Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.
Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.
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Sin3/HDAC 辅阻遏物复合体成员 SIN3B 的单倍体不足会导致综合征性智力障碍/自闭症谱系障碍。
DOI：
10.1016/j.ajhg.2021.03.017
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发表时间：
2021
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
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作者：
Latypova,Xenia;Vincent,Marie;Mollé,Alice;Adebambo,OluwadamilareA;Fourgeux,Cynthia;Khan,TahirN;Caro,Alfonso;Rosello,Monica;Orellana,Carmen;Niyazov,Dmitriy;Lederer,Damien;Deprez,Marie;Capri,Yline;Kannu,Peter;Tabet,AnneClaude;
参与转录调控的蛋白质在神经发育障碍中具有丰富的突变。 Sin3（Swi 独立 3）/组蛋白脱乙酰酶 (HDAC) 复合物在组蛋白脱乙酰化和转录抑制中发挥核心作用。在编码 Sin3 复合体的两种脊椎动物旁系同源物中，SIN3A 变体会导致综合征性智力障碍，但 SIN3B 单倍体缺陷在人类中的临床后果尚不清楚。在这里，我们描述了一种以智力障碍、发育迟缓和面部特征畸形为特征的综合征，伴有不同程度的渗透性自闭症谱系障碍、先天畸形、胼胝体缺陷和破坏性 SIN3B 变异引起的生长受损。使用染色体微阵列或外显子组测序，并通过国际数据共享工作，我们鉴定了 9 名具有杂合 SIN3B 缺失或单核苷酸变异的个体。五个个体含有包含 SIN3B 的杂合缺失，该杂合缺失位于 19p13.11 上约 230 kb 的最小重叠区域内，两个个体具有罕见的非同义替换，两个个体具有单核苷酸缺失，导致移码和预测的过早终止密码子。为了测试 SIN3Bimpairment 与人类表型可测量方面的相关性，我们通过基因组编辑和瞬时抑制破坏了直系同源斑马鱼基因座。突变体和变形幼虫表现出颅面图案改变、连合轴突缺陷和体长缩短，这支持了 Sin3 功能在前部结构生长和图案形成中的重要作用。为了进一步研究 SIN3B 变体的分子后果，我们使用 H3K27ac ChIP-seq 量化了全基因组增强子和启动子活性状态。我们发现，与 SIN3A 突变类似，SIN3B 破坏会导致外周血单核细胞中增强子和启动子子集的过度乙酰化。总之，这些数据表明 SIN3B 单倍体不足会导致迄今为止未知的智力障碍/自闭症综合征，揭示了 SIN3B 在中枢神经系统中的关键作用，并定义了与 Sin3 复合体损伤相关的表观遗传景观。
Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex,SIN3Avariants cause syndromic intellectual disability, but the clinical consequences ofSIN3Bhaploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptiveSIN3Bvariants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygousSIN3Bdeletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassingSIN3Bthat reside within a ∼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance ofSIN3Bimpairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences ofSIN3Bvariants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar toSIN3Amutations,SIN3Bdisruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate thatSIN3Bhaploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role ofSIN3Bin the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.