The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.

Danish Epilepsy Centre Filadelfia 4293 Dianalund Denmark

Danish Epilepsy Centre Filadelfia 4293 Dianalund Denmark; Institute for Regional Health Services University of Southern Denmark 5230 Odense Denmark

Department of Child Neurology Charles University 2nd Faculty of Medicine and University Hospital Motol 150 06 Prague Czech Republic

Department of Neurology and Epileptology Hertie Institute for Clinical Brain Research University of Tübingen 72076 Tübingen Germany

Department of Neurology and Epileptology Hertie Institute for Clinical Brain Research University of Tübingen 72076 Tübingen Germany; Department of Neurosurgery University of Tübingen 72076 Tübingen Germany

Department of Neurology Rabin Medical Center Petach Tikva 4941492 Israel; Sackler School of Medicine Tel Aviv University Tel Aviv 6997801 Israel

Department of Neurology University of Pennsylvania Perelman School of Medicine Philadelphia PA 19104 USA

Department of Neuropediatrics Christian Albrechts University of Kiel 24105 Kiel Germany

Division of Clinical Genomics Ambry Genetics Aliso Viejo CA 92656 USA

Division of Genetics Department of Pediatrics University of California San Francisco Fresno CA 93701 USA

Division of Neurology Children's Hospital of Philadelphia Philadelphia PA 19104 USA; Department of Biomedical and Health Informatics Children's Hospital of Philadelphia Philadelphia PA 19104 USA

Division of Neurology Children's Hospital of Philadelphia Philadelphia PA 19104 USA; Department of Biomedical and Health Informatics Children's Hospital of Philadelphia Philadelphia PA 19104 USA; Department of Neuropediatrics Christian Albrechts University of Kiel 24105 Kiel Germany; Department of Neurology University of Pennsylvania Perelman School of Medicine Philadelphia PA 19104 USA

East Tennessee Children's Hospital University of Tennessee Department of Medicine Knoxville TN 37916 USA

Epilepsy Genetics Program Department of Neurology Boston Children's Hospital Boston MA 02115 USA

Epilepsy Genetics Program Department of Neurology Boston Children's Hospital Boston MA 02115 USA; Department of Neurology Harvard Medical School Boston MA 02115 USA

Leibniz Forschungsinstitut für Molekulare Pharmakologie 13125 Berlin Germany

Leibniz Forschungsinstitut für Molekulare Pharmakologie 13125 Berlin Germany; Freie Universität Berlin Faculty of Biology Chemistry Pharmacy 14195 Berlin Germany

Luxembourg Centre for Systems Biomedicine University of Luxembourg 4365 Esch sur Alzette Luxembourg

See more in PubMed

Scheffer I.E., Berkovic S., Capovilla G., Connolly M.B., French J., Guilhoto L., Hirsch E., Jain S., Mathern G.W., Moshé S.L. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512–521. PubMed PMC

Scheffer, I.E., Berkovic, S., Capovilla, G., Connolly, M.B., French, J., Guilhoto, L., Hirsch, E., Jain, S., Mathern, G.W., Moshe, S.L., et al. (2017). ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58, 512-521. PubMed PMC

McTague A., Howell K.B., Cross J.H., Kurian M.A., Scheffer I.E. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15:304–316. PubMed

McTague, A., Howell, K.B., Cross, J.H., Kurian, M.A., and Scheffer, I.E. (2016). The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 15, 304-316. PubMed

Helbig I., Tayoun A.A. Understanding genotypes and phenotypes in epileptic encephalopathies. Mol. Syndromol. 2016;7:172–181. PubMed PMC

Helbig, I., and Tayoun, A.A. (2016). Understanding genotypes and phenotypes in epileptic encephalopathies. Mol. Syndromol. 7, 172-181. PubMed PMC

Helbig I., Heinzen E.L., Mefford H.C., International League Against Epilepsy Genetics Commission Genetic literacy series: Primer part 2-Paradigm shifts in epilepsy genetics. Epilepsia. 2018;59:1138–1147. PubMed

Helbig, I., Heinzen, E.L., and Mefford, H.C.; International League Against Epilepsy Genetics Commission (2018). Genetic literacy series: Primer part 2-Paradigm shifts in epilepsy genetics. Epilepsia 59, 1138-1147. PubMed

