Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven, Belgium.
J Med Genet. 2023 May;60(5):511-522. doi: 10.1136/jmg-2022-108713. Epub 2022 Oct 10.
Variants in , affecting the regulatory B56δ subunit of protein phosphatase 2A (PP2A), have been identified in individuals with neurodevelopmental abnormalities. However, the molecular and clinical spectra remain incompletely understood.
Individuals with variants were enrolled through Simons Variation in Individuals Project/Simons Searchlight. Data were collected from medical history interviews, medical record review, online validated instruments and neuroimaging review. Genetic variants were biochemically characterised.
We studied 76 individuals with variants, including 68 with pathogenic de novo variants, four with a variant of uncertain significance (VUS) and four siblings with a novel dominantly inherited pathogenic variant. Among 13 pathogenic variants, eight were novel and two (p.Glu198Lys and p.Glu200Lys) were highly recurrent. Functional analysis revealed impaired PP2A A/C-subunit binding, decreased short linear interaction motif-dependent substrate binding or both-with the most severe phenotypes associated with variants that completely retained one of these binding characteristics and lost the other-further supporting a dominant-negative disease mechanism. p.Glu198Lys showed the highest C-binding defect and a more severe clinical phenotype. The inherited p.Glu197Gly variant had a mild substrate binding defect, and three of four VUS had no biochemical impact. Common clinical phenotypes were language, intellectual or learning disabilities (80.6%), hypotonia (75.0%), macrocephaly (66.7%), seizures (45.8%) and autism spectrum disorder (26.4%). The mean composite Vineland score was 59.8, and most participants were in the 'moderate to low' and 'low' adaptive levels in all domains.
Our study delineates the most common features of -related neurodevelopmental disorders, expands the clinical and molecular spectrum and identifies genotype-phenotype correlations.
影响蛋白磷酸酶 2A（PP2A）调节 B56δ 亚基的 变异已在具有神经发育异常的个体中被发现。然而，其分子和临床谱仍不完全清楚。
通过 Simons 个体变异计划/ Simons 搜索灯，招募了携带 变异的个体。通过病史访谈、病历回顾、在线验证工具和神经影像学评估收集数据。对遗传变异进行了生化特征分析。
我们研究了 76 名携带 变异的个体，包括 68 名致病性新生变异个体、4 名意义不明的变异个体和 4 名携带新的显性致病性变异的兄弟姐妹。在 13 种致病性变异中，有 8 种是新的，有 2 种（p.Glu198Lys 和 p.Glu200Lys）高度重复。功能分析显示，PP2A A/C 亚基结合受损，短线性相互作用基序依赖性底物结合减少或两者兼有，与完全保留其中一种结合特性而丧失另一种结合特性的变异相关的表型最严重，进一步支持显性负性疾病机制。p.Glu198Lys 表现出最高的 C 结合缺陷和更严重的临床表型。遗传性 p.Glu197Gly 变异仅有轻度的底物结合缺陷，4 个意义不明的变异中有 3 个没有生化影响。常见的临床表型为语言、智力或学习障碍（80.6%）、张力减退（75.0%）、大头畸形（66.7%）、癫痫发作（45.8%）和自闭症谱系障碍（26.4%）。平均复合 Vineland 评分 59.8，大多数参与者在所有领域的适应水平均处于“中等至低”和“低”。
本研究描绘了 相关神经发育障碍的最常见特征，扩展了临床和分子谱，并确定了基因型-表型相关性。
