Myotubularin Mutations in CMT

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J Neurochem. 2007 Oct 31

Multiple Disease-Linked Myotubularin Mutations Cause NFL Assembly

Defects in Cultured Cells And Disrupt Myotubularin Dimerization.

Goryunov D, Nightingale A, Bornfleth L, Leung C, Liem RK.

Department of Pathology and Cell Biology, Columbia University

College of Physicians & Surgeons, 630 West 168 Street, New York, NY

10032.

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral

neuropathy that has been linked to mutations in multiple genes.

Mutations in the neurofilament light (NFL) chain gene lead to the

CMT2E form whereas mutations in the myotubularin-related protein 2

and 13 (MTMR2 and MTMR13) genes lead to the CMT4B form. These two

forms share characteristic pathological hallmarks on nerve biopsies

including concentric sheaths ( " onion bulbs " ) and, in at least one

case, myelin loops. In addition, MTMR2 protein has been shown to

interact physically with both NFL and MTMR13.

Here we present evidence that CMT-linked mutations of MTMR2 can

cause NFL aggregation in a cell line devoid of endogenous

intermediate filaments, SW13vim(-). Mutations in the protein

responsible for X-linked myotubular myopathy (myotubularin, MTM1)

also induced NFL abnormalities in these cells. We also show that two

MTMR2 mutant proteins, G103E and R283W, are unable to form dimers

and undergo phosphorylation in vivo, implicating impaired complex

formation in myotubularin-related pathology.