Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain
Standard
Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain. / Tibbe, Debora; Ferle, Pia; Krisp, Christoph; Nampoothiri, Sheela; Mirzaa, Ghayda; Assaf, Melissa; Parikh, Sumit; Kutsche, Kerstin; Kreienkamp, Hans-Jürgen.
in: LIFE SCI ALLIANCE, Jahrgang 5, Nr. 10, e202201512, 10.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain
AU - Tibbe, Debora
AU - Ferle, Pia
AU - Krisp, Christoph
AU - Nampoothiri, Sheela
AU - Mirzaa, Ghayda
AU - Assaf, Melissa
AU - Parikh, Sumit
AU - Kutsche, Kerstin
AU - Kreienkamp, Hans-Jürgen
N1 - © 2022 Tibbe et al.
PY - 2022/10
Y1 - 2022/10
N2 - CASK is a unique membrane-associated guanylate kinase (MAGUK) because of its Ca2+/calmodulin-dependent kinase (CaMK) domain. We describe four male patients with a severe neurodevelopmental disorder with microcephaly carrying missense variants affecting the CaMK domain. One boy who carried the p.E115K variant and died at an early age showed pontocerebellar hypoplasia (PCH) in addition to microcephaly, thus exhibiting the classical MICPCH phenotype observed in individuals with CASK loss-of-function variants. All four variants selectively weaken the interaction of CASK with Liprin-α2, a component of the presynaptic active zone. Liprin-α proteins form spherical phase-separated condensates, which we observe here in Liprin-α2 overexpressing HEK293T cells. Large Liprin-α2 clusters were also observed in transfected primary-cultured neurons. Cluster formation of Liprin-α2 is reversed in the presence of CASK; this is associated with altered phosphorylation of Liprin-α2. The p.E115K variant fails to interfere with condensate formation. As the individual carrying this variant had the severe MICPCH disorder, we suggest that regulation of Liprin-α2-mediated phase condensate formation is a new functional feature of CASK which must be maintained to prevent PCH.
AB - CASK is a unique membrane-associated guanylate kinase (MAGUK) because of its Ca2+/calmodulin-dependent kinase (CaMK) domain. We describe four male patients with a severe neurodevelopmental disorder with microcephaly carrying missense variants affecting the CaMK domain. One boy who carried the p.E115K variant and died at an early age showed pontocerebellar hypoplasia (PCH) in addition to microcephaly, thus exhibiting the classical MICPCH phenotype observed in individuals with CASK loss-of-function variants. All four variants selectively weaken the interaction of CASK with Liprin-α2, a component of the presynaptic active zone. Liprin-α proteins form spherical phase-separated condensates, which we observe here in Liprin-α2 overexpressing HEK293T cells. Large Liprin-α2 clusters were also observed in transfected primary-cultured neurons. Cluster formation of Liprin-α2 is reversed in the presence of CASK; this is associated with altered phosphorylation of Liprin-α2. The p.E115K variant fails to interfere with condensate formation. As the individual carrying this variant had the severe MICPCH disorder, we suggest that regulation of Liprin-α2-mediated phase condensate formation is a new functional feature of CASK which must be maintained to prevent PCH.
U2 - 10.26508/lsa.202201512
DO - 10.26508/lsa.202201512
M3 - SCORING: Journal article
C2 - 36137748
VL - 5
JO - LIFE SCI ALLIANCE
JF - LIFE SCI ALLIANCE
SN - 2575-1077
IS - 10
M1 - e202201512
ER -
