From Wikipedia, the free encyclopedia
Jump to: navigation, search
Forkhead box P2
Protein FOXP2 PDB 2a07.png
PDB rendering based on 2a07.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols FOXP2 ; CAGH44; SPCH1; TNRC10
External IDs OMIM605317 MGI2148705 HomoloGene33482 GeneCards: FOXP2 Gene
RNA expression pattern
PBB GE FOXP2 gnf1h09377 at tn.png
More reference expression data
Species Human Mouse
Entrez 93986 114142
Ensembl ENSG00000128573 ENSMUSG00000029563
UniProt O15409 P58463
RefSeq (mRNA) NM_001172766 NM_053242
RefSeq (protein) NP_001166237 NP_444472
Location (UCSC) Chr 7:
113.73 – 114.33 Mb
Chr 6:
14.9 – 15.44 Mb
PubMed search [1] [2]

Forkhead box protein P2 also known as FOXP2 is a protein that in humans is encoded by the FOXP2 gene,[1] located on human chromosome 7 (7q31, at the SPCH1 locus).[2][3] FOXP2 orthologs[4] have also been identified in all mammals for which complete genome data are available. The FOXP2 protein contains a forkhead-box DNA-binding domain, making it a member of the FOX group of transcription factors, involved in regulation of gene expression. In addition to this characteristic forkhead-box domain, the protein contains a polyglutamine tract, a zinc finger and a leucine zipper.

In humans, mutations of FOXP2 cause a severe speech and language disorder.[1][5] Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice[6] and in songbirds[7] indicate that it is important for modulating plasticity of neural circuits.[8] Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut.[9] FOXP2 directly regulates a large number of downstream target genes.[10][11]

One particular target that is directly downregulated by FOXP2 in human neurons is the CNTNAP2 gene, a member of the neurexin family; variants in this target gene have been associated with common forms of language impairment.[12] Two amino-acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees,[13] but only one of these two changes is unique to humans.[14] Evidence from genetically manipulated mice[15] and human neuronal cell models[16] suggests that these changes affect the neural functions of FOXP2.


The human gene was originally identified by Oxford University geneticists Simon Fisher and Anthony Monaco through molecular investigations of an unusual family known as the KE family. Researchers at the Institute of Child Health in London had shown that around half of the family members – fifteen individuals across three generations – suffered from severe speech and language deficits.[17] Remarkably, the transmission of the disorder from one generation to the next was consistent with autosomal dominant inheritance i.e. mutation of only a single gene on an autosome (non-sex chromosome) acting in a dominant fashion. This is one of the few known examples of Mendelian (monogenic) inheritance for a disorder affecting speech and language skills, which typically have a complex basis involving multiple genetic risk factors.[18]

In the mid-1990s Fisher, Monaco and colleagues began to search for the damaged gene in the KE family, performing a genome-wide scan of DNA samples taken from the affected and unaffected members.[2] This scan confirmed autosomal dominant monogenic inheritance and localized the gene responsible to a small section of chromosome 7.[2] The locus was given the official name "SPCH1" (for speech-and-language-disorder-1) by the Human Genome Nomenclature committee. Mapping and sequencing of the chromosomal region was performed with the aid of bacterial artificial chromosome clones.[3] Around this time, the researchers identified an individual who was unrelated to the KE family, but had a similar type of speech and language disorder. In this case the child, known as CS, carried a chromosomal rearrangement (a translocation) in which part of chromosome 7 had become exchanged with part of chromosome 5. The site of breakage of chromosome 7 was located within the SPCH1 region.[3]

The team went on to pinpoint the precise position of the chromosome-7 breakage in case CS, and found that it lay directly in the middle of a protein-coding gene.[1] Using a combination of bioinformatics and RNA analyses they deciphered the full coding region of the gene, discovering that it encoded a novel member of the forkhead-box (FOX) group of transcription factors. As such, it was assigned with the official name of FOXP2. When the researchers sequenced the FOXP2 gene in the KE family they uncovered a heterozygous point mutation that was shared by all the affected individuals, but absent from unaffected members and a large panel of controls from the general population.[1] This mutation yields an amino-acid substitution at a crucial point of the DNA-binding domain of the FOXP2 protein, disrupting its function.[19] Further screening of the gene has since identified multiple additional cases of FOXP2 disruption, including different point mutations[5] and chromosomal rearrangements,[20] providing further evidence that damage to one copy of this gene is sufficient to derail speech and language development.


