Show simple item record

dc.contributor.authorBerecki, G
dc.contributor.authorHelbig, KL
dc.contributor.authorWare, TL
dc.contributor.authorGrinton, B
dc.contributor.authorSkraban, CM
dc.contributor.authorMarsh, ED
dc.contributor.authorBerkovic, SF
dc.contributor.authorPetrou, S
dc.date.accessioned2020-11-17T03:38:48Z
dc.date.available2020-11-17T03:38:48Z
dc.date.issued2020-09-01
dc.identifierpii: ijms21176333
dc.identifier.citationBerecki, G., Helbig, K. L., Ware, T. L., Grinton, B., Skraban, C. M., Marsh, E. D., Berkovic, S. F. & Petrou, S. (2020). Novel MissenseCACNA1GMutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21 (17), https://doi.org/10.3390/ijms21176333.
dc.identifier.issn1422-0067
dc.identifier.urihttp://hdl.handle.net/11343/251568
dc.description.abstractThe 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
dc.languageEnglish
dc.publisherMDPI
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleNovel MissenseCACNA1GMutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy
dc.typeJournal Article
dc.identifier.doi10.3390/ijms21176333
melbourne.affiliation.departmentFlorey Department of Neuroscience and Mental Health
melbourne.source.titleInternational Journal of Molecular Sciences
melbourne.source.volume21
melbourne.source.issue17
melbourne.identifier.nhmrc1005050
dc.rights.licenseCC BY
melbourne.elementsid1464556
melbourne.contributor.authorPetrou, Steven
melbourne.contributor.authorGrinton, Bronwyn
melbourne.contributor.authorBerecki, Geza
melbourne.contributor.authorBerkovic, Samuel
dc.identifier.eissn1422-0067
melbourne.identifier.fundernameidNHMRC, 1005050
melbourne.accessrightsOpen Access


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record