FOXP2
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RefSeq (protein) |
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Location (UCSC) | Chr 7: 114.09 – 114.69 Mb | n/a | |||||||
PubMed search | [2] | n/a |
View/Edit Human |
Forkhead box protein P2 (FOXP2) is a
FOXP2 is found in many
Initially identified in 1998 as the genetic cause of a
Structure and function
As a
FOXP2 is required for proper brain and lung development.
FOXP2 is expressed in many areas of the brain,
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
A 2020
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
The FOXP2 gene is highly conserved in
DNA sampling from
According to a 2002 study, the FOXP2 gene showed indications of recent
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'.
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
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
Bats
FOXP2 has implications in the development of
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
History
FOXP2 and its gene were discovered as a result of investigations on an English family known as the
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.
See also
- Chimpanzee genome project
- Evolutionary linguistics
- FOX proteins
- Olduvai domain
- Origin of language
- Vocal learning
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