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      The distinct and overlapping phenotypic spectra of FOXP1 and FOXP2 in cognitive disorders

      review-article
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      Human Genetics
      Springer-Verlag

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          Abstract

          Rare disruptions of FOXP2 have been strongly implicated in deficits in language development. Research over the past decade has suggested a role in the formation of underlying neural circuits required for speech. Until recently no evidence existed to suggest that the closely related FOXP1 gene played a role in neurodevelopmental processes. However, in the last few years, novel rare disruptions in FOXP1 have been reported in multiple cases of cognitive dysfunction, including intellectual disability and autism spectrum disorder, together with language impairment. As FOXP1 and FOXP2 form heterodimers for transcriptional regulation, one may assume that they co-operate in common neurodevelopmental pathways through the co-regulation of common targets. Here we compare the phenotypic consequences of FOXP1 and FOXP2 impairment, drawing on well-known studies from the past as well as recent exciting findings and consider what these tell us regarding the functions of these two genes in neural development.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00439-012-1193-z) contains supplementary material, which is available to authorized users.

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          Most cited references72

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          Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

          Evidence for the etiology of autism spectrum disorders (ASD) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity 1,2 . We sequenced the exomes of 20 sporadic cases of ASD and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, of which 11 were protein-altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4/20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A, and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 mutation and provide functional support for a multihit model for disease risk 3 . Our results demonstrate that trio-based exome sequencing is a powerful approach for identifying novel candidate genes for ASD and suggest that de novo mutations may contribute substantially to the genetic risk for ASD.
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            A forkhead-domain gene is mutated in a severe speech and language disorder.

            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.
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              An atlas of combinatorial transcriptional regulation in mouse and man.

              Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution. (c) 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                claire.bacon@med.uni-heidelberg.de
                +49-6221-565059 , +49-6221-565155 , gudrun.rappold@med.uni-heidelberg.de
                Journal
                Hum Genet
                Hum. Genet
                Human Genetics
                Springer-Verlag (Berlin/Heidelberg )
                0340-6717
                1432-1203
                27 June 2012
                27 June 2012
                November 2012
                : 131
                : 11
                : 1687-1698
                Affiliations
                Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
                Article
                1193
                10.1007/s00439-012-1193-z
                3470686
                22736078
                13171c1c-5c32-4021-8e2c-2309def49411
                © The Author(s) 2012
                History
                : 18 May 2012
                : 11 June 2012
                Categories
                Review Paper
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2012

                Genetics
                Genetics

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