Jiang Yinmo, Wu Bingbing, Zhang Xi, Yang Lin, Wang Sujuan, Li Huiping, Zhou Shuizhen, Qian Yanyan, Wang Huijun
Center for Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai 201102, China.
Department of Rehabilitation, Children's Hospital of Fudan University, Shanghai 201102, China.
Children (Basel). 2024 Jul 26;11(8):897. doi: 10.3390/children11080897.
Neurodevelopmental disorders (NDDs) are a group of diseases that severely affect the physical and mental health of children. The gene encodes B56δ, the regulatory subunit of protein phosphatase 2A (PP2A). NDDs related to the gene have recently been defined as Houge-Janssens syndrome 1.
Clinical/whole exome sequencing was performed on approximately 3000 patients with NDDs from 2017 to 2023. In vitro experiments were performed to assess the impairment of variants to protein expression and the assembly of PP2A holoenzyme. The genetic information and phenotypes of the reported patients, as well as patients in this study, were summarized, and the genotype-phenotype relationship was analyzed. The probability of pathogenic missense variants in PPP2R5D was predicted using AlphaMissense (AM), and the relationship between certain phenotype and 3D protein structural features were analyzed.
Thirteen new patients carrying twelve gene variants were detected, including five novel missense variants and one novel frameshift variant. In vitro experiments revealed that the frameshift variant p.H463Mfs*3 resulted in a ~50 kDa truncated protein with lower expression level. Except for E420K and T536R, other missense variants impaired holoenzyme assembly. Furthermore, we found that pathogenic/likely pathogenic (P/LP) variants that have been reported so far were all missense variants and clustered in three conserved regions, and the likelihood of P/LP mutations located in these conserved regions was extremely high. In addition, the macrocephaly phenotype was related to negatively charged residues involved in substrate recruitment.
We reported thirteen new patients with gene variants and expanded the variant spectrum. We confirmed the pathogenicity of novel variants through in vitro experiments. Our findings in genotype-phenotype relationship provide inspiration for genetic counseling and interpretation of variants. We also provide directions for further research on the mechanism of macrocephaly phenotype.
神经发育障碍（NDDs）是严重影响儿童身心健康的一组疾病。该基因编码蛋白磷酸酶2A（PP2A）的调节亚基B56δ。最近，与该基因相关的NDDs被定义为豪格 - 扬森斯综合征1型。
对2017年至2023年期间约3000例NDDs患者进行临床/全外显子组测序。进行体外实验以评估变异体对蛋白质表达和PP2A全酶组装的损害。总结已报道患者以及本研究中患者的遗传信息和表型，并分析基因型 - 表型关系。使用AlphaMissense（AM）预测PPP2R5D中致病性错义变异的概率，并分析某些表型与3D蛋白质结构特征之间的关系。
检测到13例携带12种该基因变异的新患者，包括5种新型错义变异和1种新型移码变异。体外实验表明，移码变异p.H463Mfs*3产生了一个约50 kDa的截短蛋白，表达水平较低。除E420K和T536R外，其他错义变异损害全酶组装。此外，我们发现迄今为止报道的致病性/可能致病性（P/LP）变异均为错义变异，并聚集在三个保守区域，位于这些保守区域的P/LP突变可能性极高。此外，巨头畸形表型与参与底物募集的带负电荷残基有关。
我们报告了13例携带该基因变异的新患者，扩大了该变异谱。我们通过体外实验证实了新型变异的致病性。我们在基因型 - 表型关系方面的发现为遗传咨询和变异解读提供了启示。我们还为巨头畸形表型机制的进一步研究提供了方向。
