Publications

Abstract

Mutations in the human FOXP2 gene cause impaired speech development and linguistic deficits, which have been best characterised in a large pedigree called the KE family. The encoded protein is highly conserved in many vertebrates and is expressed in homologous brain regions required for sensorimotor integration and motor-skill learning, in particular corticostriatal circuits. Independent studies in multiple species suggest that the striatum is a key site of FOXP2 action. Here, we used in vivo recordings in awake-behaving mice to investigate the effects of the KE-family mutation on the function of striatal circuits during motor-skill learning. We uncovered abnormally high ongoing striatal activity in mice carrying an identical mutation to that of the KE family. Furthermore, there were dramatic alterations in striatal plasticity during the acquisition of a motor skill, with most neurons in mutants showing negative modulation of firing rate, starkly contrasting with the predominantly positive modulation seen in control animals. We also observed striking changes in the temporal coordination of striatal firing during motor-skill learning in mutants. Our results indicate that FOXP2 is critical for the function of striatal circuits in vivo, which are important not only for speech but also for other striatal-dependent skills.

Abstract

Heterozygous mutations of the human FOXP2 transcription factor gene cause the best-described examples of monogenic speech and language disorders. Acquisition of proficient spoken language involves auditory-guided vocal learning, a specialized form of sensory-motor association learning. The impact of etiological Foxp2 mutations on learning of auditory-motor associations in mammals has not been determined yet. Here, we directly assess this type of learning using a newly developed conditioned avoidance paradigm in a shuttle-box for mice. We show striking deficits in mice heterozygous for either of two different Foxp2 mutations previously implicated in human speech disorders. Both mutations cause delays in acquiring new motor skills. The magnitude of impairments in association learning, however, depends on the nature of the mutation. Mice with a missense mutation in the DNA-binding domain are able to learn, but at a much slower rate than wild type animals, while mice carrying an early nonsense mutation learn very little. These results are consistent with expression of Foxp2 in distributed circuits of the cortex, striatum and cerebellum that are known to play key roles in acquisition of motor skills and sensory-motor association learning, and suggest differing in vivo effects for distinct variants of the Foxp2 protein. Given the importance of such networks for the acquisition of human spoken language, and the fact that similar mutations in human FOXP2 cause problems with speech development, this work opens up a new perspective on the use of mouse models for understanding pathways underlying speech and language disorders.

Abstract

Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder, and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterisation of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300bp to -177bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, whilst a region -982bp to -301bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by FOXP2, a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia (DVD). Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.

Abstract

Corrigendum to CNTNAP2 variants affect early language development in the general population A. J. O. Whitehouse, D. V. M. Bishop, Q. W. Ang, C. E. Pennell and S. E. Fisher Genes Brain Behav (2011) doi: 10.1111/j.1601-183X.2011.00684.x. The authors have detected a typographical error in the Abstract of this paper. The error is in the fifth sentence, which reads: ‘‘On the basis of these findings, we performed analyses of four-marker haplotypes of rs2710102–rs759178–rs17236239–rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype GCAG,P = .0014).’’ Rather than ‘‘GCAG’’, the final haplotype should read ‘‘CGAG’’. This typographical error was made in the Abstract only and this has no bearing on the results or conclusions of the study, which remain unchanged. Reference Whitehouse, A. J. O., Bishop, D. V. M., Ang, Q. W., Pennell, C. E. & Fisher, S. E. (2011) CNTNAP2 variants affect early language development in the general population. Genes Brain Behav 10, 451–456. doi: 10.1111/j.1601-183X.2011.00684.x.

