CMT4B: Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to

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Proc Natl Acad Sci U S A. 2008 Mar 18

Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to

a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice.

FL, Niesman IR, Beiswenger KK, Dixon JE.

Departments of Pharmacology.

Charcot-Marie-Tooth disease type 4B (CMT4B) is a severe,

demyelinating peripheral neuropathy characterized by slowed nerve

conduction velocity, axon loss, and distinctive myelin outfolding and

infolding. CMT4B is caused by recessive mutations in either

myotubularin-related protein 2 (MTMR2; CMT4B1) or MTMR13 (CMT4B2).

Myotubularins are phosphoinositide (PI) 3-phosphatases that

dephosphorylate phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns

(3,5)P(2), two phosphoinositides that regulate endosomal-lysosomal

membrane traffic. Interestingly, nearly half of the metazoan

myotubularins are predicted to be catalytically inactive.

Both active and inactive myotubularins have essential functions in

mammals and in Caenorhabditis elegans. MTMR2 and MTMR13 are active

and inactive PI 3-phosphatases, respectively, and the two proteins

have been shown to directly associate, although the functional

significance of this association is not well understood.

To establish a mouse model of CMT4B2, we disrupted the Mtmr13 gene.

Mtmr13-deficient mice develop a peripheral neuropathy characterized

by reduced nerve conduction velocity and myelin outfoldings and

infoldings. Dysmyelination is evident in Mtmr13-deficient nerves at

14 days and worsens throughout life. Thus, loss of Mtmr13 in mice

leads to a peripheral neuropathy with many of the key features of

CMT4B2. Although myelin outfoldings and infoldings occur most

frequently at the paranode, our morphological analyses indicate that

the ultrastructure of the node of Ranvier and paranode is intact in

Mtmr13-deficient nerve fibers.

We also found that Mtmr2 levels are decreased by approximately 50% in

Mtmr13-deficient sciatic nerves, suggesting a mode of Mtmr2

regulation. Mtmr13-deficient mice will be an essential tool for

studying how the loss of MTMR13 leads to CMT4B2.