Congenital Hypomyelinating Neuropathy with Lethal Conduction Failure in Mice Car

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J Neurosci. 2009 Feb 25;29(8):2312-21.

Congenital Hypomyelinating Neuropathy with Lethal Conduction Failure

in Mice Carrying the Egr2 I268N Mutation.

Baloh RH, Strickland A, Ryu E, Le N, Fahrner T, Yang M, Nagarajan R,

Milbrandt J.

Departments of Neurology and Pathology, and Hope Center for

Neurological Diseases, Washington University School of Medicine, St.

Louis, Missouri 63110.

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.