Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/24861
Title: Novel Missense CACNA1G Mutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy.
Austin Authors: Berecki, Géza;Helbig, Katherine L;Ware, Tyson L;Grinton, Bronwyn;Skraban, Cara M;Marsh, Eric D;Berkovic, Samuel F ;Petrou, Steven
Affiliation: Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3052, Australia
Department of Paediatrics, Royal Hobart Hospital, Hobart, TAS 7000, Australia
Epilepsy Research Centre
Department of the Florey Institute, University of Melbourne, Parkville, VIC 3050, Australia
Division of Neurology and The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Department of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Division of Neurology and The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Issue Date: 31-Aug-2020
Date: 2020-08-31
Publication information: International Journal of Molecular Sciences 2020; 21(17): 6333
Abstract: The CACNA1G gene encodes the low-voltage-activated Cav3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Cav3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Cav3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca2+ current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with CACNA1G mutations, corroborating further the causal association with distinct complex phenotypes.
URI: https://ahro.austin.org.au/austinjspui/handle/1/24861
DOI: 10.3390/ijms21176333
ORCID: 0000-0003-3264-0902
0000-0003-4580-841X
Journal: International Journal of Molecular Sciences
PubMed URL: 32878331
Type: Journal Article
Subjects: CACNA1G mutation
deep cerebellar nuclei
developmental and epileptic encephalopathy
gain of function
loss of function
voltage-dependent T-type calcium channel
Appears in Collections:Journal articles

Show full item record

Page view(s)

34
checked on Dec 1, 2023

Google ScholarTM

Check


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.