Mutation in the Catalytic Domain of Protein Kinase C γ and Extension of the Phenotype Associated With Spinocerebellar Ataxia Type 14

Abstract

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 respon-

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

“…The results of neuropsychological testing were compatible with previously described cognitive features of cerebellar pathology 50 . Longitudinal data of neuropsychological testing available in one of our subjects indicated mild progression of cognitive dysfunction, in line with few previous descriptions 7,51,52 . Few reports of overt dementia were all in SCA‐PRKCG with long‐standing disease (Table S1) or probable comorbidity.…”

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

“…The results of neuropsychological testing were compatible with previously described cognitive features of cerebellar pathology 50 . Longitudinal data of neuropsychological testing available in one of our subjects indicated mild progression of cognitive dysfunction, in line with few previous descriptions 7,51,52 . Few reports of overt dementia were all in SCA‐PRKCG with long‐standing disease (Table S1) or probable comorbidity.…”

New mutations in protein kinase Cγ associated with spinocerebellar ataxia type 14

“…We have now added three further mutations in exon 4 (C114Y, G123R, G123E) and two missense mutations leading to amino acid substitutions in exon 10 (G360S) and exon 18 (V692G), respectively (Fig 5). In addition, we confirm the mutation in the catalytic domain (F643L) that we recently reported in another French kindred, and we suggest the existence of a founder effect for this mutation 6. None of the mutations were found on a large number of control chromosomes, and all were confirmed to segregate with the disease, except the G360S because no samples from other affected members of the families concerned were available for analysis.…”

“…The clinical phenotype frequently included cognitive impairment, as described in the large SCA14 family with the F643L mutation, in which 11 of 19 patients had executive dysfunction 6. In this study, 5 of 15 patients from unrelated families presented cognitive impairment.…”

Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

“…We further identified three mutations in the catalytic domain, a protein region, where only seven pathogenic variants have so far been described (Fig. 1), in association with an apparently more complex phenotype [1,6] a finding also seen in our patients.…”

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

“…The results of neuropsychological testing were compatible with previously described cognitive features of cerebellar pathology 50 . Longitudinal data of neuropsychological testing available in one of our subjects indicated mild progression of cognitive dysfunction, in line with few previous descriptions 7,51,52 . Few reports of overt dementia were all in SCA‐PRKCG with long‐standing disease (Table S1) or probable comorbidity.…”

New mutations in protein kinase Cγ associated with spinocerebellar ataxia type 14

“…We have now added three further mutations in exon 4 (C114Y, G123R, G123E) and two missense mutations leading to amino acid substitutions in exon 10 (G360S) and exon 18 (V692G), respectively (Fig 5). In addition, we confirm the mutation in the catalytic domain (F643L) that we recently reported in another French kindred, and we suggest the existence of a founder effect for this mutation 6. None of the mutations were found on a large number of control chromosomes, and all were confirmed to segregate with the disease, except the G360S because no samples from other affected members of the families concerned were available for analysis.…”

“…The clinical phenotype frequently included cognitive impairment, as described in the large SCA14 family with the F643L mutation, in which 11 of 19 patients had executive dysfunction 6. In this study, 5 of 15 patients from unrelated families presented cognitive impairment.…”

Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

“…We further identified three mutations in the catalytic domain, a protein region, where only seven pathogenic variants have so far been described (Fig. 1), in association with an apparently more complex phenotype [1,6] a finding also seen in our patients.…”

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

“…The results of neuropsychological testing were compatible with previously described cognitive features of cerebellar pathology 50 . Longitudinal data of neuropsychological testing available in one of our subjects indicated mild progression of cognitive dysfunction, in line with few previous descriptions 7,51,52 . Few reports of overt dementia were all in SCA‐PRKCG with long‐standing disease (Table S1) or probable comorbidity.…”

New mutations in protein kinase Cγ associated with spinocerebellar ataxia type 14

“…We have now added three further mutations in exon 4 (C114Y, G123R, G123E) and two missense mutations leading to amino acid substitutions in exon 10 (G360S) and exon 18 (V692G), respectively (Fig 5). In addition, we confirm the mutation in the catalytic domain (F643L) that we recently reported in another French kindred, and we suggest the existence of a founder effect for this mutation 6. None of the mutations were found on a large number of control chromosomes, and all were confirmed to segregate with the disease, except the G360S because no samples from other affected members of the families concerned were available for analysis.…”

“…The clinical phenotype frequently included cognitive impairment, as described in the large SCA14 family with the F643L mutation, in which 11 of 19 patients had executive dysfunction 6. In this study, 5 of 15 patients from unrelated families presented cognitive impairment.…”

Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

“…We further identified three mutations in the catalytic domain, a protein region, where only seven pathogenic variants have so far been described (Fig. 1), in association with an apparently more complex phenotype [1,6] a finding also seen in our patients.…”