Foxp2 is expressed in the developing cerebellum and the hindbrain of the embryonic day 13.5 mouse. Allen Brain Atlases

FOXP2 is required for proper brain and lung development. Knockout mice with only one functional copy of the FOXP2 gene have significantly reduced vocalizations as pups.[21] Knockout mice with no functional copies of FOXP2 are runted, display abnormalities in brain regions such as the Purkinje layer, and die an average of 21 days after birth from inadequate lung development.[9]

FOXP2 is expressed in many areas of the brain[13] including the basal ganglia and inferior frontal cortex where it is and is essential for brain maturation and speech and language development.[10]

A knockout mouse model has been used to examine FOXP2’s role in brain development and how mutations in the two copies of FOXP2 affect vocalization. Mutations in one copy result in reduced speech while abnormalities in both copies cause major brain and lung developmental issues.[9]

The expression of FOXP2 is subject to post-transcriptional regulation, particularly micro RNA, which binds to multiple miRNA binding-sites in the neocortex, causing the repression of FOXP2 3’UTR.[22]

Clinical significance[edit]

There are several abnormalities linked to FOXP2, but the most common mutation results in a modified form of FOXP2. This modified FOXP2 is associated with severe speech impairment known as developmental verbal dyspraxia which is caused by a translocation in the 7q31.2 region [t(5;7)(q22;q31.2)].[3][1]

Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene.[23] Such individuals have little or no cognitive handicaps but are unable to correctly perform the coordinated movements required for speech. fMRI analysis of these individuals performing silent verb generation and spoken word repetition tasks showed underactivation of Broca's area and the putamen, brain centers thought to be involved in language tasks. Because of this, FOXP2 has been dubbed the "language gene". People with this mutation also experience symptoms not related to language (not surprisingly, as FOXP2 is known to affect development in other parts of the body as well).[24] Scientists have also looked for associations between FOXP2 and autism and both positive and negative findings have been reported.[25][26]

There is some evidence that the linguistic impairments associated with a mutation of the FOXP2 gene are not simply the result of a fundamental deficit in motor control. For example:

  • the impairments include difficulties in comprehension;
  • brain imaging of affected individuals indicates functional abnormalities in language-related cortical and basal/ganglia regions, demonstrating that the problems extend beyond the motor system.


Human FOXP2 gene and evolutionary conservation is shown in a multiple alignment (at bottom of figure) in this image from the UCSC Genome Browser. Note that conservation tends to cluster around coding regions (exons).

FOXP2 in humans and chimpanzees differs by the substitution of two amino acids, threonine to asparagine substitution at position 303 (T303N) and asparagine to serine substitution at position 325 (N325S).

The FOXP2 protein sequence is generally thought to be highly conserved. Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators.[27][28] However, recent studies in bats (chiroptera) has prompted some researchers to conclude that FoxP2 is not well conserved in non-human mammals and write: "We found that contrary to previous reports, FOXP2 is not highly conserved across all nonhuman mammals but is extremely diverse in echolocating bats."[29] Aside from a polyglutamine tract, human FOXP2 differs from chimp FOXP2 by only two amino acids, mouse FOXP2 by only 3 amino acids, and zebra finch FOXP2 by only 7 amino acids.[13][30][31] One of the two amino acid difference between human and chimps also arose independently in carnivores and bats.[14][32] A recent extraction of DNA from Neanderthal bones indicates that Neanderthals had the same version (allele) of the FOXP2 gene as modern humans.[33] Evidence that the two amino acid substitutions existed so far back in evolutionary history is corroborated by a more recent extraction of DNA from the remains of a related, previously unknown hominid in Denisova Cave.[34] in that, according to University of Wisconsin Professor John Hawk's website,[35] this hominid also shares the two substitutions. Nevertheless, Coop et al. (2008) point out that "modern human contamination ...could produce the observed results".[36] They further point out that the molecular data suggests a more recent origin than 300,000 years ago because "...the selected haplotype appears to have accumulated few mutations since."

