Department of Pediatrics, Unaizah College of Medicine and Medical Sciences, Qassim University, Saudi Arabia.
Department of Pediatrics, Division of Pediatric Neurology, McGill University Health Center, Montreal, Quebec, Canada.
Am J Med Genet A. 2023 Sep;191(9):2416-2421. doi: 10.1002/ajmg.a.63307. Epub 2023 May 30.
Heterozygous pathogenic variants in PPP2R5D gene are associated with PPP2R5D-related neurodevelopmental disorder, a rare autosomal dominant condition, characterized by neurodevelopmental impairment in childhood, macrocephaly/megalencephaly, hypotonia, epilepsy, and dysmorphic features. Up-to-date, only approximately 100 cases have been published in the literature and the full phenotypic and genotypic spectrum have not yet been fully described. PPP2R5D gene encodes the B56δ subunit of the PP2A enzyme complex. We describe a neonatal form of PPP2R5D-related disorder with early infantile death, caused by a novel in-frame deletion causing loss of 8 amino acids and insertion of serine at position 201 (p.Phe194_Pro201delinsSer) of the B56δ subunit. This deletion is predicted to disrupt a critical acidic loop of amino acids important for binding other subunits of the PP2A enzyme complex, and harbors many of the residues previously reported to cause a mild-moderate form of this condition. This report describes a neonatal lethal presentation of the PPP2R5D-related neurodevelopmental disorder and provides additional evidence that disruption of the acidic loop is an important pathomechanism underlying PPP2R5D-related disorder.
PPP2R5D 基因杂合致病性变异与 PPP2R5D 相关神经发育障碍相关，这是一种罕见的常染色体显性疾病，其特征为儿童时期神经发育障碍、大头畸形/巨脑畸形、张力减退、癫痫发作和发育异常特征。迄今为止，文献中仅报道了约 100 例病例，且尚未充分描述其完整的表型和基因型谱。PPP2R5D 基因编码 PP2A 酶复合物的 B56δ 亚基。我们描述了一种由新型框内缺失导致 8 个氨基酸缺失并在 B56δ 亚基第 201 位插入丝氨酸（p.Phe194_Pro201delinsSer）引起的 PPP2R5D 相关疾病的新生儿形式，导致该疾病。该缺失预计会破坏对结合 PP2A 酶复合物其他亚基至关重要的关键酸性环，并且包含许多先前报道导致该疾病轻度至中度形式的残基。本报告描述了 PPP2R5D 相关神经发育障碍的新生儿致死表现，并提供了额外的证据，表明酸性环的破坏是 PPP2R5D 相关疾病的重要发病机制。
