A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy

Content Provider	Scilit
Author	Helbig, Ingo Lopez-Hernandez, Tania Shor, Oded Galer, Peter Ganesan, Shiva Pendziwiat, Manuela Rademacher, Annika Ellis, Colin A. Hümpfer, Nadja Schwarz, Niklas Seiffert, Simone Peeden, Joseph Shen, Joseph Štěrbová, Katalin Hammer, Trine Bjørg Møller, Rikke S. Shinde, Deepali N. Tang, Sha Smith, Lacey Poduri, Annapurna Krause, Roland Benninger, Felix Helbig, Katherine L. Haucke, Volker Weber, Yvonne G. Balling, Rudi Barisic, Nina Baulac, Stéphanie Caglayan, Hande Craiu, Dana Jonghe, Peter De Depienne, Christel Guerrini, Renzo Hjalgrim, Helle Hoffman-Zacharska, Dorota Jähn, Johanna Klein, Karl Martin Koeleman, Bobby P. C. Komarek, Vladimir Leguern, Eric Lehesjoki, Anna-Elina Lemke, Johannes R. Lerche, Holger Linnankivi, Tarja Marini, Carla May, Patrick Muhle, Hiltrud Pal, Deb K. Palotie, Aarno Rosenow, Felix Schubert-Bast, Susanne Selmer, Kaja Serratosa, Jose M. Sisodiya, Sanjay Stephani, Ulrich Striano, Pasquale Suls, Arvid Talvik, Tiina von Spiczak, Sarah Weckhuysen, Sarah Zara, Federico Avillach, Paul Bartels, Anna Biswas, Sawona Bourgeois, Florence Devkota, Batsal Glauser, Tracy Hallinan, Barbara Heath, Allison Hirschhorn, Joel Kilbourn, Judson Kong, Sek Won Krantz, Ian Lee, In-Hee Mandl, Kenneth D. Marsh, Eric Sund, Kristen Taylor, Deanne White, Peter
Copyright Year	2019
Description	Journal: American Journal of Human Genetics 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.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556875/pdf http://www.cell.com/article/S0002929719301478/pdf
Ending Page	1072
Page Count	13
Starting Page	1060
ISSN	00029297
e-ISSN	15376605
DOI	10.1016/j.ajhg.2019.04.001
Journal	American Journal of Human Genetics
Issue Number	6
Volume Number	104
Language	English
Publisher	Elsevier BV
Publisher Date	2019-05-16
Access Restriction	Open
Subject Keyword	Journal: American Journal of Human Genetics Clathrin-mediated Endocytosis Developmental and Epileptic Encephalopathy Synaptic Transmission Computational Phenotypes Human Phenotype Ontology Neurodevelopmental Disorders
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)