FOXP2

Source: Wikipedia, the free encyclopedia.

FOXP2
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

n/a

RefSeq (protein)

n/a

Location (UCSC)Chr 7: 114.09 – 114.69 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Forkhead box protein P2 (FOXP2) is a

transcription factors, proteins that regulate gene expression by binding to DNA. It is expressed in the brain, heart, lungs and digestive system.[3][4]

FOXP2 is found in many

birdsong) and echolocation in bats. FOXP2 is also required for the proper development of speech and language in humans.[5] In humans, mutations in FOXP2 cause the severe speech and language disorder developmental verbal dyspraxia.[5][6] Studies of the gene in mice and songbirds indicate that it is necessary for vocal imitation and the related motor learning.[7][8][9] Outside the brain, FOXP2 has also been implicated in development of other tissues such as the lung and digestive system.[10]

Initially identified in 1998 as the genetic cause of a

evolutionary selection of FOXP2 in humans.[13][14]

Structure and function

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

As a

FOX protein, FOXP2 contains a forkhead-box domain. In addition, it contains a polyglutamine tract, a zinc finger and a leucine zipper. The protein attaches to the DNA of other proteins and controls their activity through the forkhead-box domain. Only a few targeted genes have been identified, however researchers believe that there could be up to hundreds of other genes targeted by the FOXP2 gene. The forkhead box P2 protein is active in the brain and other tissues before and after birth, many studies show that it is paramount for the growth of nerve cells and transmission between them. The FOXP2 gene is also involved in synaptic plasticity, making it imperative for learning and memory.[15]

FOXP2 is required for proper brain and lung development.

Purkinje layer, and die an average of 21 days after birth from inadequate lung development.[10]

FOXP2 is expressed in many areas of the brain,

frontal cortex, where it is essential for brain maturation and speech and language development.[18] In mice, the gene was found to be twice as highly expressed in male pups than female pups, which correlated with an almost double increase in the number of vocalisations the male pups made when separated from mothers. Conversely, in human children aged 4–5, the gene was found to be 30% more expressed in the Broca's areas of female children. The researchers suggested that the gene is more active in "the more communicative sex".[19][20]

The expression of FOXP2 is subject to

Three amino acid substitutions distinguish the human FOXP2 protein from that found in mice, while two amino acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees,[17] but only one of these changes is unique to humans.[10] Evidence from genetically manipulated mice[22] and human neuronal cell models[23] suggests that these changes affect the neural functions of FOXP2.

Clinical significance

The FOXP2 gene has been implicated in several cognitive functions including; general brain development, language, and synaptic plasticity. The FOXP2 gene region acts as a transcription factor for the forkhead box P2 protein. Transcription factors affect other regions, and the forkhead box P2 protein has been suggested to also act as a transcription factor for hundreds of genes. This prolific involvement opens the possibility that the FOXP2 gene is much more extensive than originally thought.[15] Other targets of transcription have been researched without correlation to FOXP2. Specifically, FOXP2 has been investigated in correlation with autism and dyslexia, however with no mutation was discovered as the cause.[24][6] One well identified target is language.[25] Although some research disagrees with this correlation,[26] the majority of research shows that a mutated FOXP2 causes the observed production deficiency.[15][25][27][24][28][29]

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. 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.[30]

Mutations in FOXP2 are among several (26 genes plus 2 intergenic) loci which correlate to

ADHD diagnosis in adults – clinical ADHD is an umbrella label for a heterogeneous group of genetic and neurological phenomena which may result from FOXP2 mutations or other causes.[31]

A 2020

single-nucleotide polymorphisms (SNPs) of FOXP2 in susceptibility to cannabis use disorder.[32]

Language disorder

It is theorized that the translocation of the 7q31.2 region of the FOXP2 gene causes a severe language impairment called developmental verbal dyspraxia (DVD)[25] or childhood apraxia of speech (CAS)[33] So far this type of mutation has only been discovered in three families across the world including the original KE family.[29] A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE.[34] This would cause a normally basic residue to be fairly acidic and highly reactive at the body's pH. A heterozygous nonsense mutation, R328X variant, produces a truncated protein involved in speech and language difficulties in one KE individual and two of their close family members. R553H and R328X mutations also affected nuclear localization, DNA-binding, and the transactivation (increased gene expression) properties of FOXP2.[6]

