Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

Abstract Introduction Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by mutations in PRKCG, a gene encoding protein kinase C gamma (PKCγ), a master regulator of Purkinje cells development. Methods We performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia. Results We identified fourteen patients in ten families harboring nine pathogenic heterozygous variants in PRKCG, seven of which were novel. We encountered four patients with not previously described phenotypes: one with episodic ataxia, one with a spastic paraparesis dominating her clinical manifestations, and two children with an unusually severe phenotype. Conclusions Our study broadens the genetic and clinical spectrum of SCA14.

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Deregulation of the actin cytoskeleton and macropinocytosis in response to phorbol ester by the mutant protein kinase C gamma that causes spinocerebellar ataxia type 14

Frontiers in Physiology ◽

10.3389/fphys.2014.00126 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 8

Author(s):

Kazuhiro Yamamoto ◽

Takahiro Seki ◽

Hikaru Yamamoto ◽

Naoko Adachi ◽

Shigeru Tanaka ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Actin Cytoskeleton ◽

Spinocerebellar Ataxia ◽

Phorbol Ester ◽

Mutant Protein ◽

Spinocerebellar Ataxia Type ◽

Kinase C ◽

Protein Kinase C Gamma ◽

Spinocerebellar Ataxia Type 14

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Protein Kinase C gamma Mutations Drive Spinocerebellar Ataxia Type 14 by Impairing Autoinhibition

10.1101/2021.06.24.449810 ◽

2021 ◽

Author(s):

Caila A. Pilo ◽

Alexandr P. Kornev ◽

Timothy R. Baffi ◽

Maya T. Kunkel ◽

Liang-Chin Huang ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Cell Degeneration ◽

Basal Activity ◽

Kinase C ◽

Protein Kinase C Gamma ◽

Spinocerebellar Ataxia Type 14 ◽

C1 Domains

Spinocerebellar ataxia type 14 (SCA14) is a neurodegenerative disease caused by germline mutations in the diacylglycerol (DG)/Ca2+-regulated protein kinase C gamma (PKCγ), leading to Purkinje cell degeneration and progressive cerebellar dysfunction. The majority of the approximately 50 mutations identified in PKCγ cluster to the DG-sensing C1 domains. Here, we use a FRET-based activity reporter to show that ataxia-associated PKCγ mutations enhance basal activity by compromising autoinhibition. Although impaired autoinhibition generally leads to PKC degradation, the C1 domain mutations protect PKCγ from phorbol ester-induced downregulation. Furthermore, it is the degree of disrupted autoinhibition, not changes in the amplitude of agonist-stimulated activity, that correlate with disease severity. Specifically, a SCA14 mutation in which phenylalanine 48 in the C1A domain is deleted had high basal activity both in cells and in vitro, yet was unresponsive to agonist stimulation. Validating that the pathology arises from disrupted autoinhibition, we show that the degree of impaired autoinhibition correlates inversely with age of disease onset in patients: mutations that cause high basal activity are associated with early onset, whereas those that only modestly increase basal activity, including a previously undescribed mutation D115Y, are associated with later onset. Molecular modeling indicates that almost all SCA14 mutations that are not in the C1 domains are at interfaces with the C1B domain, and bioinformatics analysis reveals that mutations in the C1B domain are under-represented in cancer. Thus, clustering of SCA14 mutations to the C1B domain provides a unique mechanism to enhance PKCγ basal activity while protecting the enzyme from downregulation.

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