Published 2019
| Version v1
Publication
A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy
Creators
- Helbig I.
- Lopez-Hernandez T.
- Shor O.
- Galer P.
- Ganesan S.
- Pendziwiat M.
- Rademacher A.
- Ellis C. A.
- Humpfer N.
- Schwarz N.
- Seiffert S.
- Peeden J.
- Shen J.
- Sterbova K.
- Hammer T. B.
- Moller R. S.
- Shinde D. N.
- Tang S.
- Smith L.
- Poduri A.
- Krause R.
- Benninger F.
- Helbig K. L.
- Haucke V.
- Weber Y. G.
- Balling R.
- Barisic N.
- Baulac S.
- Caglayan H.
- Craiu D.
- De Jonghe P.
- Depienne C.
- Guerrini R.
- Hjalgrim H.
- Hoffman-Zacharska D.
- Jahn J.
- Klein K. M.
- Koeleman B. P. C.
- Komarek V.
- Leguern E.
- Lehesjoki A. -E.
- Lemke J. R.
- Lerche H.
- Linnankivi T.
- Marini C.
- May P.
- Muhle H.
- Pal D. K.
- Palotie A.
- Rosenow F.
- Schubert-Bast S.
- Selmer K.
- Serratosa J. M.
- Sisodiya S.
- Stephani U.
- Striano P.
- Suls A.
- Talvik T.
- von Spiczak S.
- Weckhuysen S.
- Zara F.
- Avillach P.
- Bartels A.
- Biswas S.
- Bourgeois F.
- Devkota B.
- Glauser T.
- Hallinan B.
- Heath A.
- Hirschhorn J.
- Kilbourn J.
- Kong S. W.
- Krantz I.
- Lee I. -H.
- Mandl K. D.
- Marsh E.
- Sund K.
- Taylor D.
- White P.
Contributors
Others:
- Helbig, I.
- Lopez-Hernandez, T.
- Shor, O.
- Galer, P.
- Ganesan, S.
- Pendziwiat, M.
- Rademacher, A.
- Ellis, C. A.
- Humpfer, N.
- Schwarz, N.
- Seiffert, S.
- Peeden, J.
- Shen, J.
- Sterbova, K.
- Hammer, T. B.
- Moller, R. S.
- Shinde, D. N.
- Tang, S.
- Smith, L.
- Poduri, A.
- Krause, R.
- Benninger, F.
- Helbig, K. L.
- Haucke, V.
- Weber, Y. G.
- Balling, R.
- Barisic, N.
- Baulac, S.
- Caglayan, H.
- Craiu, D.
- De Jonghe, P.
- Depienne, C.
- Guerrini, R.
- Hjalgrim, H.
- Hoffman-Zacharska, D.
- Jahn, J.
- Klein, K. M.
- Koeleman, B. P. C.
- Komarek, V.
- Leguern, E.
- Lehesjoki, A. -E.
- Lemke, J. R.
- Lerche, H.
- Linnankivi, T.
- Marini, C.
- May, P.
- Muhle, H.
- Pal, D. K.
- Palotie, A.
- Rosenow, F.
- Schubert-Bast, S.
- Selmer, K.
- Serratosa, J. M.
- Sisodiya, S.
- Stephani, U.
- Striano, P.
- Suls, A.
- Talvik, T.
- von Spiczak, S.
- Weckhuysen, S.
- Zara, F.
- Avillach, P.
- Bartels, A.
- Biswas, S.
- Bourgeois, F.
- Devkota, B.
- Glauser, T.
- Hallinan, B.
- Heath, A.
- Hirschhorn, J.
- Kilbourn, J.
- Kong, S. W.
- Krantz, I.
- Lee, I. -H.
- Mandl, K. D.
- Marsh, E.
- Sund, K.
- Taylor, D.
- White, P.
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>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.
Additional details
Identifiers
- URL
- http://hdl.handle.net/11567/1021892
- URN
- urn:oai:iris.unige.it:11567/1021892
Origin repository
- Origin repository
- UNIGE