These individuals present with deletions, translocations, and missense mutations. When tasked with repetition and verb generation, these individuals with DVD/CAS had decreased activation in the putamen and Broca's area in fMRI studies. These areas are commonly known as areas of language function.[35] This is one of the primary reasons that FOXP2 is known as a language gene. They have delayed onset of speech, difficulty with articulation including slurred speech, stuttering, and poor pronunciation, as well as dyspraxia.[29] It is believed that a major part of this speech deficit comes from an inability to coordinate the movements necessary to produce normal speech including mouth and tongue shaping.[25] Additionally, there are more general impairments with the processing of the grammatical and linguistic aspects of speech.[6] These findings suggest that the effects of FOXP2 are not limited to motor control, as they include comprehension among other cognitive language functions. General mild motor and cognitive deficits are noted across the board.[27] Clinically these patients can also have difficulty coughing, sneezing, or clearing their throats.[25]

While FOXP2 has been proposed to play a critical role in the development of speech and language, this view has been challenged by the fact that the gene is also expressed in other mammals as well as birds and fish that do not speak.[36] It has also been proposed that the FOXP2 transcription-factor is not so much a hypothetical 'language gene' but rather part of a regulatory machinery related to externalization of speech.[37]

Evolution

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).

The FOXP2 gene is highly conserved in

alligators.[41][42]

DNA sampling from

Homo sapiens (i.e. humans).[43][44] Previous genetic analysis had suggested that the H. sapiens FOXP2 gene became fixed in the population around 125,000 years ago.[45] Some researchers consider the Neanderthal findings to indicate that the gene instead swept through the population over 260,000 years ago, before our most recent common ancestor with the Neanderthals.[45] Other researchers offer alternative explanations for how the H. sapiens version would have appeared in Neanderthals living 43,000 years ago.[45]

According to a 2002 study, the FOXP2 gene showed indications of recent

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, and a decrease in maze learning time. A reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed.[22]

Interactions

FOXP2 is known to regulate CNTNAP2, CTBP1,[47] SRPX2 and SCN3A.[48][18][49]

FOXP2 downregulates CNTNAP2, a member of the neurexin family found in neurons. CNTNAP2 is associated with common forms of language impairment.[50]

FOXP2 also downregulates SRPX2, the 'Sushi Repeat-containing Protein X-linked 2'.

synapse formation in the cerebral cortex and is more highly expressed in childhood. SRPX2 appears to specifically increase the number of glutamatergic synapses in the brain, while leaving inhibitory GABAergic synapses unchanged and not affecting dendritic spine length or shape. On the other hand, FOXP2's activity does reduce dendritic spine length and shape, in addition to number, indicating it has other regulatory roles in dendritic morphology.[51]

In other animals

Chimpanzees

In chimpanzees, FOXP2 differs from the human version by two amino acids.[53] A study in Germany sequenced FOXP2's complementary DNA in chimps and other species to compare it with human complementary DNA in order to find the specific changes in the sequence.[17] FOXP2 was found to be functionally different in humans compared to chimps. Since FOXP2 was also found to have an effect on other genes, its effects on other genes is also being studied.[54] Researchers deduced that there could also be further clinical applications in the direction of these studies in regards to illnesses that show effects on human language ability.[23]

Mice

In a mouse FOXP2

cerebellar circuits.[7]

Humanized FOXP2 mice display altered cortico-basal ganglia circuits. The human allele of the FOXP2 gene was transferred into the mouse embryos through homologous recombination to create humanized FOXP2 mice. The human variant of FOXP2 also had an effect on the exploratory behavior of the mice. In comparison to knockout mice with one non-functional copy of FOXP2, the humanized mouse model showed opposite effects when testing its effect on the levels of dopamine, plasticity of synapses, patterns of expression in the striatum and behavior that was exploratory in nature.[22]

When FOXP2 expression was altered in mice, it affected many different processes including the learning motor skills and the plasticity of synapses. Additionally, FOXP2 is found more in the

autism, bipolar disorder and intellectual disabilities.[56]

Bats

FOXP2 has implications in the development of

baleen cetaceans.[40] Within bats, however, amino acid variation correlated with different echolocating types.[40]

Birds

In songbirds, FOXP2 most likely regulates genes involved in neuroplasticity.[8][58] Gene knockdown of FOXP2 in area X of the basal ganglia in songbirds results in incomplete and inaccurate song imitation.[8] Overexpression of FOXP2 was accomplished through injection of adeno-associated virus serotype 1 (AAV1) into area X of the brain. This overexpression produced similar effects to that of knockdown; juvenile zebra finch birds were unable to accurately imitate their tutors.[59] Similarly, in adult canaries, higher FOXP2 levels also correlate with song changes.[39]

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.[58] "Directed" singing refers to when a male is singing to a female usually for a courtship display. "Undirected" singing occurs when for example, a male sings when other males are present or is alone.[60] Studies have found that FoxP2 levels vary depending on the social context. When the birds were singing undirected song, there was a decrease of FoxP2 expression in Area X. This downregulation was not observed and FoxP2 levels remained stable in birds singing directed song.[58]

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.

