Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia

Am J Hum Genet. 2003 Apr;72(4):839-49. doi: 10.1086/373883. Epub 2003 Mar 17.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Conserved Sequence
  • Female
  • Genes, Dominant
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Polymorphism, Genetic*
  • Protein Conformation
  • Protein Kinase C / chemistry
  • Protein Kinase C / genetics*
  • Reference Values
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Spinocerebellar Ataxias / genetics*


  • Isoenzymes
  • protein kinase C gamma
  • Protein Kinase C

Associated data

  • RefSeq/NM_002739