Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene

Shirafuji, Toshihiko; Shimazaki, Hideyuki; Miyagi, Tatsuhiro; Ueyama, Takeshi; Adachi, Naoko; Tanaka, Shigeru; Hide, Izumi; Saito, Naoaki; Sakai, Norio

doi:10.1016/j.mcn.2019.05.005

Cited by 14 publications

(21 citation statements)

References 45 publications

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“…In this manuscript we show that the constitutive activation of PKCγ in the PKCγ-A24E mouse model is sufficient to induce a pathology related to SCA14, and this finding is supported by the recent identification of a human patient with a mutation at the same position (Chelban et al, 2018). However, other mutations causing SCA14 in humans affect the regulation of PKCγ differently or even are kinase dead (Shirafuji et al, 2019) and of course most SCAs are caused by mutations in different genes. Nevertheless, slowly a picture is emerging that many of these mutations affect the mGluR1-PKCγ-Inositol1,4,5-trisphosphate receptor type1 (Ip3r1) -calcium release pathway and can cause disease irrespective of stimulation or inhibition of this pathway (Shimobayashi and Kapfhammer, 2018), meaning that it is not so important in which direction the activity if this pathway is pushed, but rather that the dynamic regulation of the activity of this pathway is disturbed.…”

Section: Pkcγ Signaling and Scassupporting

confidence: 58%

A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCγ Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior

Shimobayashi

Kapfhammer

2021

J. Neurosci.

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Spinocerebellar ataxias (SCAs) are diseases characterized by cerebellar atrophy and loss of Purkinje neurons caused by mutations in diverse genes. In SCA14, the disease is caused by point mutations or small deletions in protein kinase C γ (PKCγ), a crucial signaling protein in Purkinje cells. It is still unclear whether increased or decreased PKCγ activity may be involved in the SCA14 pathogenesis. In this study, we present a new knock-in mouse model related to SCA14 with a point mutation in the pseudosubstrate domain, PKCγ-A24E, known to induce a constitutive PKCγ activation. In this protein conformation, the kinase domain of PKCγ is activated, but at the same time the protein is subject to dephosphorylation and protein degradation. As a result, we find a dramatic reduction of PKCγ protein expression in PKC γ -A24E mice of either sex. Despite this reduction, there is clear evidence for an increased PKC activity in Purkinje cells from PKC γ -A24E mice. Purkinje cells derived from PKCγ-A24E have short thickened dendrites typical for PKC activation. These mice also develop a marked ataxia and signs of Purkinje cell dysfunction making them an interesting new mouse model related to SCA. Recently, a similar mutation in a human patient was discovered and found to be associated with overt SCA14. RNA profiling of PKC γ -A24E mice showed a dysregulation of related signaling pathways, such as mGluR1 or mTOR. Our results show that the induction of PKCγ activation in Purkinje cells results in the SCA-like phenotype indicating PKC activation as one pathogenetic avenue leading to a SCA. SIGNIFICANCE STATEMENT Spinocerebellar ataxias (SCAs) are hereditary diseases affecting cerebellar Purkinje cells and are a one of neurodegenerative diseases. While mutation in several genes have been identified as causing SCAs, it is unclear how these mutations cause the disease phenotype. Mutations in PKCγ cause one subtype of SCAs, SCA14. In this study, we have generated a knock-in mouse with a mutation in the pseudosubstrate domain of PKCγ, which keeps PKCγ in the constitutive active open conformation. We show that this mutation leading to a constant activation of PKCγ results in a SCA-like phenotype in these mice. Our findings establish the constant activation of PKC signaling as one pathogenetic avenue leading to an SCA phenotype and a mechanism causing a neurodegenerative disease.

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Section: Pkcγ Signaling and Scassupporting

confidence: 58%

A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCγ Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior

Shimobayashi

Kapfhammer

2021

J. Neurosci.

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“…Few reports of overt dementia were all in SCA‐PRKCG with long‐standing disease (Table S1) or probable comorbidity. In one report, marked cognitive decline coincided with hearing loss, diabetes, and epilepsy, suggestive of other pathology 53 . A role of (physiologically weak) neocortical expression of mutant PRKCG is not excluded, but dementia of rather subcortical type, normal structural MRI, MR spectroscopy, 27 and histopathology of cerebral cortex 20,21 argue against it.…”

Section: Discussionmentioning

confidence: 99%

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult‐onset disorder

Schmitz‐Hübsch

Lux

Bauer

et al. 2021

Ann Clin Transl Neurol

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Objectives Genetic variant classification is a challenge in rare adult‐onset disorders as in SCA‐PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA‐PRKCG a comprehensive phenotype description from a German multi‐center cohort, including standardized 3D MR imaging. Methods This cross‐sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). Results Our sample included 25 cases confirmed as SCA‐PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA‐PRKCG included slowly progressive ataxia (onset at 4–50 years), preceded in some by early‐onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive‐affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA‐PRKCG cases but in none of the controls. Interpretation In this largest cohort to date, SCA‐PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non‐ataxia movement disorders and cognitive‐affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA‐PRKCG.

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“…This gene shows biased expression in brain. Chen et al, 2003Shirafuji et al, 2019 Mutations in this gene results in neurodegenerative disorder spinocerebellar ataxia-14 (SCA14).…”

Section: Mittelsteadt Et Al 2009mentioning

confidence: 99%

Super‐variants identification for brain connectivity

Wang

et al. 2020

Human Brain Mapping

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Identifying genetic biomarkers for brain connectivity helps us understand genetic effects on brain function. The unique and important challenge in detecting associations between brain connectivity and genetic variants is that the phenotype is a matrix rather than a scalar. We study a new concept of super‐variant for genetic association detection. Similar to but different from the classic concept of gene, a super‐variant is a combination of alleles in multiple loci but contributing loci can be anywhere in the genome. We hypothesize that the super‐variants are easier to detect and more reliable to reproduce in their associations with brain connectivity. By applying a novel ranking and aggregation method to the UK Biobank databases, we discovered and verified several replicable super‐variants. Specifically, we investigate a discovery set with 16,421 subjects and a verification set with 2,882 subjects, where they are formed according to release date, and the verification set is used to validate the genetic associations from the discovery phase. We identified 12 replicable super‐variants on Chromosomes 1, 3, 7, 8, 9, 10, 12, 15, 16, 18, and 19. These verified super‐variants contain single nucleotide polymorphisms that locate in 14 genes which have been reported to have association with brain structure and function, and/or neurodevelopmental and neurodegenerative disorders in the literature. We also identified novel loci in genes RSPO2 and TMEM74 which may be upregulated in brain issues. These findings demonstrate the validity of the super‐variants and its capability of unifying existing results as well as discovering novel and replicable results.

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Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene

Cited by 14 publications

References 45 publications

A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCγ Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior

A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCγ Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult‐onset disorder

Super‐variants identification for brain connectivity

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