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Forkhead box protein P2 (FOXP2) is a protein that, in humans, is encoded by the FOXP2 gene, also known as CAGH44, SPCH1 or TNRC10, and is required for proper development of speech and language.[3] FOXP2 is a transcription factor, meaning that it encodes for a regulatory protein. The gene is shared with many vertebrates, where it generally plays a role in communication (for instance, the development of bird song).

FOXP2
Protein FOXP2 PDB 2a07.png
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesFOXP2, CAGH44, SPCH1, TNRC10, forkhead box P2
External IDsOMIM: 605317 HomoloGene: 33482 GeneCards: FOXP2
Gene location (Human)
Chromosome 7 (human)
Chr.Chromosome 7 (human)[1]
Chromosome 7 (human)
Genomic location for FOXP2
Genomic location for FOXP2
Band7q31.1Start114,086,327 bp[1]
End114,693,772 bp[1]
RNA expression pattern
PBB GE FOXP2 gnf1h09377 at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
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

Initially identified as the genetic factor of speech disorder in KE family, FOXP2 is the first gene discovered associated with speech and language.[4] The gene is located on chromosome 7 (7q31, at the SPCH1 locus) and is expressed in fetal and adult brain, heart, lung and gut.[5][6] FOXP2 orthologs[7] have also been identified in other 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. The gene is more active in females than in males, to which could be attributed better language learning in females.[8]

In humans, mutations of FOXP2 cause a severe speech and language disorder.[3][9] Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice[10] and in songbirds[11] indicate that it is important for modulating plasticity of neural circuits.[12] Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut.[13]

FOXP2 is popularly dubbed the "language gene", but this is only partly correct since there are other genes involved in language development.[14] It directly regulates a number of other genes, including CNTNAP2, CTBP1, SRPX2 and SCN3A.[15][16][17]

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,[18] but only one of these changes is unique to humans.[13] Evidence from genetically manipulated mice[19] and human neuronal cell models[20] suggests that these changes affect the neural functions of FOXP2.

Contents

DiscoveryEdit

FOXP2 and its gene were discovered as a result of investigations on an English family known as the KE family, half of whom (fifteen individuals across three generations) suffered from a speech and language disorder called developmental verbal dyspraxia. Their case was studied at the Institute of Child Health of University College London.[21] In 1990 Myrna Gopnik, Professor of Linguistics at McGill University, reported that the disorder-affected KE family had severe speech impediment with incomprehensible talk, largely characterized by grammatical deficits.[22] She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability.[23] (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.[24][25]) In 1995, the University of Oxford and the Institute of Child Health researchers found that the disorder was purely genetic.[26] Remarkably, the inheritance 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.[27]

 
FOXP2 gene is located on the long (q) arm of 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.[5] The chromosomal region (locus) contained 70 genes.[28] 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.[6] 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.[6]

In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene.[3] Using a combination of bioinformatics and RNA analyses, they discovered that the gene codes for a novel protein belonging to 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 found a heterozygous point mutation shared by all the affected individuals, but not in unaffected members of the family and other people.[3] This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the FOXP2 protein.[29] Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations[9] and chromosomal rearrangements,[30] providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.

FunctionEdit

 
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.[31] 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.[13]

FOXP2 is expressed in many areas of the brain[18] including the basal ganglia and inferior frontal cortex where it is essential for brain maturation and speech and language development.[16]

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.[13]

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.[32]

Clinical SignificanceEdit

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.[33] 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.[34][35] One well identified target is language.[36] Although some research disagrees with this correlation[37] the majority of research shows that a mutated FOXP2 causes the observed production deficiency.[33][36][38][34][39][40]

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 examples, 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.

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 heterogenous group of genetic and neurological phonomena which may result from FOXP2 mutations or other causes.[41]

Language DisorderEdit

 
Ptosis, unilateral eye droops, is often seen correlated with CAS motor dyspraxia.

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)[36] or Childhood Apraxia of Speech (CAS)[42] So far this type of mutation has only been discovered in three families across the world including the original KE family.[40] A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE.[43] 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. [44]

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.[45] 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.[40] 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.[36] Additionally, there are more general impairments with the processing of the grammatical and linguistic aspects of speech.[44] 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.[46] Clinically these patients can also have difficulty coughing, sneezing, and/or clearing their throats.  [36]

EvolutionEdit

 
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 mammals.[47] The human gene differs from that in non-human primates by the substitution of two amino acids, a threonine to asparagine substitution at position 303 (T303N) and an asparagine to serine substitution at position 325 (N325S).[48] In mice it differs from that of humans by three substitutions, and in zebra finch by seven amino acids.[18][49][50] One of the two amino acid differences between human and chimps also arose independently in carnivores and bats.[13][51] Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators.[52][53]

DNA sampling from Homo neanderthalensis bones indicates that their FOXP2 gene is a little different, though largely similar to those of Homo sapiens (i.e. humans).[54][55] Previous genetic analysis had suggested that the H. sapiens FOXP2 gene became fixed in the population around 125,000 years ago.[56] 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.[56] Other researchers offer alternative explanations for how the H. sapiens version would have appeared in Neanderthals living 43,000 years ago.[56]

