A double point mutation in the DNA-binding region of Egr2 switches its function from inhibition to induction of proliferation: A potential contribution to the development of congenital hypomyelinating neuropathy

Neurobiol Dis. 2006 Oct;24(1):159-69. doi: 10.1016/j.nbd.2006.06.006. Epub 2006 Jul 26.

Abstract

Mutations in the DNA-binding domain of EGR2 are associated with severe autosomal dominant forms of peripheral neuropathy. In this study, we show that one such Egr2 mutant (S382R, D383Y), when expressed in Schwann cells in vitro, is not transcriptionally inactive but retains residual wild-type Egr2 functions, including inhibition of transforming growth factor-beta-induced Schwann cell death and an ability to induce the cytoskeletal protein periaxin. More importantly, this mutant Egr2 has aberrant effects in Schwann cells, enhancing DNA synthesis both in the presence and absence of the putative axonal mitogen, beta-neuregulin 1. This is in stark contrast to wild-type Egr2, which causes withdrawal from the cell cycle. Furthermore, mutant Egr2 upregulates cyclin D1 and reduces levels of the cell cycle inhibitor, p27. These observations add significant new evidence to explain how this mutation leads to congenital hypomyelinating neuropathy in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Antimetabolites
  • Blotting, Western
  • Bromodeoxyuridine
  • Cell Death / genetics
  • Cell Death / physiology
  • Cell Proliferation
  • Cell Survival / physiology
  • DNA / metabolism*
  • Early Growth Response Protein 2 / genetics*
  • Early Growth Response Protein 2 / metabolism
  • Immunohistochemistry
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Myelin P0 Protein / genetics
  • Myelin Sheath / genetics*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Nervous System Diseases / congenital
  • Nervous System Diseases / genetics*
  • Neuregulin-1 / genetics
  • Point Mutation
  • Proto-Oncogene Proteins c-jun / biosynthesis
  • Proto-Oncogene Proteins c-jun / genetics
  • Rats
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • Schwann Cells / metabolism
  • Signal Transduction / physiology
  • Transforming Growth Factor beta / genetics

Substances

  • Antimetabolites
  • Early Growth Response Protein 2
  • Egr2 protein, rat
  • Membrane Proteins
  • Myelin P0 Protein
  • Nab2 protein, rat
  • Neoplasm Proteins
  • Neuregulin-1
  • Proto-Oncogene Proteins c-jun
  • Repressor Proteins
  • Transforming Growth Factor beta
  • neuregulin beta
  • periaxin
  • DNA
  • Bromodeoxyuridine