|
Title
|
|
|
|
A recurrent missense variant in AP2M1 impairs clathrin-mediated endocytosis and causes developmental and epileptic encephalopathy
| |
|
Author
|
|
|
|
| |
|
Institution/Organisation
|
|
|
|
EuroEPINOMICS-RES Consortium
GRIN Consortium
| |
|
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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
The American journal of human genetics / American Society of Human Genetics [Bethesda, Md] - New York, N.Y., 1949, currens
| |
|
Publication
|
|
|
|
New York, N.Y.
:
2019
| |
|
ISSN
|
|
|
|
0002-9297
[print]
1537-6605
[online]
| |
|
DOI
|
|
|
|
10.1016/J.AJHG.2019.04.001
| |
|
Volume/pages
|
|
|
|
104
:6
(2019)
, p. 1060-1072
| |
|
ISI
|
|
|
|
000470240000004
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|