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 SET-binding factor 2). 
MTMR2 encodes a member of the myotubularin family of 
phosphoinositide-3-phosphatases, which dephosphorylate phosphatidylinositol 
3-phosphate (PI(3)P) and bisphosphate PI(3,5)P2. MTMR13 encodes a large, 
uncharacterized member of the myotubularin family. The MTMR13 phosphatase domain 
is catalytically inactive because 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 found 
that the endogenous MTMR2 and MTMR13 proteins are associated in human embryonic 
kidney 293 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 subcellular fractionation. We found 
that (i) MTMR13 is a predominantly membrane-associated protein; (ii) MTMR2 and 
MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction; 
and (iii) MTMR13 membrane association is mediated by the segment of the protein 
which 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.