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A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy
I. Helbig, T. Lopez-Hernandez, O. Shor, P. Galer, S. Ganesan, M. Pendziwiat, A. Rademacher, CA. Ellis, N. Hümpfer, N. Schwarz, S. Seiffert, J. Peeden, J. Shen, K. Štěrbová, TB. Hammer, RS. Møller, DN. Shinde, S. Tang, L. Smith, A. Poduri, R....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
T32 NS091008
NINDS NIH HHS - United States
NLK
Cell Press Free Archives
od 1997-01-01 do Před 6 měsíci
Free Medical Journals
od 1949 do Před 6 měsíci
PubMed Central
od 1949 do Před 6 měsíci
Europe PubMed Central
od 1949 do Před 6 měsíci
Open Access Digital Library
od 2005-01-01
- MeSH
- adaptorový proteinový komplex - mu-podjednotky genetika MeSH
- adaptorový proteinový komplex 2 genetika MeSH
- dítě MeSH
- endocytóza * MeSH
- epilepsie etiologie patologie MeSH
- klathrin genetika metabolismus MeSH
- kojenec MeSH
- lidé MeSH
- missense mutace * MeSH
- mladiství MeSH
- myši knockoutované MeSH
- myši MeSH
- nemoci mozku etiologie patologie MeSH
- neurovývojové poruchy etiologie patologie MeSH
- předškolní dítě MeSH
- sekvenování exomu MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
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
Department of Neurology Harvard Medical School Boston MA 02115 USA
Department of Neurology Rabin Medical Center Petach Tikva 4941492 Israel
Department of Neuropediatrics Christian Albrechts University of Kiel 24105 Kiel Germany
Department of Neurosurgery University of Tübingen 72076 Tübingen Germany
Division of Clinical Genomics Ambry Genetics Aliso Viejo CA 92656 USA
Division of Neurology Children's Hospital of Philadelphia Philadelphia PA 19104 USA
Epilepsy Genetics Program Department of Neurology Boston Children's Hospital Boston MA 02115 USA
Freie Universität Berlin Faculty of Biology Chemistry Pharmacy 14195 Berlin Germany
Institute for Regional Health Services University of Southern Denmark 5230 Odense Denmark
Leibniz Forschungsinstitut für Molekulare Pharmakologie 13125 Berlin Germany
Luxembourg Centre for Systems Biomedicine University of Luxembourg 4365 Esch sur Alzette Luxembourg
Sackler School of Medicine Tel Aviv University Tel Aviv 6997801 Israel
Citace poskytuje Crossref.org
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