Missense Mutations in the Regulatory Domain of PKCγ: A New Mechanism for Dominant Nonepisodic Cerebellar Ataxia

Abstract

We report a nonepisodic autosomal dominant (AD) spinocerebellar ataxia (SCA) not caused by a nucleotide repeat expansion that is, to our knowledge, the first such SCA. The AD SCAs currently comprise a group of > or =16 genetically distinct neurodegenerative conditions, all characterized by progressive incoordination of gait and limbs and by speech and eye-movement disturbances. Six of the nine SCAs for which the genes are known result from CAG expansions that encode polyglutamine tracts. Noncoding CAG, CTG, and ATTCT expansions are responsible for three other SCAs. Approximately 30% of families with SCA do not have linkage to the known loci. We recently mapped the locus for an AD SCA in a family (AT08) to chromosome 19q13.4-qter. A particularly compelling candidate gene, PRKCG, encodes protein kinase C gamma (PKC gamma), a member of a family of serine/threonine kinases. The entire coding region of PRKCG was sequenced in an affected member of family AT08 and in a group of 39 unrelated patients with ataxia not attributable to trinucleotide expansions. Three different nonconservative missense mutations in highly conserved residues in C1, the cysteine-rich region of the protein, were found in family AT08, another familial case, and a sporadic case. The mutations cosegregated with disease in both families. Structural modeling predicts that two of these amino acid substitutions would severely abrogate the zinc-binding or phorbol ester-binding capabilities of the protein. Immunohistochemical studies on cerebellar tissue from an affected member of family AT08 demonstrated reduced staining for both PKC gamma and ataxin 1 in Purkinje cells, whereas staining for calbindin was preserved. These results strongly support a new mechanism for neuronal cell dysfunction and death in hereditary ataxias and suggest that there may be a common pathway for PKC gamma-related and polyglutamine-related neurodegeneration.

Protein kinase C as a stress sensor

“…Mutations in the PKCγ C1B domain have been implicated in the movement and cognitive disorder spinocellebellar ataxia type 14 (SCA14) [65]. Because it has been demonstrated that these mutations occur in the C1B region of PKCγ, it is assumed that this would prevent activation by oxidative signals [66].…”

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

“…On the other hand, deletion and/or point mutations were identified in the SPTBN2, KCNC3, PRKCG, and FGF14 genes, recently attributed to SCA5, SCA13, SCA14, and SCA27 respectively Waters et al 2006;Yamashita et al 2000;Chen et al 2003;Yabe et al 2003;Van Swieten et al 2003). Point mutations may result in decreased stability of the proteins, and frameshift mutations in truncated proteins (Van Swieten et al 2003;Dalski et al 2005).…”

Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia

“…The expansion of noncoding trinucleotide (CAG or CTG) or pentanucleotide (ATTCT) repeats are involved in SCA8, SCA10, and SCA12 (Holmes et al 1999;Koob et al 1999;Matsuura et al 2000). Very few families are affected by missense mutations in beta-III spectrin (SPTBN2) (SCA5 (see Ikeda et al 2006)), voltage-gated potassium channel KCNC3 (SCA13 (see Waters et al 2006)), protein kinase C gamma (PKC gamma) (SCA14 (see Chen et al 2003)), and FGF14 genes (ADCA with FGF14 mutation (see van Swieten et al 2003). However, genes or even loci remain unidentified for 20-40% of families with ADCA (Sasaki et al 2003).…”