BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription.
BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription.
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DOI：
10.1016/j.ajhg.2016.05.030
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发表时间：
2016-08-04
影响因子：
9.8
通讯作者：
Logan DW
中科院分区：
文献类型：
--
作者：
Dias C;Estruch SB;Graham SA;McRae J;Sawiak SJ;Hurst JA;Joss SK;Holder SE;Morton JE;Turner C;Thevenon J;Mellul K;Sánchez-Andrade G;Ibarra-Soria X;Deriziotis P;Santos RF;Lee SC;Faivre L;Kleefstra T;Liu P;Hurles ME;DDD Study;Fisher SE;Logan DW
智力残疾(ID)是一种常见的疾病，具有相当大的遗传异质性。下一代大型队列测序已经确定了越来越多的与ID有关的基因，但它们在神经发育中的作用在很大程度上仍未被探索。在这里，我们报告了一例ID综合征，由BCL11A的从头杂合错义、无义和移码突变引起，BCL11A编码一个转录因子，该转录因子是BAF Swi/SNF染色质重塑复合体的假定成员。使用一种综合的方法来模拟ID疾病，包括人类细胞分析和小鼠的行为、神经解剖学和分子表型，我们为表型效应提供了多条功能证据。病原学错义变异聚集在人BCL11A的氨基末端区域，我们证明它们都扰乱了BCL11A的定位、二聚化和转录调节活性，与功能丧失一致。我们发现，小鼠的BCL11A单倍体缺陷会导致认知障碍、社会行为异常和小头畸形，符合人类的表型。此外，我们还鉴定了这些小鼠模型的大脑皮层和海马区共有的异常转录图谱。因此，我们的工作表明BCL11A单倍体功能不全与神经发育障碍有关，并定义了该基因调控的其他靶点，这与我们对ID和相关综合征的理解具有广泛的相关性。
Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.