BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells
BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells
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DOI：
10.1093/brain/awy173
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发表时间：
2018-08-01
期刊：
影响因子：
14.5
通讯作者：
Kubisch, Christian
中科院分区：
文献类型：
--
作者：
Lessel, Davor;Gehbauer, Christina;Kubisch, Christian
转录因子BCL11B对神经系统和免疫系统的发育是必不可少的，而BCL11B缺乏会导致小鼠大脑结构缺陷、学习能力下降和免疫细胞发育受损。然而，BCL11B在人类中的确切作用在很大程度上尚不清楚，除了一名BCL11B错义突变患者，受到多系统异常和严重的免疫缺陷的影响。通过大规模平行测序，我们确定了13名BCL11B基因杂合性生殖系改变的患者。值得注意的是，所有这些人都受到全球发育迟缓的影响，包括言语障碍和智力残疾；然而，没有人表现出明显的免疫缺陷的临床迹象。6个移码突变、2个无义突变、1个错义突变和2个导致BCL11B表达减弱的染色体重排重新出现。另一种移码突变是从一位同样受到影响的母亲那里传播的。有趣的是，受影响最严重的患者在BCL11B的锌指结构域中存在错义突变，可能会影响DNA结合结构界面，类似于最近发表的患者。此外，大多数位于C末端的提前终止密码子突变不能挽救Bcl11b缺陷小鼠海马片培养中的祖细胞增殖缺陷。关于BCL11B在免疫系统中的作用，我们的患者的广泛免疫表型显示T细胞室的变化和缺乏外周2型固有淋巴样细胞(ILC2s)，这与在Bcl11b缺陷小鼠中描述的结果一致。对102个T淋巴细胞亚群的非监督分析表明，患者明显地与健康儿童分开，进一步支持了这种疾病的常见病因。综上所述，我们在这里表明，导致BCL11B单倍体功能不全或BCL11B蛋白截短的突变在临床上会导致非综合征神经发育延迟。此外，我们认为影响锌指结构域内特定位置的错义突变可能导致不同的和更严重的临床结果。
The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.