Mutation in the catalytic domain of protein kinase C gamma and extension of the phenotype associated with spinocerebellar ataxia type 14.
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.


OBJECTIVE
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 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.
INSERM U289, Institut Fédératif de Recherche en Neuroscience, Assistance Publique Hôpitaux de Paris, Hôpital de al Salpêtrière, Paris, France.
Giovanni
G
Stevanin
Valérie
V
Hahn
Ebba
E
Lohmann
Naima
N
Bouslam
Michel
M
Gouttard
Caroline
C
Soumphonphakdy
Marie-Laure
ML
Welter
Elisabeth
E
Ollagnon-Roman
Arnaud
A
Lemainque
Merle
M
Ruberg
Alexis
A
Brice
Alexandra
A
Durr
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D020134:Catalytic Domain / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000201:enzymology / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011493:Protein Kinase C / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
C087857:protein kinase C gamma; D011493:Protein Kinase C