Some researchers have speculated that the two amino acid differences between chimps and humans led to the evolution of language in humans.[13] Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.[27][28] Insertion of both human mutations into mice, whose version of FOXP2 otherwise differs from the human and chimpanzee versions in only one additional base pair, causes changes in vocalizations as well as other behavioral changes, such as a reduction in exploratory tendencies; a reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed.[15] It may also be, based on general observations of development and songbird results, that any difference between humans and non-humans would be due to regulatory sequence divergence (affecting where and when FOXP2 is expressed) rather than the two amino acid differences mentioned above.[24] However the mutation rate of FOXP2 is slower in the human lineage than in the lineage before the human-chimpanzee split, and proposed that purifying selection would not have relaxed due to deleterious effects.[14] Thus, it was most likely positive selection that drove the two amino acid differences to fixation in humans,[14] suggesting that differences between humans and non-humans are a result of the two amino acid changes.

Li et al. (2007) found that exons 7 and 17 of FoxP2 in bats are highly variable and not as conserved as in other vertebrates.[32] Twenty-two sequences of non-bat eutherian mammals revealed a total number of 20 nonsynonymous mutations in contrast to half that number of bat sequences, which showed 44 nonsynonymous mutations.[32] Interestingly, all cetaceans share three amino acid substitutions, but there are not differences between echolocating and non-echolocating baleen cetaceans.[32] Within bats, however, amino acid variation correlated with different echolocating types.[32] Accelerated evolution in bats is likely due to positive selection on echolocation.[32] Given this hypothesis that a novel FOXP2 sequence can aid echolocation, echolocating and non-echolocating cetaceans might be predicted to display differences in their FOXP2 sequences. However, they produce the necessary sounds for echolocation with a complex called a melon (located on the forehead) rather than with the orofacial muscles. Li et al. speculate that because FOXP2 has been tied to orofacial muscle control in humans[1] its role in bat echolocation may be to increase coordination in these muscles, and that therefore echolocating and non-echolocating cetaceans would not necessarily be expected to show a diverse FOXP2 genotype.[32]

In songbirds[edit]

Different studies of FOXP2 in songbirds suggest that FOXP2 may regulate genes involved in neuroplasticity: During song learning FOXP2 is upregulated in brain regions critical for song learning in young zebra finches. Knockdown of FOXP2 in Area X of the basal ganglia of these birds results in incomplete and inaccurate song imitation.[7] Similarly, in adult canaries higher FOXP2 levels also correlate with song changes.[37] In addition, levels of FOXP2 in adult zebra finches are significantly higher when males direct their song to females than when they sing song in other contexts.[38] Differences between song-learning and non-song-learning birds have been shown to be caused by differences in FOXP2 gene expression, rather than differences in the amino acid sequence of the FOXP2 protein.[24]

FOXP2 also has possible implications in the development of bat echolocation.[32]


FOXP2 has been shown to interact with CTBP1.[39]

See also[edit]


