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

Ingo Helbig; Tania Lopez-Hernandez; Oded Shor; Peter Galer; Shiva Ganesan; Manuela Pendziwiat; Annika Rademacher; Colin Ellis; Nadja Hümpfer; Niklas Schwarz; Simone Seiffert; Joseph Peeden; Joseph Shen; Katalin Štěrbová; Trine Bjørg Hammer; Rikke Møller; Deepali Shinde; Sha Tang; Lacey Smith; Annapurna Poduri; Roland Krause; Felix Benninger; Katherine Helbig; Volker Haucke; Yvonne Weber; Rudi Balling; Nina Barisic; Stéphanie Baulac; Hande Caglayan; Dana Craiu; Peter de Jonghe; Christel Depienne; Renzo Guerrini; Helle Hjalgrim; Dorota Hoffman-Zacharska; Johanna Jähn; Karl Martin Klein; Bobby P.C. Koeleman; Vladimir Komarek; Eric Leguern; Anna-Elina Lehesjoki; Johannes Lemke; Holger Lerche; Tarja Linnankivi; Carla Marini; Patrick May; Hiltrud Muhle; Deb Pal; Aarno Palotie; Felix Rosenow; Susanne Schubert-Bast; Kaja Selmer; Jose Serratosa; Sanjay Sisodiya; Ulrich Stephani; Pasquale Striano; Arvid Suls; Tiina Talvik; Sarah von Spiczak; Sarah Weckhuysen; Federico Zara; Paul Avillach; Anna Bartels; Sawona Biswas; Florence Bourgeois; Batsal Devkota; Tracy Glauser; Barbara Hallinan; Allison Heath; Joel Hirschhorn; Judson Kilbourn; Sek Won Kong; Ian Krantz; In-Hee Lee; Kenneth Mandl; Eric Marsh; Kristen Sund; Deanne Taylor; Peter White; Rudi Balling; Nina Barisic; Stéphanie Baulac; Hande Caglayan; Dana Craiu; Peter De Jonghe; Christel Depienne; Renzo Guerrini; Helle Hjalgrim; Dorota Hoffman-Zacharska; Johanna Jähn; Karl Martin Klein; Bobby P.C. Koeleman; Vladimir Komarek; Eric Leguern; Anna-Elina Lehesjoki; Johannes R. Lemke; Holger Lerche; Tarja Linnankivi; Carla Marini; Patrick May; Hiltrud Muhle; Deb K. Pal; Aarno Palotie; Felix Rosenow; Susanne Schubert-Bast; Kaja Selmer; Jose M. Serratosa; Sanjay Sisodiya; Ulrich Stephani; Pasquale Striano; Arvid Suls; Tiina Talvik; Sarah Von Spiczak; Sarah Weckhuysen; Federico Zara; Paul Avillach; Anna Bartels; Sawona Biswas; Florence Bourgeois; Batsal Devkota; Tracy Glauser; Barbara Hallinan; Allison Heath; Joel Hirschhorn; Judson Kilbourn; Sek Won Kong; Ian Krantz; In-Hee Lee; Kenneth D. Mandl; Eric Marsh; Kristen Sund; Deanne Taylor; Peter White

doi:10.1016/j.ajhg.2019.04.001

Journal Articles American Journal of Human Genetics Year : 2019

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

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Ingo Helbig

Function : Author
PersonId : 1378726
ORCID : 0000-0001-8486-0558

Children’s Hospital of Philadelphia

Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel

Perelman School of Medicine

Tania Lopez-Hernandez

Function : Author

Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne]

Oded Shor

Function : Author

Sackler School of Medicine

Peter Galer

Function : Author

Children’s Hospital of Philadelphia

Shiva Ganesan

Function : Author

Children’s Hospital of Philadelphia

Manuela Pendziwiat

Function : Author

University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein

Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel

Annika Rademacher

Function : Author

Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel

Colin Ellis

Function : Author

Perelman School of Medicine

Nadja Hümpfer

Function : Author

Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne]

Niklas Schwarz

Function : Author

Hertie Institute for Clinical Brain Research [Tubingen]

Simone Seiffert

Function : Author

Hertie Institute for Clinical Brain Research [Tubingen]

Joseph Peeden

Function : Author

Joseph Shen

Function : Author

University of California [San Francisco]

Katalin Štěrbová

Function : Author

University Hospital Motol [Prague]

Trine Bjørg Hammer

Function : Author

Rikke Møller

Function : Author

University of Southern Denmark

Deepali Shinde

Function : Author

Ambry Genetics [Aliso Viejo, CA, USA]

Sha Tang

Function : Author

Ambry Genetics [Aliso Viejo, CA, USA]

Lacey Smith

Function : Author

Boston Children's Hospital

Annapurna Poduri

Function : Author

Boston Children's Hospital

Harvard Medical School [Boston]

Roland Krause

Function : Author

Luxembourg Centre For Systems Biomedicine

Felix Benninger

Function : Author

Sackler School of Medicine

Katherine Helbig

Function : Author

Children’s Hospital of Philadelphia

Volker Haucke

Function : Author

Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne]

Yvonne Weber

Function : Author

Hertie Institute for Clinical Brain Research [Tubingen]

