De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder
De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder
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DOI：
10.1016/j.ajhg.2018.07.003
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发表时间：
2018-08-02
影响因子：
9.8
通讯作者：
Zweier, Christiane
中科院分区：
文献类型：
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作者：
Gregor, Anne;Sadleir, Lynette G.;Zweier, Christiane
下一代测序与国际数据共享相结合，极大地促进了新的疾病相关基因和突变的识别。对于遗传上极其异质的实体，如神经发育障碍（NDD），尤其如此。通过外显子组测序和全球范围的合作，我们鉴定并组装了20个FBXO 11中具有从头变异的个体。他们表现出与一系列特征相关的轻度至重度发育迟缓，包括身材矮小（4/20）或高大（2/20）、肥胖（5/20）、小头畸形（4/19）或大头畸形（2/19）、行为问题（17/20）、癫痫发作（5/20）、唇腭裂或双悬雍垂（3/20）和轻微骨骼异常。FBXO 11编码F-Box蛋白家族的成员，构成E3-泛素连接酶复合物的亚基。这种复合物参与泛素化和蛋白酶体降解，从而通过调节蛋白质周转来控制关键的生物过程。鉴定的从头畸变包括两个大的缺失，10个可能的基因破坏变体和8个分布在整个FBXO 11的错义变体。位于CASH或锌指UBR结构域的错义变体的结构建模表明蛋白质的不稳定。这一点，结合观察到的光谱和定位的确定的变体和缺乏明显的基因型-表型相关性，是兼容的功能丧失或单倍不足的潜在机制。我们牵连从头错义和可能的基因破坏FBXO 11变异的神经发育障碍与变量智力残疾和各种其他功能。
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.