The Genetic Basis of a Severe Speech and Language Disorder
The KE family represent the only documented case of single-gene inheritance of a speech and language disorder. There has been some debate over the specificity of their impairment and the precise nature of the core deficit. Nevertheless, it is generally ag
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Summary The KE family represent the only documented case of single-gene inheritance of a speech and language disorder. There has been some debate over the specificity of their impairment and the precise nature of the core deficit. Nevertheless, it is generally agreed that the gene that is disrupted in affected members of this family must play a key role in neurological mechanisms that are important for speech and language acquisition. The simple transmission pattern of the difficulties in the KE family allowed geneticists to use a traditional strategy to map the gene responsible to a small interval on chromosome 7. They then exploited data from large-scale human genomic sequencing efforts to assemble a detailed map of genes in this chromosomal region. A child was identified (unrelated to the KE family) who has speech and language disorder associated with a gross chromosomal abnormality involving the candidate region of chromosome 7. It was demonstrated that the abnormality in this child directly interrupts a novel gene encoding a polyglutamine repeat and a forkhead/winged-helix DNA-binding domain. The gene, known as FOXP2, is strongly expressed in the developing brain during embryogenesis and belongs to a large family of transcription factors involved in switching on and off other genes. Mutation screening of FOXP2 in the KE family revealed a point mutation in all affected individuals, which leads to alteration of a key residue in the DNA-binding domain, and is predicted to disrupt the function of the protein. In the future, studies of FOXP2 may provide a unique entrypoint for investigating molecular processes mediating speech and language development.
Introduction In the last decade there has been considerable interest in investigations of an intriguing three-generational family from the United Kingdom known as KE. About half of the members of this family are affected with a severe disability that appears to be passed down from generation to generation in a simple fashion
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Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford, OX3 7BN, UK; e-mail: [email protected] Mallet/Christen Neurosciencess at the Postgenomic Era © Springer-Verlag Berlin Heidelberg 2003
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S.E. Fisher
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Fig. 1. Pedigree diagram of family KE. Squares represent males; circles represent females. A diagonal line indicates that the individual is deceased. Family members with speech and language impairment are shaded. Asterisks indicate those individuals who were unavailable for linkage analysis. From Fisher et al. (1998) © Nature America Inc. Reprinted with permission.
(Hurst et al. 1990). As can be seen from the pedigree diagram (Fig. 1), this is a classic textbook example of Mendelian inheritance with a dominant mode of transmission. In other words, the family history suggests that a mutation in a single gene accounts for the disorder, and that inheriting only one defective copy of this putative gene is enough to cause difficulties. On the face of it there is nothing odd about t
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