title: Congenital hypomyelinating neuropathy with lethal conduction failure in mice carrying the Egr2 I268N mutation.
abstract: Mouse models of human disease are helpful for understanding the pathogenesis of the disorder and ultimately for testing potential therapeutic agents. Here, we describe the engineering and characterization of a mouse carrying the I268N mutation in Egr2, observed in patients with recessively inherited Charcot-Marie-Tooth (CMT) disease type 4E, which is predicted to alter the ability of Egr2 to interact with the Nab transcriptional coregulatory proteins. Mice homozygous for Egr2(I268N) develop a congenital hypomyelinating neuropathy similar to their human counterparts. Egr2(I268N) is expressed at normal levels in developing nerve but is unable to interact with Nab proteins or to properly activate transcription of target genes critical for proper peripheral myelin development. Interestingly, Egr2(I268N/I268N) mutant mice maintain normal weight and have only mild tremor until 2 weeks after birth, at which point they rapidly develop worsening weakness and uniformly die within several days. Nerve electrophysiology revealed conduction block, and neuromuscular junctions showed marked terminal sprouting similar to that seen in animals with pharmacologically induced blockade of action potentials or neuromuscular transmission. These studies describe a unique animal model of CMT, whereby weakness is due to conduction block or neuromuscular junction failure rather than secondary axon loss and demonstrate that the Egr2-Nab complex is critical for proper peripheral nerve myelination.
authors.affiliation: Department of Neurology, and Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, Missouri 63110, USA. rbaloh@wustl.edu
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.forename: Amy
authors.initials: A
authors.lastname: Strickland
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ryu
authors.forename: Nam
authors.initials: N
authors.lastname: Le
authors.forename: Timothy
authors.initials: T
authors.lastname: Fahrner
authors.forename: Mao
authors.initials: M
authors.lastname: Yang
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagarajan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
mesh_terms: D000818:Animals; D001216:Asparagine / Q000235:genetics*; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003389:Cranial Nerve Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D051767:Early Growth Response Protein 2 / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D007532:Isoleucine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009185:Myelin Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009431:Neural Conduction / Q000235:genetics*; D011901:Ranvier's Nodes / Q000235:genetics / Q000473:pathology; D012097:Repressor Proteins / Q000378:metabolism; D012583:Schwann Cells / Q000502:physiology; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure
chemical_list: D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D009185:Myelin Proteins; C099945:Nab2 protein, mouse; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D007532:Isoleucine; D001216:Asparagine