De Novo Mutations in FOXP1 in Cases with Intellectual Disability, Autism, and Language Impairment
De Novo Mutations in FOXP1 in Cases with Intellectual Disability, Autism, and Language Impairment
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DOI：
10.1016/j.ajhg.2010.09.017
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发表时间：
2010-11-12
影响因子：
9.8
通讯作者：
Michaud, Jacques L.
中科院分区：
文献类型：
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作者：
Hamdan, Fadi F.;Daoud, Hussein;Michaud, Jacques L.
编码叉头转录因子的FOXP2中的杂合突变已被证明会引起发育性言语运动障碍和语言障碍FOXP2及其最接近的同源物FOXP1，在对语言重要的脑区域共表达，并协同调节发育过程，提高FOXP1也可能参与与语言障碍相关的发育条件的可能性。可能性，我们在智力残疾患者中寻找FOXP1的突变，我们首先对散发性非综合征性ID（NSID）（n = 30）或ASD（n = 80）病例进行了基于阵列的基因组杂交。除了对散发性NSID（n = 110）或MD（n = 135）病例以及570例对照中FOXP 1的所有编码外显子进行测序外，发现了一个新的无义突变（c 1573C>T [p R525X]）在NSID和孤独症患者的保守叉头DNA结合域中，荧光素酶报告基因检测显示，pR525X的改变破坏了蛋白质的活性。FOXP1的新突变也表现出严重的语言障碍，情绪不稳定，伴有身体攻击性，以及特定的强迫和强迫。总之，FOXP1和FOXP2都与语言障碍有关，但前者的减少对大脑发育的影响比后者更全面
Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor have been shown to cause developmental verbal dyspraxia and language impairment FOXP2 and its closest homolog FOXP1, are coexpressed in brain regions that are Important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID mental retardation) and/or autism spectrum disorders (ASD) We first performed array based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features In addition sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or MD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c 1573C>T [p R525X]) in the conserved forkhead DNA binding domain in a patient with NSID and autism Luciferase reporter assays showed that the p R525X alteration disrupts the activity of the protein Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment mood lability with physical aggressiveness, and specific obsessions and compulsions In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter