Reference : A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Cause...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Systems Biomedicine
A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.
Helbig, Ingo [> >]
Lopez-Hernandez, Tania [> >]
Shor, Oded [> >]
Galer, Peter [> >]
Ganesan, Shiva [> >]
Pendziwiat, Manuela [> >]
Rademacher, Annika [> >]
Ellis, Colin A. [> >]
Humpfer, Nadja [> >]
Schwarz, Niklas [> >]
Seiffert, Simone [> >]
Peeden, Joseph [> >]
Shen, Joseph [> >]
Sterbova, Katalin [> >]
Hammer, Trine Bjorg [> >]
Moller, Rikke S. [> >]
Shinde, Deepali N. [> >]
Tang, Sha [> >]
Smith, Lacey [> >]
Poduri, Annapurna [> >]
Krause, Roland mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Benninger, Felix [> >]
Helbig, Katherine L. [> >]
Haucke, Volker [> >]
Weber, Yvonne G. [> >]
EuroEPINOMICS-RES Consortium []
Balling, Rudi mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
GRIN consortium []
American journal of human genetics
Yes (verified by ORBilu)
United States
[en] Human Phenotype Ontology ; clathrin-mediated endocytosis ; computational phenotypes ; developmental and epileptic encephalopathy ; neurodevelopmental disorders ; synaptic transmission
[en] 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 mu-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 mu-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2mu 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group)
Copyright (c) 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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