Mark Stevenson, Asha L Bayliss, Victoria J Stokes, Katherine A English, Kreepa G Kooblall, Roman Fischer, Raphael Heilig, Iolanda Vendrell, Maria E W A Albers, Meghan Bartos, Amber Begtrup, Alexia Bourgois, Rebecca Buchert, David J Carey, Deanna A Carere, Amanda Carnevale, Kristl G Claeys, Benjamin Cogne, Gregory Costain, Nicole de Leeuw, Anne-Sophie Denommé-Pichon, Elizabeth J Donner, Eftychia Drogouti, David A Dyment, Balram Gangaram, Tobias B Haack, Jeremy S Haley, Solveig Heide, Ralf A Hussain, Bertrand Isidor, Louise Izatt, Adeline Jacquinet, Jane Juusola, Juliette J Kahle, Boris Keren, Eric W Klee, Evgenia Kokosali, Brendan C Lanpher, Erica L Macke, Elysa J Marco, Kirsty McWalter, Bryce A Mendelsohn, Aubrey Milunshy, Matthew Osmond, Amelie Piton, Angelika Riess, Valentin Ruault, Patrick Rump, Sarah Schuhmann, Amelle L Shillington, Diane T Smelser, Lot Snijders Blok, Frederic Tran Mau-Them, Christos Tsakalidis, Abigail Turnwald, Koen L I Van Gassen, Kristof Van Schil, Georgia Vasileiou, Marissa Vawter-Lee, Marjolaine Willems, Marjolein H Willemsen, Lily C Wong-Kisiel, Antje Wonneberger, Ioannis Zaganas, Genomics England Research Consortium, Fadil M Hannan, Kate E Lines, Rajesh V Thakker
{"title":"与神经发育障碍相关的适配蛋白 2 sigma 亚基 (AP2S1) 变体","authors":"Mark Stevenson, Asha L Bayliss, Victoria J Stokes, Katherine A English, Kreepa G Kooblall, Roman Fischer, Raphael Heilig, Iolanda Vendrell, Maria E W A Albers, Meghan Bartos, Amber Begtrup, Alexia Bourgois, Rebecca Buchert, David J Carey, Deanna A Carere, Amanda Carnevale, Kristl G Claeys, Benjamin Cogne, Gregory Costain, Nicole de Leeuw, Anne-Sophie Denommé-Pichon, Elizabeth J Donner, Eftychia Drogouti, David A Dyment, Balram Gangaram, Tobias B Haack, Jeremy S Haley, Solveig Heide, Ralf A Hussain, Bertrand Isidor, Louise Izatt, Adeline Jacquinet, Jane Juusola, Juliette J Kahle, Boris Keren, Eric W Klee, Evgenia Kokosali, Brendan C Lanpher, Erica L Macke, Elysa J Marco, Kirsty McWalter, Bryce A Mendelsohn, Aubrey Milunshy, Matthew Osmond, Amelie Piton, Angelika Riess, Valentin Ruault, Patrick Rump, Sarah Schuhmann, Amelle L Shillington, Diane T Smelser, Lot Snijders Blok, Frederic Tran Mau-Them, Christos Tsakalidis, Abigail Turnwald, Koen L I Van Gassen, Kristof Van Schil, Georgia Vasileiou, Marissa Vawter-Lee, Marjolaine Willems, Marjolein H Willemsen, Lily C Wong-Kisiel, Antje Wonneberger, Ioannis Zaganas, Genomics England Research Consortium, Fadil M Hannan, Kate E Lines, Rajesh V Thakker","doi":"10.1101/2024.07.22.24310683","DOIUrl":null,"url":null,"abstract":"Adaptor-Related Protein Complex 2 Sigma-1 Subunit (AP2S1) encodes AP2σ2, which forms part of the heterotetrameric AP2 complex that is composed of α, β2, μ2, and σ2 subunits and has a pivotal role in clathrin-mediated endocytosis (CME). AP2S1 variants involving the Arg15 residue are associated with familial hypocalciuric hypercalcaemia type 3 (FHH3). Here, we report 5 different AP2S1 variants (AP2σ2: p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His) in 26 patients with neurodevelopmental delay, of whom >70% had epilepsy, 50% had brain abnormalities, and none had hypercalcaemia. All 5 variants decreased cell viability, 4 reduced CME transferrin uptake, and 4 disrupted interactions with other AP2 complex subunits, thereby affecting AP2 formation. Furthermore, AP2σ2 p.Arg10Trp had reduced interactions with 44 human proteins including intersectin 1, a component required for clathrin-coated pit formation and synaptic vesicle dynamics in neurones. Thus, our results show that AP2σ2 variants may disrupt CME and be associated with neurodevelopmental disorders.