Heyne H.O., Singh T., Stamberger H., Abou Jamra R., Caglayan H., Craiu D., De Jonghe P., Guerrini R., Helbig K.L., Koeleman B.P.C., EuroEPINOMICS RES Consortium De novo variants in neurodevelopmental disorders with epilepsy. Nat. Genet. 2018;50:1048–1053. PubMed

Heyne, H.O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K.L., Koeleman, B.P.C., et al.; EuroEPINOMICS RES Consortium (2018). De novo variants in neurodevelopmental disorders with epilepsy. Nat. Genet. 50, 1048-1053. PubMed

Helbig K.L., Farwell Hagman K.D., Shinde D.N., Mroske C., Powis Z., Li S., Tang S., Helbig I. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet. Med. 2016;18:898–905. PubMed

Helbig, K.L., Farwell Hagman, K.D., Shinde, D.N., Mroske, C., Powis, Z., Li, S., Tang, S., and Helbig, I. (2016). Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet. Med. 18, 898-905. PubMed

Lindy A.S., Stosser M.B., Butler E., Downtain-Pickersgill C., Shanmugham A., Retterer K., Brandt T., Richard G., McKnight D.A. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia. 2018;59:1062–1071. PubMed

Lindy, A.S., Stosser, M.B., Butler, E., Downtain-Pickersgill, C., Shanmugham, A., Retterer, K., Brandt, T., Richard, G., and McKnight, D.A. (2018). Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia 59, 1062-1071. PubMed

Djémié T., Weckhuysen S., von Spiczak S., Carvill G.L., Jaehn J., Anttonen A.K., Brilstra E., Caglayan H.S., de Kovel C.G., Depienne C., EuroEPINOMICS-RES Dravet working group Pitfalls in genetic testing: The story of missed SCN1A mutations. Mol. Genet. Genomic Med. 2016;4:457–464. PubMed PMC

Djemie, T., Weckhuysen, S., von Spiczak, S., Carvill, G.L., Jaehn, J., Anttonen, A.K., Brilstra, E., Caglayan, H.S., de Kovel, C.G., Depienne, C., et al.; EuroEPINOMICS-RES Dravet working group (2016). Pitfalls in genetic testing: The story of missed SCN1A mutations. Mol. Genet. Genomic Med. 4, 457-464. PubMed PMC

Claes L., Del-Favero J., Ceulemans B., Lagae L., Van Broeckhoven C., De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 2001;68:1327–1332. PubMed PMC

Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., and De Jonghe, P. (2001). De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 68, 1327-1332. PubMed PMC

Stamberger H., Nikanorova M., Willemsen M.H., Accorsi P., Angriman M., Baier H., Benkel-Herrenbrueck I., Benoit V., Budetta M., Caliebe A. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology. 2016;86:954–962. PubMed

Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., et al. (2016). STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology 86, 954-962. PubMed

Wolff M., Johannesen K.M., Hedrich U.B.S., Masnada S., Rubboli G., Gardella E., Lesca G., Ville D., Milh M., Villard L. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain. 2017;140:1316–1336. PubMed

Wolff, M., Johannesen, K.M., Hedrich, U.B.S., Masnada, S., Rubboli, G., Gardella, E., Lesca, G., Ville, D., Milh, M., Villard, L., et al. (2017). Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 140, 1316-1336. PubMed

EuroEPINOMICS-RES Consortium. Electronic address: euroepinomics-RES@ua.ac.be. Epilepsy Phenome/Genome Project. Epi4K Consortium. EuroEPINOMICS-RES Consortium De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am. J. Hum. Genet. 2017;100:179. PubMed PMC

EuroEPINOMICS-RES Consortium. Electronic address: euroepinomics-RES@ua.ac.be; Epilepsy Phenome/Genome Project; Epi4K Consortium; EuroEPINOMICS-RES Consortium (2017). De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am. J. Hum. Genet. 100, 179. PubMed PMC

Allen A.S., Berkovic S.F., Cossette P., Delanty N., Dlugos D., Eichler E.E., Epstein M.P., Glauser T., Goldstein D.B., Han Y., Epi4K Consortium. Epilepsy Phenome/Genome Project De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–221. PubMed PMC

Allen, A.S., Berkovic, S.F., Cossette, P., Delanty, N., Dlugos, D., Eichler, E.E., Epstein, M.P., Glauser, T., Goldstein, D.B., Han, Y., et al.; Epi4K Consortium; Epilepsy Phenome/Genome Project (2013). De novo mutations in epileptic encephalopathies. Nature 501, 217-221. PubMed PMC

