Center for Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai 201102, China.
Neurology Department, Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai 201102, China.
Genes (Basel). 2023 Sep 1;14(9):1750. doi: 10.3390/genes14091750.
Neurodevelopmental disorders (NDDs) are a group of high-incidence rare diseases with genetic heterogeneity. PPP2R1A, the regulatory subunit of protein phosphatase 2A, is a recently discovered gene associated with NDDs. Whole/clinical exome sequencing was performed in five patients with a family with NDDs. In vitro experiments were performed to evaluate the mutants' expression and interactions with the complex. The genotype-phenotype correlations of reported cases as well as our patients with variants were reviewed. We reported five unrelated individuals with PPP2R1A variants, including two novel missense variants and one frameshift variant. The protein expression of the Arg498Leu variant was less than that of the wild-type protein, the frameshift variant Asn282Argfs*14 was not decreased but truncated, and these two variants impaired the interactions with endogenous PPP25RD and PPP2CA. Furthermore, we found that pathogenic variants clustered in HEAT repeats V, VI and VII, and patients with the Met180Val/Thr variants had macrocephaly, severe ID and hypotonia, but no epilepsy, whereas those with Arg258 amino acid changes had microcephaly, while a few had epilepsy or feeding problems. In this study, we reported five NDD patients with gene variants and expanded PPP2R1A pathogenic variant spectrum. The genotype and phenotype association findings provide reminders regarding the prognostication and evidence for genetic counseling.
神经发育障碍（NDDs）是一组具有遗传异质性的高发病率罕见疾病。蛋白磷酸酶 2A 的调节亚基 PPP2R1A 是最近发现的与 NDDs 相关的基因。对 5 名具有 NDD 家族的患者进行了全外显子/临床外显子测序。进行了体外实验来评估突变体的表达及其与复合物的相互作用。对报道的病例以及我们的患者的基因型-表型相关性进行了回顾。我们报道了 5 名具有 PPP2R1A 变异的无关个体，包括 2 种新的错义变异和 1 种移码变异。Arg498Leu 变异的蛋白表达低于野生型蛋白，移码变异 Asn282Argfs*14 没有减少但截短，这两种变异会损害与内源性 PPP25RD 和 PPP2CA 的相互作用。此外，我们发现致病性变异聚集在 HEAT 重复 V、VI 和 VII 中，具有 Met180Val/Thr 变异的患者有大头畸形、严重的智力障碍和张力减退，但没有癫痫，而具有 Arg258 氨基酸变化的患者有小头畸形，少数有癫痫或进食问题。在这项研究中，我们报道了 5 名具有 基因变异的 NDD 患者，并扩展了 PPP2R1A 致病性变异谱。基因型和表型相关性的发现为预后提供了提示，并为遗传咨询提供了证据。
