Département de Génétique, Hôpital Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, Paris, France.
Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
J Med Genet. 2021 Mar;58(3):205-212. doi: 10.1136/jmedgenet-2019-106335. Epub 2020 May 19.
Ubiquitination has a central role in numerous biological processes, including cell development, stress responses and ageing. Perturbed ubiquitination has been implicated in human diseases ranging from cancer to neurodegenerative diseases. encodes a RING-type E3 ubiquitin ligase involved in protein ubiquitination. Among numerous other roles, SIAH1 regulates metabotropic glutamate receptor signalling and affects neural cell fate. Moreover, SIAH1 positively regulates Wnt signalling through ubiquitin-mediated degradation of Axin and accumulation of β-catenin.
Trio exome sequencing followed by Sanger validation was undertaken in five individuals with syndromic developmental delay. Three-dimensional structural modelling was used to predict pathogenicity of affected residues. Wnt stimulatory activity was measured by luciferase reporter assays and Axin degradation assays in HEK293 cells transfected with wild-type and mutant SIAH1 expression plasmids.
We report five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia, in whom exome sequencing identified de novo monoallelic variants in . In silico protein modelling suggested alteration of conserved functional sites. In vitro experiments demonstrated loss of Wnt stimulatory activity with the SIAH1 mutants, suggesting variant pathogenicity.
Our results lend support to as a candidate Mendelian disease gene for a recognisable syndrome, further strengthening the connection between and neurodevelopmental disorders. Furthermore, the results suggest that dysregulation of the Wnt/β-catenin pathway may be involved in the pathogenesis.
泛素化在许多生物过程中起着核心作用，包括细胞发育、应激反应和衰老。失调的泛素化与从癌症到神经退行性疾病等人类疾病有关。编码一种参与蛋白质泛素化的 RING 型 E3 泛素连接酶。在众多其他作用中，SIAH1 调节代谢型谷氨酸受体信号转导，并影响神经细胞命运。此外，SIAH1 通过泛素介导的 Axin 降解和β-catenin 积累正向调节 Wnt 信号。
对五名综合征性发育迟缓个体进行了外显子组测序，随后进行 Sanger 验证。三维结构建模用于预测受影响残基的致病性。通过转染野生型和突变 SIAH1 表达质粒的 HEK293 细胞中的荧光素酶报告基因测定和 Axin 降解测定来测量 Wnt 刺激活性。
我们报道了五名无亲缘关系的个体，他们具有发育迟缓、婴儿性低张力、发育异常和喉软化的共同特征，在外显子组测序中发现了新的单等位基因变异。体内蛋白质建模表明保守功能位点发生改变。体外实验表明，SIAH1 突变体的 Wnt 刺激活性丧失，提示变异的致病性。
我们的结果支持 作为一种可识别综合征的候选孟德尔疾病基因，进一步加强了 与神经发育障碍之间的联系。此外，结果表明 Wnt/β-catenin 途径的失调可能参与发病机制。
