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Functional Genomic Dissection of Speech and Language Disorders

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Genomics, Proteomics, and the Nervous System

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 2))

Abstract

Mutations of the human FOXP2 gene have been shown to cause severe difficulties in learning to make coordinated sequences of articulatory gestures that underlie speech (developmental verbal dyspraxia or DVD). Affected individuals are impaired in multiple aspects of expressive and receptive linguistic processing and ­display abnormal grey matter volume and functional activation patterns in cortical and subcortical brain regions. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerization. This chapter describes the successful use of FOXP2 as a unique molecular window into neurogenetic pathways that are important for speech and language development, adopting several complementary strategies. These include direct functional investigations of FOXP2 splice variants and the effects of etiological mutations. FOXP2’s role as a transcription factor also enabled the development of functional genomic routes for dissecting neurogenetic mechanisms that may be relevant for speech and language. By identifying downstream target genes regulated by FOXP2, it was possible to identify common regulatory themes in modulating synaptic plasticity, neurodevelopment, and axon guidance. These targets represent novel entrypoints into in vivo pathways that may be disturbed in speech and language disorders. The identification of FOXP2 target genes has also led to the discovery of a shared neurogenetic pathway between clinically distinct language disorders; the rare Mendelian form of DVD and a complex and more common form of language ­disorder known as Specific Language Impairment.

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Abbreviations

ASD:

Autism spectrum disorder

CFDE:

Cortical dysplasia–focal epilepsy

ChIP:

Chromatin-immunoprecipitation

DVD:

Developmental verbal dyspraxia

EMSA:

Electrophoretic mobility shift assay

FOX:

Forkhead-box

NLS:

Nuclear localisation signal

SLI:

Specific language impairment

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Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Sonja C. Vernes

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  1. Sonja C. Vernes
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  2. Simon E. Fisher
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Correspondence to Sonja C. Vernes .

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  1. Nathan S. Kline Institute for, Psychiatric Research, New York University, Old Orangeburg Road 140, Orangeburg, 10962, New York, USA

    James D Clelland

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Vernes, S.C., Fisher, S.E. (2011). Functional Genomic Dissection of Speech and Language Disorders. In: Clelland, J. (eds) Genomics, Proteomics, and the Nervous System. Advances in Neurobiology, vol 2. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7197-5_10

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