Type 4B research news update

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J Biol Chem. 2005 Jul 5

The phosphoinositide 3-phosphatase MTMR2 associates with MTMR13, a

novel membrane-associated pseudophosphatase also mutated in type 4B

Charcot-Marie-tooth disease.

FL, Dixon JE.

Department of Pharmacology, University of California San Diego, La

Jolla, CA 92093-0721.

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

demyelinating peripheral neuropathy characterized by distinctive,

focally folded myelin sheaths. CMT4B is caused by recessively

inherited mutations in either myotubularin-related 2 (MTMR2) or

MTMR13 (also called SBF2).

MTMR2 encodes a member of the myotubularin family of phosphoinositide

3-phosphatases, which dephosphorylate phosphatidylinositol-3-

phosphate (PI(3)P) and PI(3,5)P2. MTMR13 encodes a large,

uncharacterized member of the myotubularin family. The MTMR13

phosphatase domain is catalytically inactive, as the essential Cys

and Arg residues are absent.

Given the genetic association of both MTMR2 and MTMR13 with CMT4B, we

investigated the biochemical relationship between these two proteins.

We find that the endogenous MTMR2 and MTMR13 proteins are associated

in HEK293 cells. MTMR2-MTMR13 association is mediated by coiled-coil

sequences present in each protein. We also examined the cellular

localization of MTMR2 and MTMR13 using fluorescence microscopy and

sub-cellular fractionation.

We find that (i) MTMR13 is a predominantly membrane-associated

protein, (ii) MTMR2 and MTMR13 co-fractionate in both a light

membrane fraction and a cytosolic fraction, and (iii) MTMR13 membrane

association is mediated by the segment of the protein that contains

the pseudophosphatase domain.

This work, which describes the first cellular or biochemical

investigation of the MTMR13 pseudophosphatase protein, suggests that

MTMR13 functions in association with MTMR2. Loss of MTMR13 function

in CMT4B2 patients may lead to alterations in MTMR2 function, and

subsequent alterations in 3-phosphoinositide signaling.

Such a mechanism would explain the strikingly similar phenotypes of

patients with recessive mutations in either MTMR2 or MTMR13.