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Spinocerebellar ataxia type 14 (SCA14) is a rare autosomal dominant cerebellar ataxia marked by progressive gait instability, dysarthria, and often myoclonus. The protein kinase C gamma gene PRKCG encodes PKCγ, and heterozygous missense mutations in PRKCG underlie Spinocerebellar Ataxia Type 14. Since initial linkage to chromosome 19q13.4-qter and the discovery of the first catalytic‐domain variant (c.1927T>C (p.Phe643Leu)) in a French pedigree of 14 affected individuals (and 4 probable) [PMID:15313841], over 50 unrelated probands across more than 20 families have been reported. These data firmly establish PRKCG as the SCA14 causative gene.
Extensive familial and population studies have characterized an autosomal dominant inheritance mode with complete segregation of PRKCG variants in at least 23 affected relatives across multiple pedigrees. For example, six affected members in an Australian kindred harbored an exon 5 variant c.449G>C (p.Cys150Phe) [PMID:16291902], and three relatives in a Japanese family carried c.383G>A (p.Gly128Asp) [PMID:18986758]. A broad allelic spectrum includes missense changes clustering in the regulatory C1 and C2 domains and the catalytic region, with recurrent and founder mutations such as c.353G>A (p.Gly118Asp) in the Dutch population [PMID:15841389]. Age at onset ranges from childhood to 60 years, with variable extracerebellar signs including cognitive impairment and dystonia.
Variants reported in PRKCG span over 40 distinct missense substitutions, small in‐frame deletions, and splice‐site changes. Pathogenic alleles include c.1927T>C (p.Phe643Leu), c.383G>A (p.Gly128Asp), and c.300_305del (p.His101_Lys102del). Founder effects (e.g., p.Gly118Asp in the Netherlands) illustrate population specificity, while de novo cases expand the phenotypic range. All reported variants meet criteria for complete co‐segregation in affected members and absence in large control cohorts.
Functional and experimental evidence supports a gain‐of‐function and dominant‐negative mechanism. Biochemical assays of the H101Q variant (c.303C>G (p.His101Gln)) demonstrate decreased PKCγ stability and solubility, leading to reduced phosphorylation capacity [PMID:16189624]. Patient‐derived iPSC and post‐mortem cerebellar studies reveal mutant PKCγ mislocalization, aggregation, and hyperactivity of kinase substrates [PMID:30249303]. C1A domain variants show increased basal activity but impaired down-regulation, consistent across cellular models.
No significant conflicting evidence has emerged; all reported PRKCG variants in SCA14 families show concordant segregation and functional impact. There are no refuting studies of PRKCG involvement in alternative phenotypes for SCA14.
Overall, the genetic and functional data integrate into a coherent pathogenic model in which heterozygous PRKCG variants induce Purkinje cell dysfunction via disrupted kinase regulation and aggregation, leading to cerebellar neurodegeneration. Genetic testing for PRKCG mutations is clinically available and valuable for diagnosis in ataxia cohorts.
Key Take-home: PRKCG variants cause autosomal dominant SCA14 through gain-of-function mechanisms; molecular testing enables precise diagnosis and informs genetic counseling.
Gene–Disease AssociationDefinitiveOver 50 unrelated probands in >20 families over >15 years, robust multi‐family segregation, concordant functional data ([PMID:15313841], [PMID:15824357], [PMID:16189624]) Genetic EvidenceStrong
Functional EvidenceModerateBiochemical and cell‐based assays show altered PKCγ stability, aggregation, hyperactivity, and recapitulation in patient‐derived iPSCs ([PMID:16189624], [PMID:30249303]) |