Bruce Heather A, Margolis Russell L
Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Hum Genet. 2002 Aug;111(2):136-44. doi: 10.1007/s00439-002-0768-5. Epub 2002 Jul 16.
FOXP2 is a transcription factor containing a polyglutamine tract, a zinc-finger motif, and a forkhead DNA-binding domain. The FOXP2 gene is located on 7q31. A missense mutation in the forkhead domain (exon 14) and a balanced reciprocal translocation t(5;7)(q22;q31.2) with a breakpoint between exons 3b and 4 have recently been associated with a speech and language disorder (SPCH1). The role of FOXP2 in this neurodevelopmental disorder suggests that mutations in FOXP2 could cause other neuropsychiatric disorders. To begin investigation of this possibility, we examined the genomic structure and CAG/CAA repeat region of FOXP2. We detected little polymorphism and no expansions in the FOXP2 CAG/CAA repeat in 142 individuals with progressive movement disorders. We found evidence of alternate splice variants and six previously undetected exons: three 5' untranslated exons (s1, s2, s3), two additional untranslated exons (2a and 2b) between exons 2 and 3, a translated exon (4a) between exons 4 and 5, and a longer version of exon 10 (10+) that contains an alternate stop codon and produces a truncated protein (FOXP2-S). Our results suggest that FOXP2 spans at least 603 kb of genomic DNA, more than twice the previously defined region, and provide evidence of a promoter region flanking exon s1. This demonstration of additional FOXP2 exons and splice variants should facilitate understanding of FOXP2 function and the search for additional FOXP2 mutations.
FOXP2是一种转录因子，包含一个多聚谷氨酰胺序列、一个锌指基序和一个叉头DNA结合结构域。FOXP2基因位于7q31。最近发现，叉头结构域（外显子14）中的一个错义突变以及一个断点位于外显子3b和4之间的平衡相互易位t(5;7)(q22;q31.2)与一种言语和语言障碍（SPCH1）有关。FOXP2在这种神经发育障碍中的作用表明，FOXP2突变可能导致其他神经精神疾病。为了开始研究这种可能性，我们检测了FOXP2的基因组结构和CAG/CAA重复区域。我们在142名进行性运动障碍患者中未检测到FOXP2 CAG/CAA重复序列的多态性，也未发现其扩增。我们发现了交替剪接变体的证据以及六个先前未检测到的外显子：三个5'非翻译外显子（s1、s2、s3）、位于外显子2和3之间的另外两个非翻译外显子（2a和2b）、位于外显子4和5之间的一个翻译外显子（4a）以及一个更长版本的外显子10（10+），该外显子包含一个交替终止密码子并产生一种截短蛋白（FOXP2-S）。我们的结果表明，FOXP2跨越至少603 kb的基因组DNA，是先前定义区域的两倍多，并提供了一个位于外显子s1侧翼的启动子区域的证据。这些额外的FOXP2外显子和剪接变体的发现应有助于理解FOXP2的功能以及寻找其他FOXP2突变。