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Adaptor protein 2 sigma subunit (AP2S1) variants associated with neurodevelopmental disorders\",\"authors\":\"Mark Stevenson, Asha L Bayliss, Victoria J Stokes, Katherine A English, Kreepa G Kooblall, Roman Fischer, Raphael Heilig, Iolanda Vendrell, Maria E W A Albers, Meghan Bartos, Amber Begtrup, Alexia Bourgois, Rebecca Buchert, David J Carey, Deanna A Carere, Amanda Carnevale, Kristl G Claeys, Benjamin Cogne, Gregory Costain, Nicole de Leeuw, Anne-Sophie Denommé-Pichon, Elizabeth J Donner, Eftychia Drogouti, David A Dyment, Balram Gangaram, Tobias B Haack, Jeremy S Haley, Solveig Heide, Ralf A Hussain, Bertrand Isidor, Louise Izatt, Adeline Jacquinet, Jane Juusola, Juliette J Kahle, Boris Keren, Eric W Klee, Evgenia Kokosali, Brendan C Lanpher, Erica L Macke, Elysa J Marco, Kirsty McWalter, Bryce A Mendelsohn, Aubrey Milunshy, Matthew Osmond, Amelie Piton, Angelika Riess, Valentin Ruault, Patrick Rump, Sarah Schuhmann, Amelle L Shillington, Diane T Smelser, Lot Snijders Blok, Frederic Tran Mau-Them, Christos Tsakalidis, Abigail Turnwald, Koen L I Van Gassen, Kristof Van Schil, Georgia Vasileiou, Marissa Vawter-Lee, Marjolaine Willems, Marjolein H Willemsen, Lily C Wong-Kisiel, Antje Wonneberger, Ioannis Zaganas, Genomics England Research Consortium, Fadil M Hannan, Kate E Lines, Rajesh V Thakker\",\"doi\":\"10.1101/2024.07.22.24310683\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Adaptor-Related Protein Complex 2 Sigma-1 Subunit (AP2S1) encodes AP2σ2, which forms part of the heterotetrameric AP2 complex that is composed of α, β2, μ2, and σ2 subunits and has a pivotal role in clathrin-mediated endocytosis (CME). AP2S1 variants involving the Arg15 residue are associated with familial hypocalciuric hypercalcaemia type 3 (FHH3). Here, we report 5 different AP2S1 variants (AP2σ2: p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His) in 26 patients with neurodevelopmental delay, of whom >70% had epilepsy, 50% had brain abnormalities, and none had hypercalcaemia. All 5 variants decreased cell viability, 4 reduced CME transferrin uptake, and 4 disrupted interactions with other AP2 complex subunits, thereby affecting AP2 formation. Furthermore, AP2σ2 p.Arg10Trp had reduced interactions with 44 human proteins including intersectin 1, a component required for clathrin-coated pit formation and synaptic vesicle dynamics in neurones. Thus, our results show that AP2σ2 variants may disrupt CME and be associated with neurodevelopmental disorders.\",\"PeriodicalId\":501375,\"journal\":{\"name\":\"medRxiv - Genetic and Genomic Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-07-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"medRxiv - Genetic and Genomic Medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2024.07.22.24310683\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv - Genetic and Genomic Medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.07.22.24310683","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Adaptor protein 2 sigma subunit (AP2S1) variants associated with neurodevelopmental disorders
Adaptor-Related Protein Complex 2 Sigma-1 Subunit (AP2S1) encodes AP2σ2, which forms part of the heterotetrameric AP2 complex that is composed of α, β2, μ2, and σ2 subunits and has a pivotal role in clathrin-mediated endocytosis (CME). AP2S1 variants involving the Arg15 residue are associated with familial hypocalciuric hypercalcaemia type 3 (FHH3). Here, we report 5 different AP2S1 variants (AP2σ2: p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His) in 26 patients with neurodevelopmental delay, of whom >70% had epilepsy, 50% had brain abnormalities, and none had hypercalcaemia. All 5 variants decreased cell viability, 4 reduced CME transferrin uptake, and 4 disrupted interactions with other AP2 complex subunits, thereby affecting AP2 formation. Furthermore, AP2σ2 p.Arg10Trp had reduced interactions with 44 human proteins including intersectin 1, a component required for clathrin-coated pit formation and synaptic vesicle dynamics in neurones. Thus, our results show that AP2σ2 variants may disrupt CME and be associated with neurodevelopmental disorders.
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