The FOXP2 gene showed indications of recent positive selection.[47][57] Some researchers have speculated that positive selection is crucial for the evolution of language in humans.[18] Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.[52][53] Recent data from a large sample of globally distributed genomes showed no evidence of positive selection, suggesting that the original signal of positive selection may be driven by sample composition.[58] 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, and a decrease in maze learning time. A reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed.[19]

However, FOXP2 is extremely diverse in echolocating bats.[59] 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.[51] All cetaceans share three amino acid substitutions, but no differences were found between echolocating toothed whales and non-echolocating baleen cetaceans.[51] Within bats, however, amino acid variation correlated with different echolocating types.[51]

InteractionsEdit

FOXP2 interacts with a regulatory gene CTBP1.[60] It also downregulates CNTNAP2 gene, a member of the neurexin family found in neurons. The target gene is associated with common forms of language impairment.[61] It regulates the repeat-containing protein X-linked 2 (SRPX2), which is an epilepsy and language-associated gene in humans, and sound-controlling gene in mice.[62]

MiceEdit

In a mouse FOXP2 gene knockouts, loss of both copies of the gene caues severe motor impairment related to cerebellar abnormalities and lack of ultrasonic vocalisations normally elicited when pups are removed from their mothers.[31] These vocalizations have important communicative roles in mother-offspring interactions. Loss of one copy was associated with impairment of ultrasonic vocalisations and a modest developmental delay. Male mice on encountering female mice produce complex ultrasonic vocalisations that have characteristics of song.[63] Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal synaptic plasticity in striatal and cerebellar circuits.[10]

Humanized FOXP2 mice display altered cortico-basal ganglia circuits.[19]

The human allele of the FOXP2 gene was transferred into the mouse embryos through homologous recombination was used to create humanized FOXP2 mice.  The human variant of FOXP2 also had an effect on the exploratory behavior of the mice.  In comparison with how this gene mutation functions in humans, in 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.[19]

When FOXP2 expression was altered in mice, it effected many different processes including the learning motor skills and the plasticity of synapses.  It makes sense for the gene to have a role in the processing of sensory inputs because of its effects in the cortical and subcortical regions of the brain such as in the olfactory bulb, auditory and visual circuits as well as in somatosensory regions of the thalamus.  Additionally, FOXP2 is found more in the sixth layer of the cortex than in the fifth so this is consistent with it having greater roles in sensory integration. FOXP2 was also found in the medial geniculate nucleus of the mouse brain which is the processing area that auditory inputs must go through in the thalamus so it was found that its mutations play a role in delaying the development of language learning.  It also makes sense for FOXP2 mutations to have roles in the learning, integrating and outputs of motor functions due to its high expression found in the Purkinje cells and cerebellar nuclei of the Cortico-cerebellar circuits.  High FOXP2 expression has also been shown in the spiny neurons which express type 1 dopamine receptors in the striatum, substantia nigra, subthalamic nucleus and ventral tegmental area.  The negative effects of the mutations of FOXP2 in these brain regions on motor abilities were shown in mice through tasks in lab studies.  When analyzing the brain circuitry in these cases, scientists found greater levels of dopamine and decreased lengths of dendrites which caused defects in long term depression which is implicated in motor function learning and maintenance.  Through EEG studies, it was also found that these mice had increased levels of activity in their striatum which contribute to these results.  There is further evidence for mutations of targets of the FOXP2 gene shown to have roles in schizophrenia, epilepsy, autism, bipolar and intellectual disabilities.  [64]

BirdsEdit

In songbirds, FOXP2 most likely regulates genes involved in neuroplasticity.[11][65]Gene knockdown of FOXP2 in Area X of the basal ganglia in songbirds results in incomplete and inaccurate song imitation.[11] 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.[66] Similarly, in adult canaries higher FOXP2 levels also correlate with song changes.[50]

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.[65] “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.[67] 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.[65]

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.

FOXP2 also has possible implications in the development of bat echolocation.[48][51][68]

Chimpanzees compared to humansEdit

Chimpanzees were also found to have the FOXP2 gene, however the human version of the gene differs by a mutation change of two amino acids.[69] FOXP2 gene mutation are implicated in a developmental speech disorder that was transmitted through a family with an autosomal dominant inheritance pattern.[3] 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 that have evolved through natural selection.[70] FOXP2 was found to be functionally different in humans compared to chimps and this difference is said to account for the development of structures that allow the human capability of language which chimps lack. Since FOXP2 was also found to have an effect on other genes, its effects on other genes is also being studied.[71] This mutation in the FOXP2 gene present in humans was also found in Neanderthals.[72] The human version of the gene differs from the chimp in their functions and in their appearance, due to the amino acid substitution that has evolved in the version that humans carry.  Since FOXP2 is a transcription factor, it has been found to control other genes which are being studied in their functions in language development. Additionally, there were found different effects onto the targets of the FOXP2 gene in humans in how and whether there was expression of these additional genes.  In this way, it is the FOXP2 gene’s functioning that allows humans to be able to have language but does not allow chimps this same ability. Researchers deduced that this finding could be used to further study other unique human abilities such as higher up cognitive functioning that chimps are not able to exhibit.  There can also be further clinical applications in the direction of these studies in regards to illnesses that show effects on human language ability.[20]

See alsoEdit

ReferencesEdit

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