Abstract

Several quantitative trait loci (QTLs) that influence developmental dyslexia (reading disability [RD]) have been mapped to chromosome regions by linkage analysis. The most consistently replicated area of linkage is on chromosome 6p23-21.3. We used association analysis in 223 siblings from the United Kingdom to identify an underlying QTL on 6p22.2. Our association study implicates a 77-kb region spanning the gene TTRAP and the first four exons of the neighboring uncharacterized gene KIAA0319. The region of association is also directly upstream of a third gene, THEM2. We found evidence of these associations in a second sample of siblings from the United Kingdom, as well as in an independent sample of twin-based sibships from Colorado. One main RD risk haplotype that has a frequency of ∼12% was found in both the U.K. and U.S. samples. The haplotype is not distinguished by any protein-coding polymorphisms, and, therefore, the functional variation may relate to gene expression. The QTL influences a broad range of reading-related cognitive abilities but has no significant impact on general cognitive performance in these samples. In addition, the QTL effect may be largely limited to the severe range of reading disability.

Abstract

Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are common highly heritable disorders of childhood, which frequently co-occur. Data from twin and family studies suggest that this overlap is, in part, due to shared genetic underpinnings. Here, we report the first genome-wide linkage analysis of measures of reading ability in children with ADHD, using a sample of 233 affected sibling pairs who previously participated in a genome-wide scan for susceptibility loci in ADHD. Quantitative trait locus (QTL) analysis of a composite reading factor defined from three highly correlated reading measures identified suggestive linkage (multipoint maximum lod score, MLS>2.2) in four chromosomal regions. Two regions (16p, 17q) overlap those implicated by our previous genome-wide scan for ADHD in the same sample: one region (2p) provides replication for an RD susceptibility locus, and one region (10q) falls approximately 35 cM from a modestly highlighted region in an independent genome-wide scan of siblings with ADHD. Investigation of an individual reading measure of Reading Recognition supported linkage to putative RD susceptibility regions on chromosome 8p (MLS=2.4) and 15q (MLS=1.38). Thus, the data support the existence of genetic factors that have pleiotropic effects on ADHD and reading ability--as suggested by shared linkages on 16p, 17q and possibly 10q--but also those that appear to be unique to reading--as indicated by linkages on 2p, 8p and 15q that coincide with those previously found in studies of RD. Our study also suggests that reading measures may represent useful phenotypes in ADHD research. The eventual identification of genes underlying these unique and shared linkages may increase our understanding of ADHD, RD and the relationship between the two.

Abstract

Specific language impairment (SLI) is defined as an unexplained failure to acquire normal language skills despite adequate intelligence and opportunity. We have reported elsewhere a full-genome scan in 98 nuclear families affected by this disorder, with the use of three quantitative traits of language ability (the expressive and receptive tests of the Clinical Evaluation of Language Fundamentals and a test of nonsense word repetition). This screen implicated two quantitative trait loci, one on chromosome 16q (SLI1) and a second on chromosome 19q (SLI2). However, a second independent genome screen performed by another group, with the use of parametric linkage analyses in extended pedigrees, found little evidence for the involvement of either of these regions in SLI. To investigate these loci further, we have collected a second sample, consisting of 86 families (367 individuals, 174 independent sib pairs), all with probands whose language skills are ⩾1.5 SD below the mean for their age. Haseman-Elston linkage analysis resulted in a maximum LOD score (MLS) of 2.84 on chromosome 16 and an MLS of 2.31 on chromosome 19, both of which represent significant linkage at the 2% level. Amalgamation of the wave 2 sample with the cohort used for the genome screen generated a total of 184 families (840 individuals, 393 independent sib pairs). Analysis of linkage within this pooled group strengthened the evidence for linkage at SLI1 and yielded a highly significant LOD score (MLS = 7.46, interval empirical P<.0004). Furthermore, linkage at the same locus was also demonstrated to three reading-related measures (basic reading [MLS = 1.49], spelling [MLS = 2.67], and reading comprehension [MLS = 1.99] subtests of the Wechsler Objectives Reading Dimensions).

Abstract

We completed fine mapping of nine positional candidate regions for attention-deficit/hyperactivity disorder (ADHD) in an extended population sample of 308 affected sibling pairs (ASPs), constituting the largest linkage sample of families with ADHD published to date. The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in our sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=.024) and 17p11 (MLS 3.63; empiric P=.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions—5p13, 6q12, 16p13, and 17p11—are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size.

Abstract

Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.