  1. ^ a b c d e f Lai CSL, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP (2001). "A forkhead-domain gene is mutated in a severe speech and language disorder". Nature 413 (6855): 519–23. doi:10.1038/35097076. PMID 11586359. 
  2. ^ a b c Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME (1998). "Localisation of a gene implicated in a severe speech and language disorder". Nature Genetics 18 (2): 168–70. doi:10.1038/ng0298-168. PMID 9462748. 
  3. ^ a b c d Lai CS, Fisher SE, Hurst JA, Levy ER, Hodgson S, Fox M, Jeremiah S, Povey S, Jamison DC, Green ED, Vargha-Khadem F, Monaco AP (2000). "The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder". Am. J. Hum. Genet. 67 (2): 357–68. doi:10.1086/303011. PMC 1287211. PMID 10880297. 
  4. ^ "OrthoMaM phylogenetic marker: FOXP2 coding sequence". 
  5. ^ a b MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, Vargha-Khadem F, McKenzie F, Smith RL, Monaco AP, Fisher SE (2005). "Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits". Am. J. Hum. Genet. 76 (6): 1074–80. doi:10.1086/430841. PMC 1196445. PMID 15877281. 
  6. ^ Groszer M, Keays DA, Deacon RM, de Bono JP, Prasad-Mulcare S, Gaub S, Baum MG, French CA, Nicod J, Coventry JA, Enard W, Fray M, Brown SD, Nolan PM, Pääbo S, Channon KM, Costa RM, Eilers J, Ehret G, Rawlins JN, Fisher SE (2008). "Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits". Curr. Biol. 18 (5): 354–62. doi:10.1016/j.cub.2008.01.060. PMC 2917768. PMID 18328704. 
  7. ^ a b Haesler S, Rochefort C, Georgi B, Licznerski P, Osten P, Scharff C (2007). "Incomplete and inaccurate vocal imitation after knockdown of FoxP2 in songbird basal ganglia nucleus Area X". PLoS Biol. 5 (12): e321. doi:10.1371/journal.pbio.0050321. PMC 2100148. PMID 18052609. 
  8. ^ Fisher SE, Scharff C (2009). "FOXP2 as a molecular window into speech and language". Trends Genet. 25 (4): 166–77. doi:10.1016/j.tig.2009.03.002. PMID 19304338. 
  9. ^ a b c Shu W, Lu MM, Zhang Y, Tucker PW, Zhou D, Morrisey EE (2007). "Foxp2 and Foxp1 cooperatively regulate lung and esophagus development". Development 134 (10): 1991–2000. doi:10.1242/dev.02846. PMID 17428829. 
  10. ^ a b Spiteri E, Konopka G, Coppola G, Bomar J, Oldham M, Ou J, Vernes SC, Fisher SE, Ren B, Geschwind DH (2007). "Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain". Am. J. Hum. Genet. 81 (6): 1144–57. doi:10.1086/522237. PMC 2276350. PMID 17999357. 
  11. ^ Vernes SC, Spiteri E, Nicod J, Groszer M, Taylor JM, Davies KE, Geschwind DH, Fisher SE (2007). "High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders". Am. J. Hum. Genet. 81 (6): 1232–50. doi:10.1086/522238. PMC 2276341. PMID 17999362. 
  12. ^ Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcón M, Oliver PL, Davies KE, Geschwind DH, Monaco AP, Fisher SE (2008). "A functional genetic link between distinct developmental language disorders". N. Engl. J. Med. 359 (22): 2337–45. doi:10.1056/NEJMoa0802828. PMC 2756409. PMID 18987363. 
  13. ^ a b c d Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Pääbo S (2002). "Molecular evolution of FOXP2, a gene involved in speech and language". Nature 418 (6900): 869–72. doi:10.1038/nature01025. PMID 12192408. 