Zebrafish

In

telencephalon, diencephalon where it likely plays a role in nervous system development. The zebrafish FOXP2 gene has an 85% similarity to the human FOX2P ortholog.[61]

History

FOXP2 and its gene were discovered as a result of investigations on an English family known as the

Mendelian (monogenic) inheritance for a disorder affecting speech and language skills, which typically have a complex basis involving multiple genetic risk factors.[68]

chromosome 7
, at position 31.

In 1998, Oxford University geneticists Simon Fisher, Anthony Monaco, Cecilia S. L. Lai, Jane A. Hurst, and Faraneh Vargha-Khadem identified an autosomal dominant monogenic inheritance that is localized on a small region of chromosome 7 from DNA samples taken from the affected and unaffected members.[3] The chromosomal region (locus) contained 70 genes.[69] 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.[4] 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.[4]

In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene.

heterozygous point mutation shared by all the affected individuals, but not in unaffected members of the family and other people.[5] This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the FOXP2 protein.[70] Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations[6] and chromosomal rearrangements,[71]
providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000128573 - Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^
    S2CID 3190318
    .
  4. ^ .
  5. ^ .
  6. ^ .
  7. ^ .
  8. ^ .
  9. .
  10. ^ .
  11. .
  12. ^ Harpaz Y. "Language gene found". human-brain.org. Archived from the original on 25 October 2014. Retrieved 31 October 2014.
  13. ^
    PMID 30078708
    .
  14. ^ a b "Language Gene Dethroned". The Scientist Magazine®. Retrieved 28 January 2020.
  15. ^ a b c "FOXP2 Gene". Genetics Home Reference. U.S. National Library of Medicine, National Institutes of Health. September 2016.
  16. ^
    PMID 15983371
    .
  17. ^
    S2CID 4416233. Archived from the original
    (PDF) on 30 August 2006.
  18. ^ .
  19. ^ Balter M (February 2013). "'Language Gene' More Active in Young Girls Than Boy". Science: 360.
  20. PMID 23426656
    .
  21. .
  22. ^ .
  23. ^ .
  24. ^
    S2CID 39762074
    .
  25. ^ a b c d e "FOXP2-related speech and language disorder". Genetics Home Reference. U.S. National Library of Medicine, National Institutes of Health. Retrieved 26 February 2019.
  26. PMID 11894222
    .
  27. ^ .
  28. .
  29. ^ .
  30. .
  31. .
  32. .
  33. .
  34. ^ .
  35. .
  36. .
  37. .
  38. .
  39. ^ .
  40. ^ .
  41. ^ .
  42. ^ .
  43. ^ Zimmer C (17 March 2016). "Humans Interbred With Hominins on Multiple Occasions, Study Finds". The New York Times. Retrieved 17 March 2016.
  44. S2CID 9518208
    . See also Benítez-Burraco A, Longa VM, Lorenzo G, Uriagereka J (November 2008). "Also sprach Neanderthalis... Or Did She?". Biolinguistics. 2 (2–3): 225–232.
    S2CID 60864520
    .
  45. ^ .
  46. .
  47. .
  48. .
  49. .
  50. .
  51. ^ .
  52. ^ Pennisi E (31 October 2013). "'Language Gene' Has a Partner". Science. Retrieved 30 October 2014.
  53. ISSN 1744-7933
    .
  54. ^ "Why can't chimps talk? It's more than just genes". Reuters. 11 November 2009. Retrieved 21 February 2019.
  55. PMID 16248680
    .
  56. .
  57. .
  58. ^ .
  59. .
  60. .
  61. .
  62. .
  63. .
  64. .
  65. .
  66. .
  67. .
  68. .
  69. ^ "Genes that are essential for speech". The Brain from Top to Bottom. Retrieved 31 October 2014.
  70. PMID 16984964
    .
  71. .

External links

This page is based on the copyrighted Wikipedia article: FOXP2. Articles is available under the CC BY-SA 3.0 license; additional terms may apply.Privacy Policy