Eberhard Karls Universität Tübingen = University of Tübingen

Rudi Balling

Function : Author

Nina Barisic

Function : Author

Stéphanie Baulac

Function : Author

Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute

Hande Caglayan

Function : Author

Dana Craiu

Function : Author

Peter de Jonghe

Function : Author

Christel Depienne

Function : Author

Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute

Renzo Guerrini

Function : Author

Helle Hjalgrim

Function : Author

Dorota Hoffman-Zacharska

Function : Author

Johanna Jähn

Function : Author

Karl Martin Klein

Function : Author

Bobby P.C. Koeleman

Function : Author

Vladimir Komarek

Function : Author

Eric Leguern

Function : Author

Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute

Anna-Elina Lehesjoki

Function : Author

Johannes Lemke

Function : Author

Holger Lerche

Function : Author

Tarja Linnankivi

Function : Author

Carla Marini

Function : Author

Patrick May

Function : Author

Hiltrud Muhle

Function : Author

Deb Pal

Function : Author

Aarno Palotie

Function : Author

Felix Rosenow

Function : Author

Susanne Schubert-Bast

Function : Author

Kaja Selmer

Function : Author

Jose Serratosa

Function : Author

Sanjay Sisodiya

Function : Author

Ulrich Stephani

Function : Author

Pasquale Striano

Function : Author

Arvid Suls

Function : Author

Tiina Talvik

Function : Author

Sarah von Spiczak

Function : Author

Sarah Weckhuysen

Function : Author

Federico Zara

Function : Author

Paul Avillach

Function : Author

Anna Bartels

Function : Author

Sawona Biswas

Function : Author

Florence Bourgeois

Function : Author

Batsal Devkota

Function : Author

Tracy Glauser

Function : Author

Barbara Hallinan

Function : Author

Allison Heath

Function : Author

Joel Hirschhorn

Function : Author

Judson Kilbourn

Function : Author

Sek Won Kong

Function : Author

Ian Krantz

Function : Author

In-Hee Lee

Function : Author

Kenneth Mandl

Function : Author

Eric Marsh

Function : Author

Kristen Sund

Function : Author

Deanne Taylor

Function : Author

Peter White

Function : Author

Rudi Balling

Function : Author

Nina Barisic

Function : Author

Stéphanie Baulac

Function : Author

Hande Caglayan

Function : Author

Dana Craiu

Function : Author

Peter De Jonghe

Function : Author

Christel Depienne

Function : Author

Renzo Guerrini

Function : Author

Helle Hjalgrim

Function : Author

Dorota Hoffman-Zacharska

Function : Author

Johanna Jähn

Function : Author

Karl Martin Klein

Function : Author

Bobby P.C. Koeleman

Function : Author

Vladimir Komarek

Function : Author

Eric Leguern

Function : Author

Anna-Elina Lehesjoki

Function : Author

Johannes R. Lemke

Function : Author

Holger Lerche

Function : Author

Tarja Linnankivi

Function : Author

Carla Marini

Function : Author

Patrick May

Function : Author

Hiltrud Muhle

Function : Author

Deb K. Pal

Function : Author

Aarno Palotie

Function : Author

Felix Rosenow

Function : Author

Susanne Schubert-Bast

Function : Author

Kaja Selmer

Function : Author

Jose M. Serratosa

Function : Author

Sanjay Sisodiya

Function : Author

Ulrich Stephani

Function : Author

Pasquale Striano

Function : Author

Arvid Suls

Function : Author

Tiina Talvik

Function : Author

Sarah Von Spiczak

Function : Author

Sarah Weckhuysen

Function : Author

Federico Zara

Function : Author

Paul Avillach

Function : Author

Anna Bartels

Function : Author

Sawona Biswas

Function : Author

Florence Bourgeois

Function : Author

Batsal Devkota

Function : Author

Tracy Glauser

Function : Author

Barbara Hallinan

Function : Author

Allison Heath

Function : Author

Joel Hirschhorn

Function : Author

Judson Kilbourn

Function : Author

Sek Won Kong

Function : Author

Ian Krantz

Function : Author

In-Hee Lee

Function : Author

Kenneth D. Mandl

Function : Author

Eric Marsh

Function : Author

Kristen Sund

Function : Author

Deanne Taylor

Function : Author

Peter White

Function : Author

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

Domains

Life Sciences [q-bio]

Gestionnaire HAL 4 Sorbonne Université : Connect in order to contact the contributor

https://hal.sorbonne-universite.fr/hal-04560692

Submitted on : Friday, April 26, 2024-1:55:36 PM

Last modification on : Wednesday, September 25, 2024-9:56:03 AM

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hal-04560692 , version 1 (26-04-2024)

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HAL Id : hal-04560692 , version 1
DOI : 10.1016/j.ajhg.2019.04.001
PUBMED : 31104773
PUBMEDCENTRAL : PMC6556875

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Ingo Helbig, Tania Lopez-Hernandez, Oded Shor, Peter Galer, Shiva Ganesan, et al.. A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy. American Journal of Human Genetics, 2019, 104 (6), pp.1060-1072. ⟨10.1016/j.ajhg.2019.04.001⟩. ⟨hal-04560692⟩

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

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