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FOXP2 and the neuroanatomy of speech and language

Key Points

  • Familial disorders of speech and language provided early evidence that genetic mutations could impair these abilities, but a causative mutation in a single gene was only recently identified. Mutations in FOXP2 cause an inherited verbal dyspraxia associated with an orofacial movement disorder in a family known by the label KE.

  • Although the behavioural phenotype has been carefully studied, it is still unclear whether all the effects of the mutation are caused by a single core deficit in orofacial movement, or whether there are additional core deficits that can account for the grammatical, semantic and cognitive impairments that are found in affected family members.

  • MRI scans of affected individuals showed no obvious focal abnormalities on conventional neuroradiological assesments, but more detailed analyses have revealed reductions in the volumes of several brain areas that are involved in motor functions, including the caudate nuclei, Broca's area, the precentral gyrus and the ventral cerebellum. Functional neuroimaging studies have also shown some abnormalities in patterns of activation.

  • FOXP2 encodes a transcription factor that is expressed in the brain, lungs, heart and gut. In the brain, it is widely expressed in sensory, limbic and motor structures.

  • The effects of a mutation in FOXP2, together with data on its expression, allow us to propose a model of FOXP2-dependent circuitry. We assume that the circuitry that underlies normal speech is similar to the frontostriatal and frontocerebellar circuits that modulate and control the motor cortex in the performance of other types of movement. Most of the areas in the proposed circuit express FOXP2, and several of these show abnormalities in affected members of the KE family.

  • Much work is needed to clarify the details of the deficits caused by mutations in FOXP2 and to provide evidence that supports or contradicts our proposed circuitry. This work will involve behavioural, imaging, gene expression and gene knockout studies.

Abstract

That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech.

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Figure 1: Pedigree of the KE family.
Figure 2: Bilateral voxel-based morphometry (VBM) analyses showing (in colour) some of the regions in which affected KE family members have significantly reduced grey matter.
Figure 3: Expression of mouse Foxp2 and human FOXP2 are similar in the brain at embryonic day 13.5 (mouse) and Carnegie stage 23 (56 days post-fertilization in human).
Figure 4: Proposed circuit for FOXP2-dependent speech and language.

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Acknowledgements

We are grateful to P. Strick and K. Tanji for valuable advice regarding many of the functional neuroanatomical issues raised in this article.

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Correspondence to Faraneh Vargha-Khadem.

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DATABASES

Entrez Gene

FOXC1

Foxp1

FOXP2

Foxp4

OMIM

FOXP2

FURTHER INFORMATION

Vargha-Khadem's homepage

Gadian's homepage

Copp's homepage

Mishkin's homepage

Glossary

VERBAL DYSPRAXIA

An impaired ability to perform the coordinated movements that are required for speech.

DYSPHASIA

Impairment of speech and verbal comprehension.

OROFACIAL PRAXIS OR ORAL PRAXIS

Oral praxis is the volitional control of skilled non-speech movements.

BROCA'S APHASIA

Severe impairment of verbal expression by speech or writing due to pathology of the left inferior frontal convolution, named after the French surgeon who discovered the relationship.

DERIVATIONAL AND INFLECTIONAL MORPHOLOGY

The part of grammar that deals with the formation of one word from another by the addition of a prefix or suffix, often to change the case, gender, number or tense.

T1-WEIGHTED MRI

MRI scans can be acquired with various types of contrast. T1-weighted images are weighted according to the so-called spin-lattice relaxation time (T1) of the protons that give rise to the MRI signals; such images provide good contrast between grey and white matter.

LOD SCORE

A mathematical function that provides a measure of the strength of linkage between genetic loci in a breeding study. A lod score of 3 or more is considered to provide initial evidence that linkage exists.

BACTERIAL ARTIFICIAL CHROMOSOME

(BAC). A vector containing an origin of replication that enables genomic or other DNA fragments, inserted into the vector, to be grown in bacteria.

FORKHEAD GENES

A family of evolutionarily related genes, the FOX genes. FOX proteins regulate the transcription of target genes by binding their regulatory DNA sequences. This binding is performed by a special protein structure, the winged helix, which is encoded by the forkhead DNA sequence in the FOX gene.

LEUCINE ZIPPER

A structural feature of some proteins in which two alpha helical regions, one from each protein monomer, are held together by hydrophobic interactions between leucine residues. The leucine zipper allows protein dimerization (pairing), which is necessary for the DNA-binding activity of some transcription factors.

PATCH COMPARTMENTS

These are distinguishable histochemically from the surrounding 'matrix' compartments of the neostriatum, the patches being rich in opiate receptors and substance P, and the matrix containing cholinergic neurons and a rich plexus of somatostatin-immunoreactive fibres.

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Vargha-Khadem, F., Gadian, D., Copp, A. et al. FOXP2 and the neuroanatomy of speech and language. Nat Rev Neurosci 6, 131–138 (2005). https://doi.org/10.1038/nrn1605

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