title: A forkhead-domain gene is mutated in a severe speech and language disorder.
abstract: Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Lai
authors.forename: S E
authors.initials: SE
authors.lastname: Fisher
authors.forename: J A
authors.initials: JA
authors.lastname: Hurst
authors.forename: F
authors.initials: F
authors.lastname: Vargha-Khadem
authors.forename: A P
authors.initials: AP
authors.lastname: Monaco
mesh_terms: D000595:Amino Acid Sequence; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D005260:Female; D051858:Forkhead Transcription Factors; D006801:Humans; D007806:Language Disorders / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013064:Speech Disorders / Q000235:genetics*; D014157:Transcription Factors; D014178:Translocation, Genetic
chemical_list: C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors