Mutations in the gene encoding
myotubularin-related
protein 2 (MTMR2) are responsible for autosomal recessive
Charcot-Marie-Tooth disease type 4B1 (
CMT4B1), a severe
hereditary motor and sensory neuropathy characterized by focally folded myelin sheaths and
demyelination. MTMR2 belongs to the
myotubularin family, which is characterized by the presence of a
phosphatase domain.
Myotubularin (MTM), the archetype member of this family, is mutated in
X-linked myotubular myopathy. Although MTMR2 and MTM are closely related, they are likely to have different functions. Recent studies revealed that MTM dephosphorylates specifically
phosphatidylinositol 3-phosphate. Here we analyze the biochemical properties of the
mouse Mtmr2 protein, which shares 97%
amino acid identity with human MTMR2. We show that phosphatidylinositol-3-phosphate is also a substrate for Mtmr2, but, unlike
myotubularin, Mtmr2 dephosphorylates
phosphatidylinositol 3,5-bisphosphate with high efficiency and peak activity at neutral pH. We demonstrate that the known disease-associated MTMR2 mutations lead to dramatically reduced
phosphatase activity, suggesting that the MTMR2
phosphatase activity is crucial for the proper function of peripheral nerves in
CMT4B1. Expression analysis of Mtmr2 suggests particularly high levels in neurons. Thus, the demyelinating neuropathy
CMT4B1 might be triggered by the malfunction of neural membrane recycling, membrane trafficking, and/or endocytic or exocytotic processes, combined with altered axon-Schwann cell interactions. Furthermore, the different biochemical properties of MTM and MTMR2 offer a potential explanation for the different human diseases caused by mutations in their respective genes.