Helbig I., Lindhout D. Advancing the phenome alongside the genome in epilepsy studies. Neurology. 2017;89:14–15. PubMed

Helbig, I., and Lindhout, D. (2017). Advancing the phenome alongside the genome in epilepsy studies. Neurology 89, 14-15. PubMed

Robinson P.N., Köhler S., Bauer S., Seelow D., Horn D., Mundlos S. The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am. J. Hum. Genet. 2008;83:610–615. PubMed PMC

Robinson, P.N., Kohler, S., Bauer, S., Seelow, D., Horn, D., and Mundlos, S. (2008). The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am. J. Hum. Genet. 83, 610-615. PubMed PMC

Köhler S., Vasilevsky N.A., Engelstad M., Foster E., McMurry J., Aymé S., Baynam G., Bello S.M., Boerkoel C.F., Boycott K.M. The Human Phenotype Ontology in 2017. Nucleic Acids Res. 2017;45(D1):D865–D876. PubMed PMC

Kohler, S., Vasilevsky, N.A., Engelstad, M., Foster, E., McMurry, J., Ayme, S., Baynam, G., Bello, S.M., Boerkoel, C.F., Boycott, K.M., et al. (2017). The Human Phenotype Ontology in 2017. Nucleic Acids Res. 45 (D1), D865-D876. PubMed PMC

Bastarache L., Hughey J.J., Hebbring S., Marlo J., Zhao W., Ho W.T., Van Driest S.L., McGregor T.L., Mosley J.D., Wells Q.S. Phenotype risk scores identify patients with unrecognized Mendelian disease patterns. Science. 2018;359:1233–1239. PubMed PMC

Bastarache, L., Hughey, J.J., Hebbring, S., Marlo, J., Zhao, W., Ho, W.T., Van Driest, S.L., McGregor, T.L., Mosley, J.D., Wells, Q.S., et al. (2018). Phenotype risk scores identify patients with unrecognized Mendelian disease patterns. Science 359, 1233-1239. PubMed PMC

Akawi N., McRae J., Ansari M., Balasubramanian M., Blyth M., Brady A.F., Clayton S., Cole T., Deshpande C., Fitzgerald T.W., DDD study Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat. Genet. 2015;47:1363–1369. PubMed PMC

Akawi, N., McRae, J., Ansari, M., Balasubramanian, M., Blyth, M., Brady, A.F., Clayton, S., Cole, T., Deshpande, C., Fitzgerald, T.W., et al.; DDD study (2015). Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat. Genet. 47, 1363-1369. PubMed PMC

Köhler S., Schulz M.H., Krawitz P., Bauer S., Dölken S., Ott C.E., Mundlos C., Horn D., Mundlos S., Robinson P.N. Clinical diagnostics in human genetics with semantic similarity searches in ontologies. Am. J. Hum. Genet. 2009;85:457–464. PubMed PMC

Kohler, S., Schulz, M.H., Krawitz, P., Bauer, S., Dolken, S., Ott, C.E., Mundlos, C., Horn, D., Mundlos, S., and Robinson, P.N. (2009). Clinical diagnostics in human genetics with semantic similarity searches in ontologies. Am. J. Hum. Genet. 85, 457-464. PubMed PMC

Pesquita C., Faria D., Falcão A.O., Lord P., Couto F.M. Semantic similarity in biomedical ontologies. PLoS Comput. Biol. 2009;5:e1000443. PubMed PMC

Pesquita, C., Faria, D., Falcao, A.O., Lord, P., and Couto, F.M. (2009). Semantic similarity in biomedical ontologies. PLoS Comput. Biol. 5, e1000443. PubMed PMC

Fisher R.S., Cross J.H., French J.A., Higurashi N., Hirsch E., Jansen F.E., Lagae L., Moshé S.L., Peltola J., Roulet Perez E. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:522–530. PubMed

Fisher, R.S., Cross, J.H., French, J.A., Higurashi, N., Hirsch, E., Jansen, F.E., Lagae, L., Moshe, S.L., Peltola, J., Roulet Perez, E., et al. (2017). Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia 58, 522-530. PubMed

Suls A., Jaehn J.A., Kecskés A., Weber Y., Weckhuysen S., Craiu D.C., Siekierska A., Djémié T., Afrikanova T., Gormley P., EuroEPINOMICS RES Consortium De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am. J. Hum. Genet. 2013;93:967–975. PubMed PMC

