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A forkhead-domain gene is mutated in a severe speech and language disorder

Cecilia S. L. Lai1,4, Simon E. Fisher1,4, Jane A. Hurst2, Faraneh Vargha-Khadem3 & Anthony P. Monaco1

1. 2. 3. 4.

Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK Department of Clinical Genetics, Oxford Radcliffe Hospital, Oxford OX3 7LJ, UK

Developmental Cognitive Neuroscience Unit, Institute of Child Health, Mecklenburgh Square, London WC1N 2AP, UK These authors contributed equally to this work

Correspondence to: Anthony P. Monaco1 Correspondence and requests for materials should be addressed to A.P.M. (e-mail: Email: anthony@well.ox.ac.uk).
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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 opportunity1. Although studies of twins consistently indicate that a significant genetic component is involved1, 2, 3, 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 trait4. 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 6. 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.

1. 2. 3. 4.

Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK Department of Clinical Genetics, Oxford Radcliffe Hospital, Oxford OX3 7LJ, UK

Developmental Cognitive Neuroscience Unit, Institute of Child Health, Mecklenburgh Square, London WC1N 2AP, UK These authors contributed equally to this work

Correspondence to: Anthony P. Monaco1 Correspondence and requests for materials should be addressed to A.P.M. (e-mail: Email: anthony@well.ox.ac.uk).

Resumen

Las personas que estn afectadas con trastornos en el desarrollo del habla y de lenguaje, tienen dificultades en la adquisicin del lenguaje expresivo y/o receptivo, estas personas poseen una inteligencia adecuada y no presentan ningn deterioro sensorial o neurolgico. Aunque los estudios en gemelos indican consistentemente que esta involucrado un componente gentico la mayora de las familias que presentan u n dficit en el habla y el lenguaje presentan patrones complejos de herencia y aun no se han identificado un gen que predisponga a los individuos a presentar estos trastornos. Hemos estudiado tres generaciones en pedigr nico, en el que el severo trastorno del lenguaje y del habla es trasmitido como rasgo monognico autosmico dominante. En nuestro trabajo anterior ubicamos el locus responsable, SPCH1, a un intervalo de 5,6 cm de la regin 7q31 del cromosoma 7, tambin se identific un caso individual no relacionado, CS, en el que el habla y el trastorno del lenguaje est asociado a una translocacin cromosmica que implica la SPCH1 intervalo 6 . Aqu nos muestra que el gen FOXP2 que codifica un factor de transcripcin putativo que contiene poliglutamina y un dominio de unin a DNA forkhead (cabeza de tenedor) est directamente interrumpido por las translocacin de corte en el CS. Tambin se identifica un punto de mutacin en los miembros afectados de la familia KE que altera un residuo de aminocido en el dominio forkhead (cabeza de tenedor). Nuestros hallazgos sugieren que FOXP2 est implicado en el proceso de desarrollo que culmina en el habla y el lenguaje.