  14. ^ a b c d Zhang J, Webb DM, Podlaha O (December 2002). "Accelerated protein evolution and origins of human-specific features: Foxp2 as an example". Genetics 162 (4): 1825–35. PMC 1462353. PMID 12524352. 
  15. ^ a b Enard W, Gehre S, Hammerschmidt K, et al. (2009). "A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice". Cell 137 (5): 961–71. doi:10.1016/j.cell.2009.03.041. PMID 19490899. 
  16. ^ Konopka G, Bomar JM, Winden K, Coppola G, Jonsson ZO, Gao F, Peng S, Preuss TM, Wohlschlegel JA, Geschwind DH (2009). "Human-specific transcriptional regulation of CNS development genes by FOXP2". Nature 462 (7270): 213–217. doi:10.1038/nature08549. PMC 2778075. PMID 19907493. 
  17. ^ Hurst JA, Baraitser M, Auger E, Graham F, Norell S (1990). "An extended family with a dominantly inherited speech disorder". Dev. Med. Child Neurol. 32 (4): 352–5. doi:10.1111/j.1469-8749.1990.tb16948.x. PMID 2332125. 
  18. ^ Fisher SE, Lai CS, Monaco AP (2003). "Deciphering the genetic basis of speech and language disorders". Annu. Rev. Neurosci. 26: 57–80. doi:10.1146/annurev.neuro.26.041002.131144. PMID 12524432. 
  19. ^ Vernes SC, Nicod J, Elahi FM, Coventry JA, Kenny N, Coupe AM, Bird LE, Davies KE, Fisher SE (2006). "Functional genetic analysis of mutations implicated in a human speech and language disorder". Hum. Mol. Genet. 15 (21): 3154–67. doi:10.1093/hmg/ddl392. PMID 16984964. 
  20. ^ Feuk L, Kalervo A, Lipsanen-Nyman M, Skaug J, Nakabayashi K, Finucane B, Hartung D, Innes M, Kerem B, Nowaczyk MJ, Rivlin J, Roberts W, Senman L, Summers A, Szatmari P, Wong V, Vincent JB, Zeesman S, Osborne LR, Cardy JO, Kere J, Scherer SW, Hannula-Jouppi K (2006). "Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia". Am. J. Hum. Genet. 79 (5): 965–72. doi:10.1086/508902. PMC 1698557. PMID 17033973. 
  21. ^ Shu W, Cho JY, Jiang Y, Zhang M, Weisz D, Elder GA, Schmeidler J, De Gasperi R, Sosa MA, Rabidou D, Santucci AC, Perl D, Morrisey E, Buxbaum JD (July 2005). "Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene". Proc. Natl. Acad. Sci. U.S.A. 102 (27): 9643–9648. doi:10.1073/pnas.0503739102. PMC 1160518. PMID 15983371. 
  22. ^ Clovis YM, Enard W, Marinaro F, Huttner WB, De Pietri Tonelli D (September 2012). "Convergent repression of Foxp2 3'UTR by miR-9 and miR-132 in embryonic mouse neocortex: implications for radial migration of neurons". Development 139 (18): 3332–42. doi:10.1242/dev.078063. PMID 22874921. 
  23. ^ Vargha-Khadem F, Gadian DG, Copp A, Mishkin M (2005). "FOXP2 and the neuroanatomy of speech and language". Nature Reviews Neuroscience 6 (2): 131–137. doi:10.1038/nrn1605. PMID 15685218. 
  24. ^ a b c Sean B Carroll (July 2005). "Evolution at Two Levels: On Genes and Form". PLoS Biol. 3 (7): e245. doi:10.1371/journal.pbio.0030245. PMC 1174822. PMID 16000021. 
  25. ^ Scherer SW, et al. (2003). "Human chromosome 7: DNA sequence and biology". Science 300 (5620): 767–772. doi:10.1126/science.1083423. PMC 2882961. PMID 12690205. 
  26. ^ Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP (2002). "FOXP2 is not a major susceptibility gene for autism or specific language impairment". Am J Hum Genet 70 (5): 1318–27. doi:10.1086/339931. PMC 447606. PMID 11894222. 
