the proband had developmental delay, mild dysmorphic features, mild ataxia, occasional aggressive behavior, and significant pronunciation difficulties with poor vocabulary. Her mother had intellectual disability, aggressive behavior, and developmental verbal dyspraxia. The maternal aunt of the proband had a phenotype similar to that of the mother. The maternal grandfather completed only 4 grades at school, had a severe speech defect, aggressive behavior, and balance problems. Molecular analysis in this family showed that the proband, the maternal aunt, and the maternal grandfather all carried a 6.5-Mb deletion of 7q31 including the FOXP2 gene; the mother of the proband refused study. The findings suggested no significant phenotypic difference due to parental origin of FOXP2 defects.
Enard et al. (2002) sequenced the cDNAs encoding the FOXP2 protein in chimpanzee, gorilla, orangutan, rhesus macaque, and mouse and compared them with the human cDNA. The human FOXP2 protein differs at only 3 amino acid positions from its mouse ortholog. When compared with a collection of 1,880 human-rodent gene pairs, FOXP2 is among the 5% most-conserved proteins. The chimpanzee, gorilla, and rhesus macaque FOXP2 proteins are all identical to each other and carry only 1 difference from the mouse and 2 differences from the human protein, whereas the orangutan carries 2 differences from the mouse and 3 from humans. Enard et al. (2002) suggested that the human-specific change of position 325 creates a potential target site for phosphorylation by protein kinase C (see 176960) together with a minor change in predicted secondary structure that may affect protein function related to fine orofacial movements, allowing for the development of spoken language in humans. Enard et al. (2002) showed that human FOXP2 contains changes in amino acid coding and a pattern of nucleotide polymorphism, which strongly suggests that this gene has been the target of selection during recent human evolution.
Two amino acid substitutions in human FOXP2, thr303 to asn (T303N) and asn323 to ser (N325S), occurred after separation from the chimpanzee lineage and appear to have undergone positive selection, likely due to effects on aspects of speech and language. Enard et al. (2009) introduced these substitutions into mouse Foxp2, which differs from chimpanzee Foxp2 by only 1 conservative amino acid substitution, and developed a line of mice carrying 'humanized' Foxp2, or Foxp2(hum). Foxp2(hum) segregated in mendelian ratios, and homozygous Foxp2(hum/hum) mice appeared healthy and fertile and showed normal longevity. A comprehensive phenotypic screen of Foxp2(hum/hum) animals revealed qualitatively different ultrasonic vocalizations in pups, decreased exploratory behavior in adults, and decreased brain dopamine concentrations, suggesting that the Foxp2(hum) allele affects the basal ganglia. The striatum is a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele. Medium spiny neurons from the striatum of Foxp2(hum/hum) mice had increased dendrite lengths and increased synaptic plasticity. Since mice carrying 1 nonfunctional Foxp2 allele showed opposite effects compared with Foxp2(hum/hum) mice, Enard et al. (2009) suggested that alterations in cortico-basal ganglia circuits may have had a role in evolution of speech and language in humans.
Haesler et al. (2004) found that Foxp2 was expressed predominantly in the striatum of the avian and crocodilian brain. In young zebra finches during the period when vocal learning occurs, Foxp2 expression was increased in areas of the striatal nucleus necessary for vocal learning. Adult canaries showed different seasonal Foxp2 expression; more Foxp2 expression was associated with times when song became unstable. The findings suggested that differential expression of Foxp2 in avian vocal learners may be associated with vocal plasticity and learned verbal communication.
Shu et al. (2005) found that Foxp2-null mice demonstrated severe motor abnormalities, premature death, and an absence of ultrasonic vocalizations that are usually elicited when pups are removed from their mothers. Foxp2 +/- mice showed modest developmental motor delays but significant decreases in the number of ultrasonic vocalizations. However, the duration, peak frequency, and bandwidth of the vocalizations were indistinguishable from wildtype. Neuropathologic examination showed severely abnormal early development of cerebellar neuronal cell layers in knockout mice, with less severe changes in heterozygous mice. The findings were consistent with a role for FOXP2 in social speech communication, and suggested that basic neural circuitry underlying speech includes a frontocerebellar loop.
Fujita et al. (2008) generated transgenic mice with an R552H Foxp2 mutation, which corresponds to the human R553H (605317.0001) mutation. Homozygous mice showed reduced weight, immature development of the cerebellum with incompletely folded folia, and Purkinje cells with poor dendritic arbors. At postnatal day 10, R552H homozygous mice showed severe motor impairment and ultrasonic vocalization, whereas heterozygous mice had modest impairments. In homozygous mice, mutant R552H Foxp2 localized to nuclei of Purkinje cells and neurons of the thalamus, striatum, cortex, and hippocampus, similar to wildtype protein. This finding suggested that the mutation interferes with transcriptional activity of Foxp2 but not localization. However, some cells showed Foxp2-positive nuclear aggregates in the absence of increased cell death, which may have compromised the function of Purkinje cells and cerebral neurons.
In the KE pedigree segregating developmental verbal dyspraxia (602081) originally reported by Hurst et al. (1990), Lai et al. (2001) identified a G-to-A transition in exon 14 of the FOXP2 gene, resulting in an arg-to-his substitution at codon 553 (R553H). This mutation cosegregated perfectly with all affected members of the pedigree and was absent in 364 independent chromosomes from normal Caucasian controls. The mutation disrupts an amino acid invariant in all members of the forkhead family of proteins from yeast to human. The R553 residue occurs in the third helix of the winged helix domain, which is the most highly conserved part of the forkhead domain and is adjacent to a histidine residue that makes a direct base contact with the target DNA.
Roll et al. (2010) found that the R553H substitution increased the cytoplasmic localization of FOXP2 following expression in HEK293 cells. The mutation also impaired the ability of FOXP2 to bind target sites in the SRPX2 (300642) and UPAR (PLAUR; 173391) promoters and downregulate their expression.
Walker et al. (2012) found that the R553H mutation reduced the ability of FOXP2 to downregulate DISC1 (605210).
In 2 sibs with verbal dyspraxia (602081), MacDermot et al. (2005) identified a heterozygous C-to-T transition in exon 7 of the FOXP2 gene, resulting in an arg328-to-ter (R328X) substitution. The mother, who had a history of speech problems, also carried the mutation, whereas the unaffected father did not. The R328X mutation was not identified in 252 control chromosomes. The R328X mutation is predicted to yield a truncated protein product lacking the zinc finger, leucine zipper, and forkhead DNA-binding domains.
Walker et al. (2012) found that the R328X mutation reduced the ability of FOXP2 to downregulate DISC1 (605210).
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