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

Abstract

Autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurological disorders. Point mutations in the gene encoding protein kinase Cgamma (PRKCG) are responsible for spinocerebellar ataxia 14 (SCA14). We screened for mutations in the PRKCG gene, in a large series of 284 ADCA index cases, mostly French (n=204) and German (n=48), in whom CAG repeat expansions in the known SCA genes were previously excluded. Six mutations were found that segregated with the disease and were not detected on 560 control chromosomes, including F643L (exon 18), already reported in another French kindred. Five new missense mutations were identified in exons 4 (C114Y/G123R/G123E), 10 (G360S) and 18 (V692G). All but one (V692G) were located in highly conserved regions of the regulatory or catalytic domains of the protein. All six SCA14 families were French and there was no evidence of reduced penetrance. The phenotype consisted in a very slowly progressive cerebellar ataxia with a mean age at onset of 33.5+/-14.2 years (range 15 to 60 years), occasionally associated with executive dysfunction, myoclonus, myorythmia, tremor or decreased vibration sense. SCA14 represented only 1.5% (7/454) of French ADCA families but none of the German families. It should, however, be considered in patients with slowly progressive ADCA, particularly when myoclonus and cognitive impairment are present.

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families

“…More recently, a Dutch family with SCA14 patients was also described with early onset, mildly generalized myoclonus (Vlak et al 2006;Verbeek et al 2005). SCA14 is present in various different ethnic populations (Japan, German, Dutch, Portuguese and French) and displays a heterogeneous mutation spectrum Dalski et al 2006;Verbeek et al 2005;Alonso et al2005;Klebe et al 2005).…”

A Japanese case of SCA14 with the Gly128Asp mutation

“…Mild, slowly progressive ataxia is a predominant feature of SCA14, sometimes accompanied by myoclonus, cognitive impairment, extrapyramidal signs, and sensory disturbance (Chen et al 2005;Klebe et al 2005;Stevanin G et al 2004;van de Warrenburg BP et al 2003;Verbeek DS et al 2005;Yabe et al 2003;Yamashita et al 2000). Here, we report a Japanese patient with the Gly128Asp (G128D) mutation in PRKCG, who showed pure cerebellar ataxia with onset in middle age and a protracted clinical course.…”

“…Second, a C to T substitution in the 5¢ untranslated region in the puratrophin-1 gene, a recently identified gene for 16q22.1-linked ADCA, was examined (Ishikawa et al 2005;Ohata et al 2006). Then, genetic analysis for SCA14 was performed as previously described (Klebe et al 2005;Chen et al 2003). PCR products were purified using a QIA PCR Purification kit (Qiagen) and then directly sequenced using a BigDyeR Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems), and analyzed on an Applied Biosystems 3730xl DNA Analyzer.…”

The inherited ataxias: Genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics

“…The majority of mutations (missense) have been reported in exons 4, 5, 10, and 18. It has been reported in more than 20 families from Europe, Japan, and Australia [Klebe et al, 2005]. SCA15/16 is caused by heterozygous deletions of the 5 part of the ITPR1 gene [van de Leemput et al, 2007] although a missense mutation (c.1480G>A p.V494I) has been reported.…”