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

the EuroEPINOMICS-RES Consortium, the GRIN Consortium

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind104
Udgave nummer6
Sider (fra-til)1060-1072
ISSN0002-9297
DOI
StatusUdgivet - 6. jun. 2019

Fingeraftryk

Clathrin
Endocytosis
Exome
Entropy
Membranes
Proteins

Citer dette

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title = "A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy",
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 = "clathrin-mediated endocytosis, computational phenotypes, developmental and epileptic encephalopathy, Human Phenotype Ontology, neurodevelopmental disorders, synaptic transmission",
author = "Ingo Helbig and Tania Lopez-Hernandez and Oded Shor and Peter Galer and Shiva Ganesan and Manuela Pendziwiat and Annika Rademacher and Ellis, {Colin A.} and Nadja H{\"u}mpfer and Niklas Schwarz and Simone Seiffert and Joseph Peeden and Joseph Shen and Katalin Štěrbov{\'a} and Hammer, {Trine Bj{\o}rg} and M{\o}ller, {Rikke S.} and Shinde, {Deepali N.} and Sha Tang and Lacey Smith and Annapurna Poduri and Roland Krause and Felix Benninger and Helbig, {Katherine L.} and Volker Haucke and Weber, {Yvonne G.} and Rudi Balling and Nina Barisic and St{\'e}phanie Baulac and Hande Caglayan and Dana Craiu and {De Jonghe}, Peter and Christel Depienne and Renzo Guerrini and Helle Hjalgrim and Dorota Hoffman-Zacharska and Johanna J{\"a}hn and Klein, {Karl Martin} and Koeleman, {Bobby P.C.} and Vladimir Komarek and Eric Leguern and Lehesjoki, {Anna Elina} and Lemke, {Johannes R.} and Holger Lerche and Tarja Linnankivi and Carla Marini and Patrick May and Hiltrud Muhle and Pal, {Deb K.} and Aarno Palotie and Felix Rosenow and {the EuroEPINOMICS-RES Consortium} and {the GRIN Consortium}",
year = "2019",
month = "6",
day = "6",
doi = "10.1016/j.ajhg.2019.04.001",
language = "English",
volume = "104",
pages = "1060--1072",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",

}

A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy. / the EuroEPINOMICS-RES Consortium; the GRIN Consortium.

I: American Journal of Human Genetics, Bind 104, Nr. 6, 06.06.2019, s. 1060-1072.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy

AU - Helbig, Ingo

AU - Lopez-Hernandez, Tania

AU - Shor, Oded

AU - Galer, Peter

AU - Ganesan, Shiva

AU - Pendziwiat, Manuela

AU - Rademacher, Annika

AU - Ellis, Colin A.

AU - Hümpfer, Nadja

AU - Schwarz, Niklas

AU - Seiffert, Simone

AU - Peeden, Joseph

AU - Shen, Joseph

AU - Štěrbová, Katalin

AU - Hammer, Trine Bjørg

AU - Møller, Rikke S.

AU - Shinde, Deepali N.

AU - Tang, Sha

AU - Smith, Lacey

AU - Poduri, Annapurna

AU - Krause, Roland

AU - Benninger, Felix

AU - Helbig, Katherine L.

AU - Haucke, Volker

AU - Weber, Yvonne G.

AU - Balling, Rudi

AU - Barisic, Nina

AU - Baulac, Stéphanie

AU - Caglayan, Hande

AU - Craiu, Dana

AU - De Jonghe, Peter

AU - Depienne, Christel

AU - Guerrini, Renzo

AU - Hjalgrim, Helle

AU - Hoffman-Zacharska, Dorota

AU - Jähn, Johanna

AU - Klein, Karl Martin

AU - Koeleman, Bobby P.C.

AU - Komarek, Vladimir

AU - Leguern, Eric

AU - Lehesjoki, Anna Elina

AU - Lemke, Johannes R.

AU - Lerche, Holger

AU - Linnankivi, Tarja

AU - Marini, Carla

AU - May, Patrick

AU - Muhle, Hiltrud

AU - Pal, Deb K.

AU - Palotie, Aarno

AU - Rosenow, Felix

AU - the EuroEPINOMICS-RES Consortium

AU - the GRIN Consortium

PY - 2019/6/6

Y1 - 2019/6/6

N2 - 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.

AB - 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.

KW - clathrin-mediated endocytosis

KW - computational phenotypes

KW - developmental and epileptic encephalopathy

KW - Human Phenotype Ontology

KW - neurodevelopmental disorders

KW - synaptic transmission

U2 - 10.1016/j.ajhg.2019.04.001

DO - 10.1016/j.ajhg.2019.04.001

M3 - Journal article

VL - 104

SP - 1060

EP - 1072

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -