PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy.
calcineurin
constitutive activation
epileptic syndromes
gain-of-function
loss-of-function
truncating variants
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
04
05
2021
received:
01
03
2021
accepted:
04
05
2021
pubmed:
9
5
2021
medline:
31
12
2021
entrez:
8
5
2021
Statut:
ppublish
Résumé
PPP3CA encodes the catalytic subunit of calcineurin, a calcium-calmodulin-regulated serine-threonine phosphatase. Loss-of-function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain-of-function (GoF) variants in the auto-inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26-amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early-onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.
Substances chimiques
Calcineurin
EC 3.1.3.16
PPP3CA protein, human
EC 3.1.3.16
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
227-233Subventions
Organisme : NHGRI NIH HHS
ID : U01 HG007709
Pays : United States
Informations de copyright
© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.
Références
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