A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD)
A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD)
复制标题
DOI：
10.1002/ajmg.a.32142
复制
发表时间：
2008-02-15
影响因子：
2
通讯作者：
Browning, Marsha
中科院分区：
文献类型：
--
作者：
Adegbola, Abidemi;Gao, Hanlin;Browning, Marsha
我们描述了一个发育迟缓和自闭症谱系障碍的非畸形患者，他在Jumonji AT丰富的交互结构域1C（JARID 1C）基因中有一个错义突变。该儿童在30个月大时首次出现刻板和重复行为，社会互惠和使用多种非语言行为受损，主要在语言领域发育迟缓。在47个月大的时候，他被诊断为自闭症，随后得到了证实。细胞遗传学和脆性X染色体研究正常。突变分析显示，JARID 1C基因外显子16中存在一种新型错义突变，导致第766位氨基酸（R766 W）精氨酸被色氨酸取代。与包括小鼠和斑马鱼同源蛋白在内的多种可用真核生物序列的序列比对分析表明，受影响的氨基酸是保守的。JARID 1C以前没有涉及自闭症易感性。最近的新分子证据表明，它是一个组蛋白去甲基化酶特异性的二-和三甲基化组蛋白3赖氨酸4（H3 K4），并作为转录抑制因子通过促进REST介导的神经元基因调控的功能。JARID 1C调控基因SCN 2A、CACNA 1H、BDNF和SLC 18 A1先前与自闭症和认知功能障碍有关。该患者使报告的JARID 1C突变总数达到14个。这种介绍既扩展了可归因于该基因突变的神经认知表型的范围，又说明了分子研究和DNA序列分析对自闭症单基因病因准确诊断的重要性。(c)2008 Wiley-Liss，Inc.
We describe a nondysmorphic patient with developmental delay and autism spectrum disorder who has a missense mutation in the Jumonji AT-rich interactive domain 1C (JARID1C) gene. This child first presented at 30 months of age with stereotyped and repetitive behaviors, impairment in social reciprocity and in the use of multiple nonverbal behaviors, and developmental delay primarily in the language domain. A diagnosis of autism was made and subsequently confirmed at the current age of 47 months. Cytogenetic and fragile X studies were normal. Mutational analysis revealed a novel missense mutation in exon 16 of the JARID1C gene that results in an arginine to tryptophan substitution at amino acid 766 (R766W). Sequence alignment analysis with Multiple available eukaryotic sequences including the homologous proteins of mouse and zebrafish demonstrated that the affected amino acid is conserved. JARID1C has not previously been implicated in autism susceptibility. Recent novel molecular evidence suggests that it is a histone demethylase specific for di- and trimethylated histone 3 lysine 4 (H3K4) and functions as a transcriptional repressor by fostering REST-mediated neuronal gene regulation. The JARID1C-regulated genes SCN2A, CACNA1H, BDNF, and SLC18A1 have previously been associated with autism and cognitive dysfunction. This patient brings the total number of reported JARID1C mutations to 14. This presentation both extends the range of neurocognitive phenotypes attributable to mutations in this gene and illustrates the importance of molecular studies and DNA sequence analysis for accurate diagnosis of monogenic causes of autism. (c) 2008 Wiley-Liss, Inc.