Suls, A., Jaehn, J.A., Kecskes, A., Weber, Y., Weckhuysen, S., Craiu, D.C., Siekierska, A., Djemie, T., Afrikanova, T., Gormley, P., et al.; EuroEPINOMICS RES Consortium (2013). De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am. J. Hum. Genet. 93, 967-975. PubMed PMC

Vögtle F.N., Brändl B., Larson A., Pendziwiat M., Friederich M.W., White S.M., Basinger A., Kücükköse C., Muhle H., Jähn J.A. Mutations in PMPCB encoding the catalytic subunit of the mitochondrial presequence protease cause neurodegeneration in early childhood. Am. J. Hum. Genet. 2018;102:557–573. PubMed PMC

Vogtle, F.N., Brandl, B., Larson, A., Pendziwiat, M., Friederich, M.W., White, S.M., Basinger, A., Kucukkose, C., Muhle, H., Jahn, J.A., et al. (2018). Mutations in PMPCB encoding the catalytic subunit of the mitochondrial presequence protease cause neurodegeneration in early childhood. Am. J. Hum. Genet. 102, 557-573. PubMed PMC

Farwell Hagman K.D., Shinde D.N., Mroske C., Smith E., Radtke K., Shahmirzadi L., El-Khechen D., Powis Z., Chao E.C., Alcaraz W.A. Candidate-gene criteria for clinical reporting: Diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases. Genet. Med. 2017;19:224–235. PubMed PMC

Farwell Hagman, K.D., Shinde, D.N., Mroske, C., Smith, E., Radtke, K., Shahmirzadi, L., El-Khechen, D., Powis, Z., Chao, E.C., Alcaraz, W.A., et al. (2017). Candidate-gene criteria for clinical reporting: Diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases. Genet. Med. 19, 224-235. PubMed PMC

Farwell K.D., Shahmirzadi L., El-Khechen D., Powis Z., Chao E.C., Tippin Davis B., Baxter R.M., Zeng W., Mroske C., Parra M.C. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet. Med. 2015;17:578–586. PubMed

Farwell, K.D., Shahmirzadi, L., El-Khechen, D., Powis, Z., Chao, E.C., Tippin Davis, B., Baxter, R.M., Zeng, W., Mroske, C., Parra, M.C., et al. (2015). Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet. Med. 17, 578-586. PubMed

Schlicker A., Domingues F.S., Rahnenführer J., Lengauer T. A new measure for functional similarity of gene products based on Gene Ontology. BMC Bioinformatics. 2006;7:302. PubMed PMC

Schlicker, A., Domingues, F.S., Rahnenfuhrer, J., and Lengauer, T. (2006). A new measure for functional similarity of gene products based on Gene Ontology. BMC Bioinformatics 7, 302. PubMed PMC

Deng Y., Gao L., Wang B., Guo X. HPOSim: An R package for phenotypic similarity measure and enrichment analysis based on the human phenotype ontology. PLoS ONE. 2015;10:e0115692. PubMed PMC

Deng, Y., Gao, L., Wang, B., and Guo, X. (2015). HPOSim: An R package for phenotypic similarity measure and enrichment analysis based on the human phenotype ontology. PLoS ONE 10, e0115692. PubMed PMC

Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., Shindyalov I.N., Bourne P.E. The Protein Data Bank. Nucleic Acids Res. 2000;28:235–242. PubMed PMC

Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., and Bourne, P.E. (2000). The Protein Data Bank. Nucleic Acids Res. 28, 235-242. PubMed PMC

Frappier V., Chartier M., Najmanovich R.J. ENCoM server: Exploring protein conformational space and the effect of mutations on protein function and stability. Nucleic Acids Res. 2015;43(W1):W395-400. PubMed PMC

Frappier, V., Chartier, M., and Najmanovich, R.J. (2015). ENCoM server: Exploring protein conformational space and the effect of mutations on protein function and stability. Nucleic Acids Res. 43 (W1), W395-400. PubMed PMC

Kononenko N.L., Puchkov D., Classen G.A., Walter A.M., Pechstein A., Sawade L., Kaempf N., Trimbuch T., Lorenz D., Rosenmund C. Clathrin/AP-2 mediate synaptic vesicle reformation from endosome-like vacuoles but are not essential for membrane retrieval at central synapses. Neuron. 2014;82:981–988. PubMed

