title: 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.
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.
authors.affiliation: Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Arthur-Farraj
authors.forename: Rhona
authors.initials: R
authors.lastname: Mirsky
authors.forename: David B
authors.initials: DB
authors.lastname: Parkinson
authors.forename: Kristjan R
authors.initials: KR
authors.lastname: Jessen
mesh_terms: D000483:Alleles; D000818:Animals; D000963:Antimetabolites; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004247:DNA / Q000378:metabolism*; D051767:Early Growth Response Protein 2 / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D018993:Myelin P0 Protein / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009422:Nervous System Diseases / Q000151:congenital / Q000235:genetics*; D020890:Neuregulin-1 / Q000235:genetics; D017354:Point Mutation; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D000963:Antimetabolites; D051767:Early Growth Response Protein 2; C497328:Egr2 protein, rat; D008565:Membrane Proteins; D018993:Myelin P0 Protein; C490999:Nab2 protein, rat; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; C117467:neuregulin beta; C086745:periaxin; D004247:DNA; D001973:Bromodeoxyuridine