Investigation of the roles of CMIP and ATP2C2 in Specific Language Impairment (SLI).

Specific Language Impairment (or SLI) is diagnosed in children who have problems learning to use or understand language despite normal intelligence and otherwise typical development. We know that SLI runs in families and is a complex genetic disorder. This means that some individuals carry certain gene combinations that, when accompanied by particular environmental factors, make them particularly sensitive to language deficits. It is assumed that these variations subtly alter the function of proteins important for brain development. Our team at the Wellcome Trust Centre for Human Genetics in Oxford has recently identified two genes that contribute to SLI susceptibility. I am asking for a grant to characterise these genes and the DNA sequence around them. This research will allow the identification of specific genetic elements that cause predisposition to SLI and help us to discover which protein networks are important in this process. An understanding of these systems will help the early identification of affected individuals and allow the design of better speech therapy programs. In addition, this information may also be useful for the study of related developmental disorders (such as dyslexia) and the characterisation of normal language acquisition.

Specific Language Impairment (SLI) is diagnosed in children who experience profound language deficits despite otherwise normal development and in the absence of any obvious explanatory factors. Our previous research has identified association between SNPs in two genes on chromosome 16 (CMIP and ATP2C2) and a quantitative measure of language ability, nonword repetition. This test involves the repetition of nonsensical words and is particularly problematic for individuals with SLI, leading to the postulation that this disorder may be caused by a phonological short-term memory deficit. The primary aim of the proposed project is to identify the specific causal variants that underlie the association on chromosome 16. This will be achieved by a multifaceted approach involving variant cataloguing, bioinformatic analyses, mutation screening, expression (and, if necessary, post-transcriptional) assays and functional characterisation. Initial investigations aim to take advantage of recent advances in sequencing technologies to catalogue variants across the 3Mb region of association. The putative function of identified variants will be investigated in-silico exploiting available information from relevant experiments such as expression-QTL databases, chromatin immunoprecipitation assays and cross-species sequencing. Identified variants will be genotyped in our family-based SLI sample and subjected to quantitative association analyses. Concurrent high-throughput sequencing of proband DNA will enable the identification of causative mutations or allow the detection of an increased mutational load. Complementary expression assays will focus the attention of the study to the modulation of specific transcripts. The amalgamation of the information yielded by these various routes of investigation will allow the generation of a ‘short-list‘ of possible causative variants that will subsequently verified in-vitro. The techniques applied in these stages will be particular to the variants in hand but are likely to involve the generation of luciferase reporter vectors, Electrophoretic Mobility Shift Assays (EMSAs), immunocytochemistry and RNAi. The information arising from this investigation will highlight specific variants and mechanisms which underlie the association between the genetic sequence on chromosome 16 and nonword repetition performance. This, in turn, will allow the formation of functional hypotheses that will direct future studies of SLI and related disorders. Ultimately, the data generated from this project will inform our understanding of the biological basis of language impairment and language acquisition. An understanding of these systems will help the early identification of affected individuals and allow the design of better diagnostic programs and intervention therapies and may have wider implications for the study and treatment of associated developmental disorders.