 |
|
Mutation in the Catalytic Domain of Protein Kinase C  and Extension of the Phenotype Associated With Spinocerebellar Ataxia Type 14
Giovanni Stevanin, PhD;
Valérie Hahn, PhD;
Ebba Lohmann, MD;
Naima Bouslam, MS;
Michel Gouttard, MD;
Caroline Soumphonphakdy, BS;
Marie-Laure Welter, MD;
Elisabeth Ollagnon-Roman, MD, PhD;
Arnaud Lemainque, PhD;
Merle Ruberg, PhD;
Alexis Brice, MD;
Alexandra Durr, MD, PhD
Arch Neurol. 2004;61:1242-1248.
Background Autosomal dominant cerebellar ataxias comprise a clinically, neuropathologically, and genetically heterogeneous group of neurodegenerative disorders. The vast majority of cases are caused by trinucleotide or pentanucleotide repeat expansions in 9 different genes. Spinocerebellar ataxia type 14 (SCA14) is a relatively pure form of autosomal dominant cerebellar ataxia mapped to chromosome 19q and caused by missense mutations in the gene encoding protein kinase C  (PRKCG), which are all located in the regulatory domain.
Objectives To identify new SCA14 families and to describe the associated phenotype.
Methods We describe a new SCA14 family of French ancestry with 14 patients and 4 probably affected individuals. Linkage to the SCA14 locus was evaluated according to standard procedures using 5 markers covering the SCA14 candidate interval. All 18 exons of the PRKCG gene and splice junctions were screened with direct sequencing in the index patient.
Results Linkage to the SCA14 locus was established with lod scores greater than 3 in the interval between DNA segments D19S571 and D19S926. Direct sequencing of the PRKCG gene revealed a T-to-C transition in exon 18 responsible for a novel missense mutation, F643L, which mapped to a highly conserved amino acid of the catalytic domain of protein kinase C . The mutation showed complete segregation with the disease phenotype, was present in all affected and probably affected individuals, and was not observed on 410 control chromosomes from healthy white subjects. Age at onset, assessed in 14 affected individuals, was broader than in previous reports and ranged from childhood to age 60 years. All affected patients had slowly progressive cerebellar ataxia frequently associated with brisk reflexes. Cognitive impairment was also a striking feature in this family and has not been reported previously. Interestingly, there was no axial myoclonus as reported in a Japanese SCA14 family, but electrophysiological recordings in a single patient showed diffuse myoclonus in the arms and legs.
Conclusions We have identified a new SCA14 family with the first mutation (F643L) located in the catalytic domain of the enzyme. The wide range of ages at onset, the presence of myoclonus in the limbs, and the presence of cognitive impairment extend the phenotype associated with this genetic entity.
Author Affiliations: INSERM U289, Institut Fédératif de Recherche en Neuroscience (Drs Stevanin, Lohmann, Ruberg, Brice, and Durr and Mss Bouslam and Soump honphakdy), and Fédération de Neurologie (Drs Hahn, Lohmann, Welter, and Brice) and Département de Génétique Cytogénétique et Embryologie (Drs Stevanin, Brice, and Durr), Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France; Service de Neurologie, Hôpital de Bourg-en-Bresse, Bourg-en-Bresse, France (Dr Gouttard); Consultation de Génétique, Hôpital de la Croix-Rousse, Lyon, France (Dr Ollagnon-Roman); and Centre National de Génotypage, Evry, France (Dr Lemainque).
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
PKC{gamma} mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling
Verbeek et al.
J. Cell Sci. 2008;121:2339-2349.
ABSTRACT
| FULL TEXT
Another Mutation in Cysteine 131 in Protein Kinase C{gamma} as a Cause of Spinocerebellar Ataxia Type 14
Klebe et al.
Arch Neurol 2007;64:913-914.
FULL TEXT
An autosomal dominant ataxia maps to 19q13: Allelic heterogeneity of SCA13 or novel locus?
Waters et al.
Neurology 2005;65:1111-1113.
ABSTRACT
| FULL TEXT
Mutant Protein Kinase C{gamma} Found in Spinocerebellar Ataxia Type 14 Is Susceptible to Aggregation and Causes Cell Death
Seki et al.
J. Biol. Chem. 2005;280:29096-29106.
ABSTRACT
| FULL TEXT
Spinocerebellar ataxia type 14: Opening a new door in dominant ataxia research?
Pandolfo and van de Warrenburg
Neurology 2005;64:1113-1114.
FULL TEXT
The clinical and genetic spectrum of spinocerebellar ataxia 14
Chen et al.
Neurology 2005;64:1258-1260.
ABSTRACT
| FULL TEXT
Oxidative Activation of Protein Kinase C{gamma} through the C1 Domain: EFFECTS ON GAP JUNCTIONS
Lin and Takemoto
J. Biol. Chem. 2005;280:13682-13693.
ABSTRACT
| FULL TEXT
Protein kinase C gamma mutations in spinocerebellar ataxia 14 increase kinase activity and alter membrane targeting
Verbeek et al.
Brain 2005;128:436-442.
ABSTRACT
| FULL TEXT
|
