Identification of a novel SCA14 mutation in a Dutch autosomal dominant cerebellar ataxia family

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
Neurology (Impact Factor: 8.29). 01/2004; 61(12):1760-5. DOI: 10.1212/01.WNL.0000098883.79421.73
Source: PubMed


To report a Dutch family with autosomal dominant cerebellar ataxia (ADCA) based on a novel mutation in the PRKCG gene.
The authors studied 13 affected members of the six-generation family. After excluding the known spinocerebellar ataxia (SCA) genes, a combination of the shared haplotype approach, linkage analysis, and genealogic investigations was used. Exons 4 and 5 of the candidate gene, PRKCG, were sequenced.
Affected subjects displayed a relatively uncomplicated, slowly progressive cerebellar syndrome, with a mean age at onset of 40.8 years. A focal dystonia in two subjects with an onset of disease in their early 20s suggests extrapyramidal features in early onset disease. Significant linkage to a locus on chromosome 19q was found, overlapping the SCA-14 region. Based on the recent description of three missense mutations in the PRKCG gene, located within the boundaries of the SCA-14 locus, we sequenced exons 4 and 5 of this gene and detected a novel missense mutation in exon 4, which involves a G-->A transition in nucleotide 353 and results in a glycine-to-aspartic acid substitution at residue 118.
A SCA-14-linked Dutch ADCA family with a novel missense mutation in the PRKCG gene was identified.

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Available from: Dineke S Verbeek, May 12, 2015
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    • "SCA14 patients suffer from a slowly progressive cerebellar ataxia accompanied by slurred speech and abnormal eye movements caused by degeneration of Purkinje cells in the cerebellum (Paulson 2009). Interestingly , the majority of SCA14 mutations are localized in the region encoding for the C1B domain (Fig. 1a) (Chen et al. 2003; Giorgione et al. 2003; van de Warrenburg et al. 2003; Yabe et al. 2003; Verbeek et al. 2005; Klebe et al. 2007; Adachi et al. 2008). Recently, the protein structure of fulllength PKCbII was resolved, which showed that the C1B domain, and not C1A, interacts directly with N-lobe and Clobe of the catalytic domain, C-terminus and C2 domain, forming the so-called C1B clamp (Leonard et al. 2011). "
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    ABSTRACT: The protein kinase C γ (PKCγ) undergoes multi-step activation and participates in various cellular processes in Purkinje cells. Perturbations in its phosphorylation state, conformation or localization can disrupt kinase signaling, such as in Spinocerebellar ataxia type 14 (SCA14) that is caused by missense mutations in PRKCG encoding for PKCγ. We previously showed that SCA14 mutations enhance PKCγ membrane translocation upon stimulation due to an altered protein conformation. Since the faster translocation did not result in an increased function, we examined how SCA14 mutations induce this altered conformation of PKCγ and what the consequences of this conformational change are on PKCγ life cycle. Here, we show that SCA14-related PKCγ-V138E exhibits an exposed C-terminus as shown by FRET-FLIM microscopy in living cells, indicative of its partial unfolding. This conformational change was associated with faster PMA-induced translocation and accumulation of fully phosphorylated PKCγ in the insoluble fraction, which could be rescued by co-expressing PDK1 kinase, that normally triggers PKCγ autophosphorylation. We propose that the SCA14 mutation V138E causes unfolding of the C1B domain and exposure of the C-terminus of the PKCγ-V138E molecule, resulting in a decrease of functional kinase in the soluble fraction. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2013 · Journal of Neurochemistry
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    • "The PRKCG gene encoding PKCc has also been involved in the dominant spinocerebellar ataxia type 14 in humans (Yamashita et al. 2000; Brkanac et al. 2002; Yabe et al. 2003; Klebe et al. 2005; Fahey et al. 2005). Mutations in the PRKCG gene have been reported to be implicated in this neurodegenerative disorder, characterized by a slow and progressive cerebellar dysfunction (Chen et al. 2003; van de Warrenburg et al. 2003; Yabe et al. 2003). Atrophy of the cerebellum and a reduction of PC number have been observed by magnetic resonance imaging and post-mortem analysis (van de Warrenburg et al. 2003; Brkanac et al. 2002). "
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    ABSTRACT: Retinoid-related orphan receptor alpha1 (RORalpha1) is a member of the nuclear receptor superfamily. It is highly expressed in CNS particularly in the cerebellum. Absence of this transcription factor in mice leads to several abnormalities, such as cerebellar atrophy linked to Purkinje cell death and impaired differentiation. A major role of RORalpha1 in neuronal survival is the control of reactive oxygen species homeostasis. RORalpha1 is a constitutively active receptor, but its regulation is yet not well known. Protein kinase C (PKC) also plays a major role in neuronal survival and differentiation, suggesting its possible involvement in post-translational modifications and regulation of RORalpha1 transcriptional activity. To test this hypothesis, we over-expressed the human isoform of this nuclear receptor in cortical neurons and COS-7 cells, which were then treated with different effectors acting on PKC activity. We showed for the first time that conventional PKCs induce phosphorylation and inhibition of RORalpha1 activity. We also investigated mitogen-activated protein kinase/extracellular signal-regulated kinase (1/2) involvement in this effect. Our results bring new insights into the control of RORalpha1 activity and highlight its importance in further investigations of the mechanisms involved in neuronal cell death in neurodegenerative diseases.
    Full-text · Article · Apr 2008 · Journal of Neurochemistry
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    • "Clear evidence for the essential role of protein kinase C family members in neuronal homeostasis has been provided by neurodegeneration attributable to a loss of function mutation in the PKCγ gene in spinocerebellar ataxia type 14 (SCA-14, [53]). No such genetic disorder has been mapped to the PKCι gene, but evidence from overexpression studies indicates that PKCι can be protective against a variety of cytotoxic insults including UV damage and chemotherapy [38], [54] and neurotoxic insults including beta amyloid [55]. "
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    ABSTRACT: The signaling pathways that may modulate the pathogenesis of diseases induced by expanded polyglutamine proteins are not well understood. Herein we demonstrate that expanded polyglutamine protein cytotoxicity is mediated primarily through activation of p38MAPK and that the atypical PKC iota (PKCiota) enzyme antagonizes polyglutamine-induced cell death through induction of the ERK signaling pathway. We show that pharmacological blockade of p38MAPK rescues cells from polyglutamine-induced cell death whereas inhibition of ERK recapitulates the sensitivity observed in cells depleted of PKCiota by RNA interference. We provide evidence that two unrelated proteins with expanded polyglutamine repeats induce p38MAPK in cultured cells, and demonstrate induction of p38MAPK in an in vivo model of neurodegeneration (spinocerebellar ataxia 1, or SCA-1). Taken together, our data implicate activated p38MAPK in disease progression and suggest that its inhibition may represent a rational strategy for therapeutic intervention in the polyglutamine disorders.
    Full-text · Article · Feb 2008 · PLoS ONE
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