Forkhead box protein P2 (FOXP2) is a protein that, in humans, is encoded by the FOXP2 gene, also known as CAGH44, SPCH1 orTNRC10, and is required

[루아흐]

FOXP2


• DNA binding
• sequence-specific DNA binding
• protein homodimerization activity
• transcription factor activity, sequence-specific DNA binding
• metal ion binding
• RNA polymerase II core promoter proximal region sequence-specific DNA binding
• transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding
• protein binding
• protein heterodimerization activity
• RNA polymerase II transcription factor activity, sequence-specific DNA binding

Cellular component

• nucleus

Biological process

• cell differentiation
• positive regulation of epithelial cell proliferation involved in lung morphogenesis
• regulation of transcription, DNA-templated
• lung development
• positive regulation of epithelial cell proliferation
• anatomical structure morphogenesis
• negative regulation of transcription from RNA polymerase II promoter
• post-embryonic development
• transcription, DNA-templated
• cerebellum development
• putamen development
• growth
• vocal learning
• positive regulation of mesenchymal cell proliferation
• smooth muscle tissue development
• cerebral cortex development
• caudate nucleus development
• camera-type eye development
• lung alveolus development
• righting reflex
• negative regulation of transcription, DNA-templated
• skeletal muscle tissue development



FOXP2 gene is located on the long (q) arm of chromosome 7 at position 31.

Forkhead box protein P2 (FOXP2) is a proteinthat, in humans, is encoded by the FOXP2gene, also known as CAGH44, SPCH1 orTNRC10, and is required for proper development of speech and language.



Initially identified as the genetic factor ofspeech disorder in KE family, its gene is the first gene discovered associated with speech and language.[2] The gene is located onchromosome 7 (7q31, at the SPCH1 locus), and is expressed in fetal and adult brain, heart, lung and gut.


FOXP2 orthologs have also been identified in other mammalsfor which complete genome data are available. The FOXP2 protein contains aforkhead-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 apolyglutamine tract, a zinc finger and aleucine zipper. The gene is more active in females than in males, to which could be attributed better language learning in females.

In humans, mutations of FOXP2 cause a severe speech and language disorder.

Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice and in songbirds indicate that it is important for modulating plasticity of neural circuits.

Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut.

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

Two amino acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees, but only one of these two changes is unique to humans. Evidence from genetically manipulated mice and human neuronal cell models suggests that these changes affect the neural functions ofFOXP2.

Discovery

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 calleddevelopmental verbal dyspraxia. Their case was studied at the Institute of Child Health of University London College.

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.[19] She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability.[20] (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.[21][22]) In 1995, theUniversity of Oxford and the Institute of Child Health researchers found that the disorder was purely genetic.[23] Remarkably, the inheritance of the disorder from one generation to the next was consistent withautosomal dominant inheritance, i.e., mutation of only a single gene on anautosome (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.[24]

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.[25] 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 (atranslocation) 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.[1] Using a combination of bioinformaticsand 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 mutationshared by all the affected individuals, but not in unaffected members of the family and other people.[1] This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the FOXP2 protein.[26]Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations[7] and chromosomal rearrangements,[27] 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.[28] Knockout mice with no functional copies of FOXP2 are runted, display abnormalities in brain regions such as thePurkinje layer, and die an average of 21 days after birth from inadequate lung development.[11]

FOXP2 is expressed in many areas of the brain[15] including the basal ganglia and inferior frontal cortex where it is and is essential for brain maturation and speech and language development.[13]

A knockout mouse model has been used to examine FOXP2’s role in brain development and how mutations in the two copies ofFOXP2 affect vocalization. Mutations in one copy result in reduced speech while abnormalities in both copies cause major brain and lung developmental issues.[11]

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.[29]

Clinical significanceEdit

There are several abnormalities linked toFOXP2. The most common mutation results in severe speech impairment known asdevelopmental verbal dyspraxia which is caused by a translocation in the 7q31.2 region [t(5;7)(q22;q31.2)].

A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE.

A heterozygous nonsense mutation, R328X variant, produces a truncated protein involved in speech and language difficulties in an 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.

Although DVD associated with FOXP2disruptions are thought to be rare (~2% by one estimate), a faulty copy of FOXP2 in individuals always causes speech and language problems.

Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene.

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 spokenword 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, asFOXP2 is known to affect development in other parts of the body as well).

Scientists have also looked for associations betweenFOXP2 and autism, and both positive and negative findings have been reported.

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.

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 inmammals.

Human gene differs from non-human primates by the substitution of two amino acids, threonine to asparaginesubstitution at position 303 (T303N) and asparagine to serine substitution at position 325 (N325S).


In mice it differs from that of humans by three substitutions, and in zebra finch by seven amino acids.

One of the two amino acid difference between human and chimps also arose independently in carnivores and bats.

Similar FOXP2proteins can be found in songbirds, fish, andreptiles such as alligators.

DNA sampling from Homo neanderthalensisbones indicates that their FOXP2 gene is a little different, though largely similar to those of Homo sapiens (i.e. humans).

The FOXP2 gene showed indications of recentpositive selection.

Some researchers have speculated that positive selection is crucial for the evolution of language in humans.

Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.

Insertion of both human mutations into mice, whose version ofFOXP2 otherwise differs from the human andchimpanzee 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.

However, FOXP2 is extremely diverse inecholocating bats.

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.

Interestingly, all cetaceans share three amino acid substitutions, but there are not differences between echolocating and non-echolocatingbaleen cetaceans.

Within bats, however, amino acid variation correlated with different echolocating types.