Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 359, Issue 22, Pages 2337-2345Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa0802828
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Funding
- Wellcome Trust
- Autism Speaks
- National Institute of Mental Health [MH75028-R21, MH081754-RO1, MH60233-R37, HD055784-P50]
- Christopher Welch Biological Sciences Scholarship
- University of Oxford
- Tourette Syndrome Association
- Marie Curie Intra-European Fellowship
- Wellcome Trust Principal Research Fellow
- MRC [MC_U137761449] Funding Source: UKRI
- Medical Research Council [MC_U137761449] Funding Source: researchfish
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Background: Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment. Methods: We performed genomic screening for regions bound by FOXP2 using chromatin immunoprecipitation, which led us to focus on one particular gene that was a strong candidate for involvement in language impairments. We then tested for associations between single-nucleotide polymorphisms (SNPs) in this gene and language deficits in a well-characterized set of 184 families affected with specific language impairment. Results: We found that FOXP2 binds to and dramatically down-regulates CNTNAP2, a gene that encodes a neurexin and is expressed in the developing human cortex. On analyzing CNTNAP2 polymorphisms in children with typical specific language impairment, we detected significant quantitative associations with nonsense-word repetition, a heritable behavioral marker of this disorder (peak association, P=5.0 x 10(-5) at SNP rs17236239). Intriguingly, this region coincides with one associated with language delays in children with autism. Conclusions: The FOXP2-CNTNAP2 pathway provides a mechanistic link between clinically distinct syndromes involving disrupted language.
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