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

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F19%3A10394636" target="_blank" >RIV/00064203:_____/19:10394636 - isvavai.cz</a>

  • Alternative codes found

    RIV/00216208:11130/19:10394636

  • Result on the web

    <a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=KCeq1EKftw" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=KCeq1EKftw</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1016/j.ajhg.2019.04.001" target="_blank" >10.1016/j.ajhg.2019.04.001</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

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

  • Original language description

    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&gt;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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    30103 - Neurosciences (including psychophysiology)

Result continuities

  • Project

    <a href="/en/project/NV15-33041A" target="_blank" >NV15-33041A: Massive parallel sequencing of genes related to infantile epilepsies and epileptic encephalopathies for diagnostics of epilepsy in Czech patients.</a><br>

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Others

  • Publication year

    2019

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    The American Journal of Human Genetics

  • ISSN

    0002-9297

  • e-ISSN

  • Volume of the periodical

    104

  • Issue of the periodical within the volume

    6

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    13

  • Pages from-to

    1060-1072

  • UT code for WoS article

    000470240000004

  • EID of the result in the Scopus database

    2-s2.0-85066432353