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Am J Hum Genet. 2019 Jun 6;104(6):1060-1072. doi: 10.1016/j.ajhg.2019.04.001. Epub 2019 May 16.

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

Author information

1
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. Electronic address: helbigi@email.chop.edu.
2
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany.
3
Department of Neurology, Rabin Medical Center, Petach Tikva 4941492, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
4
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.
5
Department of Neuropediatrics, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
6
Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
7
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany; Freie Universität Berlin, Faculty of Biology, Chemistry, Pharmacy, 14195 Berlin, Germany.
8
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
9
East Tennessee Children's Hospital, University of Tennessee Department of Medicine, Knoxville, TN 37916, USA.
10
Division of Genetics, Department of Pediatrics, University of California San Francisco, Fresno, CA 93701, USA.
11
Department of Child Neurology, Charles University 2nd Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
12
Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark.
13
Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, 5230 Odense, Denmark.
14
Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
15
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
16
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
17
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg.
18
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.

Abstract

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.

KEYWORDS:

Human Phenotype Ontology; clathrin-mediated endocytosis; computational phenotypes; developmental and epileptic encephalopathy; neurodevelopmental disorders; synaptic transmission

PMID:
31104773
PMCID:
PMC6556875
[Available on 2019-12-06]
DOI:
10.1016/j.ajhg.2019.04.001

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