PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy.
PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy.
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DOI：
10.1002/acn3.51634
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发表时间：
2022-09
影响因子：
5.3
通讯作者：
Maroofian, Reza
中科院分区：
文献类型：
--
作者：
Dafsari, Hormos Salimi;Pemberton, Joshua G.;Ferrer, Elizabeth A.;Yammine, Tony;Farra, Chantal;Mohammadi, Mohammad Hasan;Karimiani, Ehsan Ghayoor;Hashemi, Narges;Souaid, Mirna;Sabbagh, Sandra;Torbati, Paria Najarzadeh;Khan, Suliman;Roze, Emmanuel;Moreno-De-Luca, Andres;Bertoli-Avella, Aida M.;Houlden, Henry;Balla, Tamas;Maroofian, Reza
细胞内信号网络依赖于适当的膜组织来控制一系列细胞过程，如真核细胞和生物体中的代谢、增殖、凋亡和大自噬。磷脂酰肌醇4-磷酸（PI 4P）作为细胞器膜内的一种重要调节脂质出现，决定了其脂质组成和信号传导特性。在哺乳动物细胞中，PI 4P由四种不同的磷脂酰肌醇4-激酶（PI 4K）产生：PI 4KA、PI 4KB、PI 4K 2A、PI 4K 2B。动物模型和人类遗传学研究表明，PI 4K酶在包括神经系统在内的各种器官的发育和功能中起着重要作用。PI 4KA的双等位基因变体最近与神经发育障碍（NDD）、脑畸形、脑白质营养不良、原发性免疫缺陷和炎症性肠病相关。在这里，我们描述了两个不相关的血缘家庭与PI 4K 2A缺乏症的患者，并从功能上探讨了致病机制。通过外显子组测序确定了2例PI 4K 2A缺陷患者，表现为发育性和癫痫-运动障碍性脑病。神经影像学显示胼胝体发育不全，弥漫性白色物质体积丢失和发育不全的蚓部。除NDD外，我们还观察到幼儿期反复感染和死亡。我们用细胞测定进一步探索了鉴定的变体。这种临床表现与之前报道的两名患有纯合无义PI 4 K2 A变体的受影响兄弟姐妹的临床表现重叠。分析这些人类变体的细胞研究证实了它们对PI 4K 2A活性的有害影响，以及PI 4K 2A在Rab 7相关囊泡运输中的中心作用，建立了晚期内体-溶酶体缺陷与NDD之间的联系。我们的研究建立了PI 4K相关NDD的基因型-表型谱，并强调了与细胞内运输的其他先天性错误的几个共性。
Intracellular signaling networks rely on proper membrane organization to control an array of cellular processes such as metabolism, proliferation, apoptosis, and macroautophagy in eukaryotic cells and organisms. Phosphatidylinositol 4‐phosphate (PI4P) emerged as an essential regulatory lipid within organelle membranes that defines their lipid composition and signaling properties. PI4P is generated by four distinct phosphatidylinositol 4‐kinases (PI4K) in mammalian cells: PI4KA, PI4KB, PI4K2A, PI4K2B. Animal models and human genetic studies suggest vital roles of PI4K enzymes in development and function of various organs, including the nervous system. Bi‐allelic variants in PI4KA were recently associated with neurodevelopmental disorders (NDD), brain malformations, leukodystrophy, primary immunodeficiency, and inflammatory bowel disease. Here, we describe patients from two unrelated consanguineous families with PI4K2A deficiency and functionally explored the pathogenic mechanism. Two patients with PI4K2A deficiency were identified by exome sequencing, presenting with developmental and epileptic‐dyskinetic encephalopathy. Neuroimaging showed corpus callosum dysgenesis, diffuse white matter volume loss, and hypoplastic vermis. In addition to NDD, we observed recurrent infections and death at toddler age. We further explored identified variants with cellular assays. This clinical presentation overlaps with what was previously reported in two affected siblings with homozygous nonsense PI4K2A variant. Cellular studies analyzing these human variants confirmed their deleterious effect on PI4K2A activity and, together with the central role of PI4K2A in Rab7‐associated vesicular trafficking, establish a link between late endosome‐lysosome defects and NDD. Our study establishes the genotype–phenotype spectrum of PI4K‐associated NDD and highlights several commonalities with other innate errors of intracellular trafficking.
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影响因子：
8.8
作者：
Alvarez-Prats A;Bjelobaba I;Aldworth Z;Baba T;Abebe D;Kim YJ;Stojilkovic SS;Stopfer M;Balla T
通讯作者：
Balla T
DOI：
10.1083/jcb.200111013
发表时间：
2002-06-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hunyady L;Baukal AJ;Gaborik Z;Olivares-Reyes JA;Bor M;Szaszak M;Lodge R;Catt KJ;Balla T
通讯作者：
Balla T
DOI：
10.1093/brain/awaa459
发表时间：
2021-04-12
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Sanderson LE;Lanko K;Alsagob M;Almass R;Al-Ahmadi N;Najafi M;Al-Muhaizea MA;Alzaidan H;AlDhalaan H;Perenthaler E;van der Linde HC;Nikoncuk A;Kühn NA;Antony D;Owaidah TM;Raskin S;Vieira LGDR;Mombach R;Ahangari N;Silveira TRD;Ameziane N;Rolfs A;Alharbi A;Sabbagh RM;AlAhmadi K;Alawam B;Ghebeh H;AlHargan A;Albader AA;Binhumaid FS;Goljan E;Monies D;Mustafa OM;Aldosary M;AlBakheet A;Alyounes B;Almutairi F;Al-Odaib A;Aksoy DB;Basak AN;Palvadeau R;Trabzuni D;Rosenfeld JA;Karimiani EG;Meyer BF;Karakas B;Al-Mohanna F;Arold ST;Colak D;Maroofian R;Houlden H;Bertoli-Avella AM;Schmidts M;Barakat TS;van Ham TJ;Kaya N
通讯作者：
Kaya N
影响因子：
1.8
作者：
Dafsari, Hormos Salimi;Kawalia, Amit;Cirak, Sebahattin
通讯作者：
Cirak, Sebahattin
影响因子：
5.6
作者：
Spagnoli C;Fusco C;Percesepe A;Leuzzi V;Pisani F
通讯作者：
Pisani F