Kononenko, N.L., Puchkov, D., Classen, G.A., Walter, A.M., Pechstein, A., Sawade, L., Kaempf, N., Trimbuch, T., Lorenz, D., Rosenmund, C., et al. (2014). Clathrin/AP-2 mediate synaptic vesicle reformation from endosome-like vacuoles but are not essential for membrane retrieval at central synapses. Neuron 82, 981-988. PubMed

Posor Y., Eichhorn-Gruenig M., Puchkov D., Schöneberg J., Ullrich A., Lampe A., Müller R., Zarbakhsh S., Gulluni F., Hirsch E. Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate. Nature. 2013;499:233–237. PubMed

Posor, Y., Eichhorn-Gruenig, M., Puchkov, D., Schoneberg, J., Ullrich, A., Lampe, A., Muller, R., Zarbakhsh, S., Gulluni, F., Hirsch, E., et al. (2013). Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate. Nature 499, 233-237. PubMed

Schöneberg J., Lehmann M., Ullrich A., Posor Y., Lo W.T., Lichtner G., Schmoranzer J., Haucke V., Noé F. Lipid-mediated PX-BAR domain recruitment couples local membrane constriction to endocytic vesicle fission. Nat. Commun. 2017;8:15873. PubMed PMC

Schoneberg, J., Lehmann, M., Ullrich, A., Posor, Y., Lo, W.T., Lichtner, G., Schmoranzer, J., Haucke, V., and Noe, F. (2017). Lipid-mediated PX-BAR domain recruitment couples local membrane constriction to endocytic vesicle fission. Nat. Commun. 8, 15873. PubMed PMC

Jackson L.P., Kelly B.T., McCoy A.J., Gaffry T., James L.C., Collins B.M., Höning S., Evans P.R., Owen D.J. A large-scale conformational change couples membrane recruitment to cargo binding in the AP2 clathrin adaptor complex. Cell. 2010;141:1220–1229. PubMed PMC

Jackson, L.P., Kelly, B.T., McCoy, A.J., Gaffry, T., James, L.C., Collins, B.M., Honing, S., Evans, P.R., and Owen, D.J. (2010). A large-scale conformational change couples membrane recruitment to cargo binding in the AP2 clathrin adaptor complex. Cell 141, 1220-1229. PubMed PMC

Kononenko N.L., Claßen G.A., Kuijpers M., Puchkov D., Maritzen T., Tempes A., Malik A.R., Skalecka A., Bera S., Jaworski J., Haucke V. Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration. Nat. Commun. 2017;8:14819. PubMed PMC

Kononenko, N.L., Claßen, G.A., Kuijpers, M., Puchkov, D., Maritzen, T., Tempes, A., Malik, A.R., Skalecka, A., Bera, S., Jaworski, J., and Haucke, V. (2017). Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration. Nat. Commun. 8, 14819. PubMed PMC

Dittman J., Ryan T.A. Molecular circuitry of endocytosis at nerve terminals. Annu. Rev. Cell Dev. Biol. 2009;25:133–160. PubMed

Dittman, J., and Ryan, T.A. (2009). Molecular circuitry of endocytosis at nerve terminals. Annu. Rev. Cell Dev. Biol. 25, 133-160. PubMed

Saheki Y., De Camilli P. Synaptic vesicle endocytosis. Cold Spring Harb. Perspect. Biol. 2012;4:a005645. PubMed PMC

Saheki, Y., and De Camilli, P. (2012). Synaptic vesicle endocytosis. Cold Spring Harb. Perspect. Biol. 4, a005645. PubMed PMC

Kittler J.T., Chen G., Honing S., Bogdanov Y., McAinsh K., Arancibia-Carcamo I.L., Jovanovic J.N., Pangalos M.N., Haucke V., Yan Z., Moss S.J. Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission. Proc. Natl. Acad. Sci. USA. 2005;102:14871–14876. PubMed PMC

Kittler, J.T., Chen, G., Honing, S., Bogdanov, Y., McAinsh, K., Arancibia-Carcamo, I.L., Jovanovic, J.N., Pangalos, M.N., Haucke, V., Yan, Z., and Moss, S.J. (2005). Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission. Proc. Natl. Acad. Sci. USA 102, 14871-14876. PubMed PMC

Froemke R.C. Plasticity of cortical excitatory-inhibitory balance. Annu. Rev. Neurosci. 2015;38:195–219. PubMed PMC

Froemke, R.C. (2015). Plasticity of cortical excitatory-inhibitory balance. Annu. Rev. Neurosci. 38, 195-219. PubMed PMC

