Vernes et al. The eventual outcome at the organ or organism level may in turn be modulated by the ability of downstream genes and proteins to compensate for these variations. We can therefore view CNTNAP2 as a neuronal buffer; subtle disruptions of this gene alone may be insufficient to cause disorder but may place a critical load on neurological systems, which manifest in different ways depending on the nature of additional load factors. Once a critical threshold of load is exceeded, it is likely that neurological imbalance will ensue. These phased investigations were performed using the SLIC sample, as described above [ 53 ].
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Vernes et al. The eventual outcome at the organ or organism level may in turn be modulated by the ability of downstream genes and proteins to compensate for these variations. We can therefore view CNTNAP2 as a neuronal buffer; subtle disruptions of this gene alone may be insufficient to cause disorder but may place a critical load on neurological systems, which manifest in different ways depending on the nature of additional load factors.
Once a critical threshold of load is exceeded, it is likely that neurological imbalance will ensue. These phased investigations were performed using the SLIC sample, as described above [ 53 ]. Genome-wide linkage analyses in these families revealed a strong and consistent linkage signal on chromosome 16q with a measure of non-word repetition [ 53 , 67 - 69 ].
Individuals carrying risk alleles at both these loci had an average non-word repetition score more than 1 SD below those carrying homozygous non-risk alleles. Although this does not preclude the presence of a genuine association, as it may be caused by differences in linkage disequilibrium patterns, it does highlight the need for careful interpretation of this result as well as for further replication in additional cohorts.
Both ATP2C2 and CMIP show expression in the brain and, although little is known about their role in this tissue, hypothetical links can be made between their putative functions and language and memory-related processes. The CMIP protein forms part of the cellular scaffold linking the plasma membrane to the cytoskeleton [ 71 ], and cytoskeletal remodeling represents a critical step in neuronal migration and synaptic formation processes.
ATP2C2 is responsible for the removal of calcium and manganese from the cytosol into the Golgi body [ 74 ]. Calcium is an important ion in the regulation of many neuronal processes, including working memory, synaptic plasticity and neuronal motility [ 75 ], and manganese dysregulation has been linked to neurological disorders [ 76 ].
Interestingly, in a recent meta-analysis of genetic data for ADHD, which shows significant co-morbidity with SLI, chromosome 16q was highlighted as the most consistently linked region for this disorder [ 77 ]. Concurrent genome-wide association studies described significant association with a variant in ATP2C2 [ 78 ], reinforcing the fact that, as discussed above, the correlation between genetic susceptibility and surface phenotype is far from straightforward.
The characterization of these factors will not only provide definitive evidence for the involvement of these genes but may also lead to the identification of further neurological pathways that contribute to language acquisition. Given the proposed reliance of non-word repetition performance on short-term memory ability, one can postulate that the investigation of ATP2C2 and CMIP may provide a biological link between memory-related pathways and language acquisition.
The fact that neither ATP2C2 nor CMIP have been identified as downstream targets of FOXP2 suggests that the eventual combination of information from converging routes of investigation will enable the characterization of overlapping and interacting neurological systems that serve the acquisition of language. Conclusions The past few years have seen exciting progress in the genetics of language impairment.
The increased knowledge of the FOXP2-dependent molecular networks has enabled the identification of brain regions and pathways that this gene may influence. Although FOXP2 mutations seem to contribute to only a relatively small number of language disorder cases, it seems likely that variations in the genes it controls, such as CNTNAP2, may be implicated in common forms of language impairment.
Thus, as our understanding of downstream targets grows, so will our list of potential candidate genes for SLI. The association of CNTNAP2 variations with an array of developmental disorders indicates that alternative deficits may arise from the dysfunction of a neurological network, demonstrating the complexity of brain development processes. Thus, although language is unique to humans, we should not necessarily expect the pathways underlying it to be exclusive to humans.
Processes such as memory and motor skills have key roles in language development, but they are certainly not specific to, and may not be completely essential for, language acquisition. Rather, we expect that a variety of pre-existing and diverse neurological pathways have been adapted to promote the development of human language [ 79 ]. Characterization of these pathways and the way they overlap and interact will be an enormous task but one that is becoming increasingly feasible thanks to advances in genetic techniques.
Nonetheless, this is a worthwhile endeavor, as a better understanding of the causes of SLI will allow the development of better diagnostic systems and therapies for affected individuals. Furthermore, it is clear that the achievement of the ultimate goal - the elucidation of a genetic network underpinning language processes - will have an impact on our understanding not only of language impairment and acquisition, but also of human development, brain function and the neuropathology of associated developmental disorders.
Competing interests The authors declare that they have no competing interests. All authors read the final manuscript and agreed its content before publication. After working with APM on the identification of FOXP2, he became head of his own laboratory, which uses state-of-the-art methods to uncover how language-related genes influence the brain at multiple levels. His group works in two main areas: the genetics of neurodevelopmental disorders, including complex genetic diseases such as autism, specific language impairment and developmental dyslexia; and the positional cloning and functional characterization of monogenic neurological diseases, including chorea acanthocytosis, speech and language disorder and Menkes disease.
All three authors are members of the SLI Consortium. Acknowledgements We thank the patients and families who contributed DNA to these research projects. APM is funded by the Wellcome Trust. References Pinker S. London: Allen Lane; Is specific language impairment a valid diagnostic category? Genetic and psycholinguistic evidence. Language and independence in adolescents with and without a history of specific language impairment SLI.
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Annu Rev Psych. Common disorders are quantitative traits. Nat Rev Genet. The genetic bases of speech sound disorders: evidence from spoken and written language.
The genetic lexicon of dyslexia. Annu Rev Genomics Hum Genet. Genes, cognition, and communication: insights from neurodevelopmental disorders. Ann N Y Acad Sci. A forkhead-domain gene is mutated in a severe speech and language disorder. Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. FOXP2 is not a major susceptibility gene for autism or specific language impairment.
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Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2. Am J Med Genet A. Deletion of 7q Language features in a mother and daughter of a chromosome 7;13 translocation involving FOXP2.
Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders. Foxp2 and Foxp1 cooperatively regulate lung and esophagus development.
FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Expression of Foxp2, a gene involved in speech and language, in the developing and adult striatum. J Neurosci Res. Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Generation of mice with a conditional Foxp2 null allele. Ultrasonic vocalization impairment of Foxp2 RH knockin mice related to speech-language disorder and abnormality of Purkinje cells.
Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits. Curr Biol. Modified sound-evoked brainstem potentials in Foxp2 mutant mice. Brain Res. FoxP2 expression in avian vocal learners and non-learners. J Neurosci.
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Publication:The Quintessential Human
Metrics details Abstract Specific language impairment SLI is defined as an unexpected and persistent impairment in language ability despite adequate opportunity and intelligence and in the absence of any explanatory medical conditions. Over the past few years, investigations have begun to uncover genetic factors that may contribute to susceptibility to language impairment. Here, we describe the different ways in which these genes were identified as candidates for language impairment. We discuss how characterization of these genes, and the pathways in which they are involved, may enhance our understanding of language disorders and improve our understanding of the biological foundations of language acquisition. Introduction Language is a quintessential human trait that, for the most part, proceeds along a recognized trajectory with minimal explicit instruction [ 1 ]. In some cases, however, language acquisition is not so straightforward and language ability is delayed or permanently impaired.