De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism.
De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism.
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DOI：
10.1007/s10048-015-0466-9
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发表时间：
2016-01
期刊：
影响因子：
2.2
通讯作者：
Chung WK
中科院分区：
文献类型：
--
作者：
Shang L;Henderson LB;Cho MT;Petrey DS;Fong CT;Haude KM;Shur N;Lundberg J;Hauser N;Carmichael J;Innis J;Schuette J;Wu YW;Asaikar S;Pearson M;Folk L;Retterer K;Monaghan KG;Chung WK
蛋白磷酸酶2A（PP 2A）是一种异源三聚体蛋白丝氨酸/苏氨酸磷酸酶，参与广泛的细胞过程。PPP 2 R5 D是PP 2A的一个调节性B亚基，在PI 3 K/AKT和GSK 3 β介导的细胞生长、染色质重塑和基因转录调控等关键神经和发育调控过程中发挥重要作用。使用WES，我们在总共7个具有ID和其他共同临床特征的不相关个体中鉴定了PPP 2 R5 D的4种从头变异，包括自闭症谱系障碍、大头畸形、张力减退、癫痫发作和畸形特征。在这四种变异中，有两种是以前报道过的，还有两种是新的。所有四种氨基酸在PP 2A亚基家族中是高度保守的，并且都将带负电荷的酸性谷氨酸（E）改变为带正电荷的碱性赖氨酸（K），并且预测破坏PP 2A亚基结合并损害去磷酸化能力。我们的数据进一步支持PPP 2 R5 D是ID的遗传原因。
Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and GSK3β-mediated cell growth, chromatin remodeling and gene transcriptional regulation. Using WES, we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with ID and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures and dysmorphic features. Among the four variant, two have been previously reported, and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K), and are predicted to disrupt the PP2A subunits binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.