Mutation in the catalytic domain of protein kinase C gamma and extension of the phenotype associated with spinocerebellar ataxia type 14.
Arch Neurol. 2004-08-01; 61(8):
Lire sur PubMed
1. Arch Neurol. 2004 Aug;61(8):1242-8.
Mutation in the catalytic domain of protein kinase C gamma and extension of the
phenotype associated with spinocerebellar ataxia type 14.
Stevanin G(1), Hahn V, Lohmann E, Bouslam N, Gouttard M, Soumphonphakdy C, Welter
ML, Ollagnon-Roman E, Lemainque A, Ruberg M, Brice A, Durr A.
(1)INSERM U289, Institut Fédératif de Recherche en Neuroscience, Assistance
Publique Hôpitaux de Paris, Hôpital de al Salpêtrière, Paris, France.
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 gamma (PRKCG), which are all located in the regulatory domain.
OBJECTIVES: To identify new SCA14 families and to describe the associated
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 gamma. 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.
PMID: 15313841 [Indexed for MEDLINE]