A novel UBE3A sequence variant identified in eight related individuals with neurodevelopmental delay, results in a phenotype which does not match the clinical criteria of Angelman syndrome.
A novel UBE3A sequence variant identified in eight related individuals with neurodevelopmental delay, results in a phenotype which does not match the clinical criteria of Angelman syndrome.
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DOI：
10.1002/mgg3.1481
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发表时间：
2020-11
影响因子：
2
通讯作者：
Valstar M
中科院分区：
文献类型：
--
作者：
Geerts-Haages A;Bossuyt SNV;den Besten I;Bruggenwirth H;van der Burgt I;Yntema HG;Punt AM;Brooks A;Elgersma Y;Distel B;Valstar M
UBE3A（一种 E3 蛋白泛素连接酶）功能丧失会导致 Angelman 综合征 (AS)，这是一种神经发育障碍，其特征为严重发育迟缓、言语障碍、癫痫、运动或平衡障碍以及特征性行为模式。我们在一个有 8 名受影响个体的大家庭中发现了一种新的 UBE3A 序列变异，这些个体不符合临床 AS 标准。进行了详细的临床检查和遗传分析，以确定表型多样性和遗传原因。突变体 UBE3A 蛋白的功能根据其亚细胞定位、稳定性和 E3 泛素连接酶活性进行了评估。所有八名受影响的个体都显示出一种新的母系遗传的 UBE3A 序列变异 (NM_130838.4(UBE3A):c.1018‐1020del, p.(Asn340del)，这符合遗传性 AS 诊断。尽管他们表现出中度至重度智力障碍，但表型与 AS 的临床标准不符。与此相符，UBE3A p.Asn340del 的功能分析突变蛋白显示 UBE3A 蛋白定位、稳定性或 E3 泛素连接酶活性没有重大缺陷，p.(Asn340del) 突变蛋白的行为与之前描述的 UBE3A 中的 AS 连锁错义突变明显不同，并且导致与 AS 显着不同的表型。我们报告了与 UBE3A 丢失、重复或突变相关的表型范围。我们发现 p.Asn340del 突变蛋白的行为与之前描述的 UBE3A 中天使综合征 (AS) 相关的错义突变明显不同，并且导致与 AS 临床标准不符的表型。这项研究进一步扩展了与 UBE3A 缺失、重复相关的表型范围。或突变。
Loss of functional UBE3A, an E3 protein ubiquitin ligase, causes Angelman syndrome (AS), a neurodevelopmental disorder characterized by severe developmental delay, speech impairment, epilepsy, movement or balance disorder, and a characteristic behavioral pattern. We identified a novel UBE3A sequence variant in a large family with eight affected individuals, who did not meet the clinical AS criteria. Detailed clinical examination and genetic analysis was performed to establish the phenotypic diversity and the genetic cause. The function of the mutant UBE3A protein was assessed with respect to its subcellular localization, stability, and E3 ubiquitin ligase activity. All eight affected individuals showed the presence of a novel maternally inherited UBE3A sequence variant (NM_130838.4(UBE3A):c.1018‐1020del, p.(Asn340del), which is in line with a genetic AS diagnosis. Although they presented with moderate to severe intellectual disability, the phenotype did not match the clinical criteria for AS. In line with this, functional analysis of the UBE3A p.Asn340del mutant protein revealed no major deficits in UBE3A protein localization, stability, or E3 ubiquitin ligase activity. The p.(Asn340del) mutant protein behaves distinctly different from previously described AS‐linked missense mutations in UBE3A, and causes a phenotype that is markedly different from AS. This study further extends the range of phenotypes that are associated with UBE3A loss, duplication, or mutation. We report on the clinical phenotype and functional characterization of a novel maternally‐inherited UBE3A sequence variant, p.Asn340del, that was identified in a large family with eight affected individuals. We show that the p.Asn340del mutant protein behaves distinctly different from previously described Angelman syndrome (AS)‐linked missense mutations in UBE3A, and causes a phenotype that does not match the clinical criteria for AS. This study further extends the range of phenotypes that are associated with UBE3A loss, duplication or mutation.
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影响因子：
3.9
作者：
MARSHBURN, EC;AMAN, MG
通讯作者：
AMAN, MG
影响因子：
5.2
作者：
Gillessen-Kaesbach, G;Demuth, S;Horsthemke, B
通讯作者：
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影响因子：
2.5
作者：
Burette, Alain C.;Judson, Matthew C.;Burette, Susan;Phend, Kristen D.;Philpot, Benjamin D.;Weinberg, Richard J.
通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
Schinzel, A