Inherited cutis laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several cutis laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with cutis laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4‐kinase type IIα, caused by a homozygous missense mutation in the PI4K2A gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4‐phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl‐chain pools of PI4P and PI(4,5)P₂ were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4‐kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P₂ and PI(3,4,5)P₃. Although neurologic involvement is common, cutis laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation in PI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.

中文翻译：

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膜酶界面处磷脂酰肌醇 4-激酶 2-α 型 (PI4K2A) 的新缺陷与代谢性皮肤松弛有关。

遗传性皮肤松弛或无弹性、下垂的皮肤是过早和全身结缔组织老化的遗传状况，影响细胞外基质的各种弹性成分。几种皮肤松弛综合征是先天性代谢缺陷，会导致严重的神经系统症状。在一名患有皮肤松弛症、舞蹈病样运动障碍、畸形特征和智力障碍的患者中，我们进行了外显子组测序以阐明潜在的遗传缺陷。我们鉴定了由 PI4K2A 中的纯合错义突变引起的磷脂酰肌醇 4-激酶 IIa 型中的氨基酸取代R275W基因。我们使用脂质组学、复合体分析和功能研究来测量患者的磷脂酰肌醇 4-磷酸合成，并评估 PI4K2A 缺陷小鼠以定义一种新的代谢紊乱。位于蛋白质表面的 R275W 残基参与与膜形成静电相互作用。PI4K2A 在患者成纤维细胞中的催化活性严重降低，脂质质谱显示 PI4P 和 PI(4,5)P _{2 的}特定酰基链库减少。磷酸肌醇脂质在细胞内信号传导和运输中起主要作用，并调节增殖和凋亡之间的平衡。磷脂酰肌醇 4-激酶如 PI4K2A 介导主要代谢途径的第一步，产生 PI4P、PI(4,5)P ₂和 PI(3,4,5)P ₃。尽管神经系统受累很常见，但之前尚未报道过影响信号传导的代谢缺陷导致的皮肤松弛症。在这里，我们描述了一名具有复杂神经表型、过早衰老和PI4K2A突变的患者，说明了这种酶在生成具有特定酰化特征的肌醇脂质中的重要性。