Mitsunari T., Nakatsu F., Shioda N., Love P.E., Grinberg A., Bonifacino J.S., Ohno H. Clathrin adaptor AP-2 is essential for early embryonal development. Mol. Cell. Biol. 2005;25:9318–9323. PubMed PMC

Mitsunari, T., Nakatsu, F., Shioda, N., Love, P.E., Grinberg, A., Bonifacino, J.S., and Ohno, H. (2005). Clathrin adaptor AP-2 is essential for early embryonal development. Mol. Cell. Biol. 25, 9318-9323. PubMed PMC

Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., O’Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Exome Aggregation Consortium Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291. PubMed PMC

Lek, M., Karczewski, K.J., Minikel, E.V., Samocha, K.E., Banks, E., Fennell, T., O’Donnell-Luria, A.H., Ware, J.S., Hill, A.J., Cummings, B.B., et al.; Exome Aggregation Consortium (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285-291. PubMed PMC

Petrovski S., Wang Q., Heinzen E.L., Allen A.S., Goldstein D.B. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013;9:e1003709. PubMed PMC

Petrovski, S., Wang, Q., Heinzen, E.L., Allen, A.S., and Goldstein, D.B. (2013). Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 9, e1003709. PubMed PMC

Schubert J., Siekierska A., Langlois M., May P., Huneau C., Becker F., Muhle H., Suls A., Lemke J.R., de Kovel C.G., EuroEPINOMICS RES Consortium Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat. Genet. 2014;46:1327–1332. PubMed

Schubert, J., Siekierska, A., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J.R., de Kovel, C.G., et al.; EuroEPINOMICS RES Consortium (2014). Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat. Genet. 46, 1327-1332. PubMed

Hamdan F.F., Myers C.T., Cossette P., Lemay P., Spiegelman D., Laporte A.D., Nassif C., Diallo O., Monlong J., Cadieux-Dion M., Deciphering Developmental Disorders Study High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am. J. Hum. Genet. 2017;101:664–685. PubMed PMC

Hamdan, F.F., Myers, C.T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A.D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., et al.; Deciphering Developmental Disorders Study (2017). High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am. J. Hum. Genet. 101, 664-685. PubMed PMC

von Spiczak S., Helbig K.L., Shinde D.N., Huether R., Pendziwiat M., Lourenço C., Nunes M.E., Sarco D.P., Kaplan R.A., Dlugos D.J., Epi4K Consortium. EuroEPINOMICS-RES NLES Working Group DNM1 encephalopathy: A new disease of vesicle fission. Neurology. 2017;89:385–394. PubMed PMC

von Spiczak, S., Helbig, K.L., Shinde, D.N., Huether, R., Pendziwiat, M., Lourenço, C., Nunes, M.E., Sarco, D.P., Kaplan, R.A., Dlugos, D.J., et al.; Epi4K Consortium; EuroEPINOMICS-RES NLES Working Group (2017). DNM1 encephalopathy: A new disease of vesicle fission. Neurology 89, 385-394. PubMed PMC

Myers C.T., Stong N., Mountier E.I., Helbig K.L., Freytag S., Sullivan J.E., Ben Zeev B., Nissenkorn A., Tzadok M., Heimer G. De novo mutations in PPP3CA cause severe neurodevelopmental disease with seizures. Am. J. Hum. Genet. 2017;101:516–524. PubMed PMC

Myers, C.T., Stong, N., Mountier, E.I., Helbig, K.L., Freytag, S., Sullivan, J.E., Ben Zeev, B., Nissenkorn, A., Tzadok, M., Heimer, G., et al. (2017). De novo mutations in PPP3CA cause severe neurodevelopmental disease with seizures. Am. J. Hum. Genet. 101, 516-524. PubMed PMC

Kadlecova Z., Spielman S.J., Loerke D., Mohanakrishnan A., Reed D.K., Schmid S.L. Regulation of clathrin-mediated endocytosis by hierarchical allosteric activation of AP2. J. Cell Biol. 2017;216:167–179. PubMed PMC

Kadlecova, Z., Spielman, S.J., Loerke, D., Mohanakrishnan, A., Reed, D.K., and Schmid, S.L. (2017). Regulation of clathrin-mediated endocytosis by hierarchical allosteric activation of AP2. J. Cell Biol. 216, 167-179. PubMed PMC

Genetic Testing for Malformations of Cortical Development: A Clinical Diagnostic Study