Type 4B and genetic research

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Abstract from J Biol Chem. 2003 Jun 4 [Epub ahead of print]

Genetic analysis of the myotubularin family of phosphatases in

caenorhabditis elegans.

Xue Y, Fares H, Grant B, Li Z, Rose AM, SG, Skolnik EY.

Pharmacology Dept., New York University Medical Center, New York, NY

10016.

Summary Myotubularins (MTMs) constitute a large family of lipid

phosphatases that specifically dephosphorylate phosphatidylinositol (PI)

(3)P. MTM1 and MTM2 are mutated in X-linked myotubular myopathy and

Charcot-Marie-Tooth disease (type 4B) respectively, although.the

mechanisms whereby MTM dysfunction leads to these diseases is unknown.

To gain insight into MTM function, we undertook the study of MTMs in the

nematode C. elegans, which possess a representative homologue of the

four major subgroups of MTMs identified in mammals (vertebrates). As in

mammals, we found that C. elegans MTMs mediate distinct functions.

let-512 (vps34) encodes the C. elegans homolog of the yeast and

mammalian homolog of the phosphatidylinositol 3-kinase Vps34. We found

that reduction of mtm-6 (F53A2.8) function by RNA inhibition (RNAi)

rescued the larval lethality of let-512 (vps34) mutants and that the

reduction of mtm-1 (Y110A7A.5) activity by RNAi rescued the endocytosis

defect of let-512 animals. Together, these observations provide genetic

evidence that MTMs negatively regulate PI(3)P levels. Analysis of MTM

expression patterns using transcriptional GFP reporters demonstrated

that these two MTMs exhibit mostly nonoverlapping expression patterns

and that MTM-GFP fusion proteins are localized to different subcellular

locations. These observations suggest that some of the different

functions of MTMs might, in part, be a consequence of unique expression

and localization patterns. However, our finding that at least three

CeMTMs play essential roles in coelomocyte endocytosis, a process that

also requires vps34, indicates that MTMs do not simply turn off vps34

and unexpectedly also function as positive regulators of biological

processes.