A functional genetic link between distinct developmental language disorders.
A functional genetic link between distinct developmental language disorders.
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DOI：
10.1056/nejmoa0802828
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发表时间：
2008-11-27
期刊：
影响因子：
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通讯作者：
Fisher SE
中科院分区：
文献类型：
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作者：
Vernes SC;Newbury DF;Abrahams BS;Winchester L;Nicod J;Groszer M;Alarcón M;Oliver PL;Davies KE;Geschwind DH;Monaco AP;Fisher SE
影响FOXP 2转录因子的罕见突变导致单基因言语和语言障碍。我们假设FOXP 2下游的神经通路影响更常见的表型，如特定的语言障碍。我们使用染色质免疫沉淀法对FOXP 2结合的区域进行了基因组筛选，这使我们专注于一个特定的基因，该基因是参与语言障碍的强有力的候选基因。然后，我们在一组184个受特定语言障碍影响的家庭中检测了该基因的单核苷酸多态性（SNP）与语言障碍之间的关联。我们发现FOXP 2与CNTNAP 2结合并显著下调CNTNAP 2，CNTNAP 2是一种编码neurexin并在发育中的人类皮层中表达的基因。在分析典型的特定语言障碍儿童的CNTNAP 2多态性时，我们检测到与无意义词重复的显著定量关联，无意义词重复是这种障碍的遗传行为标记（峰值关联，SNP rs 17236239处P = 5.0×10-5）。有趣的是，这一区域与自闭症儿童的语言迟缓相关。FOXP 2-CNTNAP 2通路提供了涉及语言中断的临床不同综合征之间的机制联系。
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. 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. 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 = 5.0×10-5 at SNP rs17236239). Intriguingly, this region coincides with one associated with language delays in children with autism. The FOXP2-CNTNAP2 pathway provides a mechanistic link between clinically distinct syndromes involving disrupted language.