Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy
Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy
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DOI：
10.1016/j.ajhg.2021.04.001
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发表时间：
2021-05-06
影响因子：
9.8
通讯作者：
Reymond, Alexandre
中科院分区：
文献类型：
--
作者：
Voisin, Norine;Schnur, Rhonda E.;Reymond, Alexandre
ALF转录因子旁系同源物AFF 1、AFF 2、AFF 3和AFF 4是调节参与神经发生和发育的基因表达的转录超延伸复合物的组分。我们描述了一种常染色体显性遗传病，与AFF 3降解决定子中的新生错义变体相关，AFF 3是一种对它与泛素连接酶结合很重要的9个氨基酸序列，或与该区域的新生缺失相关。我们确定的16名受影响的个体，沿着2名先前报告的个体，呈现可识别的异常模式，我们将其命名为KINSSHIP综合征（KI为马蹄肾，NS为Nievergelt/Savarirayan型中肢发育不良，S为癫痫发作，H为增生，I为智力残疾，P为肺部受累），部分与AFF 4相关的CHOPS综合征重叠。而纯合子Aff 3基因敲除小鼠显示骨骼异常，肾脏缺陷，脑畸形，神经系统异常，敲入动物建模的微缺失和最常见的错义变体之一，在受影响的个人提出下mesomelic肢体畸形，如KINSSHIP影响的个人和早期致死性，分别。在斑马鱼中过量表达AFF 3导致体轴异常，为AFF 3含量增加的病理效应提供了一定的支持。AFF 3和AFF 4相关综合征的唯一部分表型重叠和先前发表的ALF转录因子的转录组分析表明，这些因子不是多余的，每个因子都对正常发育有独特的贡献。
The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.