CMT Type 4B1 research from Italy

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J Neurosci. 2005 Sep 14;25(37):8567-77.

Loss of Mtmr2 phosphatase in Schwann cells but not in motor neurons

causes Charcot-Marie-Tooth type 4B1 neuropathy with myelin

outfoldings.

Bolis A, Coviello S, Bussini S, Dina G, Pardini C, Previtali SC,

Malaguti M, Morana P, Del Carro U, Feltri ML, Quattrini A, Wrabetz L,

Bolino A.

Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132

Milan, Italy.

Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomal

recessive Charcot-Marie-Tooth type 4B1 (CMT4B1). This disorder is

characterized by childhood onset of weakness and sensory loss,

severely decreased nerve conduction velocity, demyelination in the

nerve with myelin outfoldings, and severe functional impairment of

affected patients, mainly resulting from loss of myelinated fibers in

the nerve. We recently generated Mtmr2-null(neo) mice, which show a

dysmyelinating neuropathy with myelin outfoldings, thus reproducing

human CMT4B1. Mtmr2 is detected in both Schwann cells and neurons, in

which it interacts with discs large 1/synapse-associated protein 97

and neurofilament light chain, respectively. Here, we specifically

ablated Mtmr2 in either Schwann cells or motor neurons. Disruption of

Mtmr2 in Schwann cells produced a dysmyelinating phenotype very

similar to that of the Mtmr2-null(neo) mouse. Disruption of Mtmr2 in

motor neurons does not provoke myelin outfoldings nor axonal defects.

We propose that loss of Mtmr2 in Schwann cells, but not in motor

neurons, is both sufficient and necessary to cause CMT4B1 neuropathy.

Thus, therapeutical approaches might be designed in the future to

specifically deliver the Mtmr2 phospholipid phosphatase to Schwann

cells in affected nerves.