  27. ^ a b Webb DM, Zhang J (2005). "FoxP2 in song-learning birds and vocal-learning mammals". J Hered. 96 (3): 212–6. doi:10.1093/jhered/esi025. PMID 15618302. 
  28. ^ a b Scharff C, Haesler S (2004). "An evolutionary perspective on FoxP2: strictly for the birds?". Curr Opin Neurobiol 15 (6): 694–703. doi:10.1016/j.conb.2005.10.004. PMID 16266802. 
  29. ^ Li G, Wang J, Rossiter SJ, Jones G, Zhang S (2007). "Accelerated FoxP2 evolution in echolocating bats". PloS ONE 2 (9): e900. doi:10.1371/journal.pone.0000900. PMC 1976393. PMID 17878935. 
  30. ^ Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA (2004). "Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction". J Neurosci. 24 (13): 3152–63. doi:10.1523/JNEUROSCI.5589-03.2004. PMID 15056695. 
  31. ^ Haesler S, Wada K, Nshdejan A, Morrisey EE, Lints T, Jarvis ED, Scharff C (2004). "FoxP2 expression in avian vocal learners and non-learners". J Neurosci. 24 (13): 3164–75. doi:10.1523/JNEUROSCI.4369-03.2004. PMID 15056696. 
  32. ^ a b c d e f g h Li G, Wang J, Rossiter SJ, Jones G, Zhang S (2007). Ellegren, Hans, ed. "Accelerated FoxP2 evolution in echolocating bats". PLoS ONE 2 (9): e900. doi:10.1371/journal.pone.0000900. PMC 1976393. PMID 17878935. 
  33. ^ Krause J, Lalueza-Fox C, Orlando L, Enard W, Green RE, Burbano HA, Hublin JJ, Hänni C, Fortea J, de la Rasilla M, Bertranpetit J, Rosas A, Pääbo S (November 2007). "The derived FOXP2 variant of modern humans was shared with Neandertals". Curr. Biol. 17 (21): 1908–12. doi:10.1016/j.cub.2007.10.008. PMID 17949978. Lay summaryNew York Times (19 October 2007).  See also Antonio Benítez-Burraco, Víctor M. Longa, Guillermo Lorenzo, Juan Uriagereka (November 2008). "Also sprach Neanderthalis... Or Did She?". Biolinguistics 2 (2): 225–232. 
  34. ^ Reich D, Green RE, Kircher M, Krause J, Patterson N, Durand EY, Viola B, Briggs AW, Stenzel U, Johnson PL, Maricic T, Good JM, Marques-Bonet T, Alkan C, Fu Q, Mallick S, Li H, Meyer M, Eichler EE, Stoneking M, Richards M, Talamo S, Shunkov MV, Derevianko AP, Hublin JJ, Kelso J, Slatkin M, Pääbo S (December 2010). "Genetic history of an archaic hominin group from Denisova Cave in Siberia". Nature 468 (7327): 1053–60. doi:10.1038/nature09710. PMID 21179161. 
  35. ^ John Hawks (5 January 2001). "Denisova FOXP2 status". John Hawks Weblog. 
  36. ^ Coop G, Bullaughey K, Luca F, Przeworski M (July 2008). "The timing of selection at the human FOXP2 gene". Mol. Biol. Evol. 25 (7): 1257–9. doi:10.1093/molbev/msn091. PMC 2429961. PMID 18413354. 
  37. ^ Haesler S, Wada K, Nshdejan A, Morrisey EE, Lints T, Jarvis ED, Scharff C (March 2004). "FoxP2 expression in avian vocal learners and non-learners". J. Neurosci. 24 (13): 3164–75. doi:10.1523/JNEUROSCI.4369-03.2004. PMID 15056696. 
  38. ^ Teramitsu I, White SA (July 2006). "FoxP2 regulation during undirected singing in adult songbirds". J. Neurosci. 26 (28): 7390–4. doi:10.1523/JNEUROSCI.1662-06.2006. PMC 2683919. PMID 16837586. 
  39. ^ Li S, Weidenfeld J, Morrisey EE (January 2004). "Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions". Mol. Cell. Biol. 24 (2): 809–22. doi:10.1128/MCB.24.2.809-822.2004. PMC 343786. PMID 14701752. 

External links[edit]