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CMT4B1 is an autosomal recessive peripheral neuropathy characterized by severe progressive muscular atrophy with childhood onset, decreased conduction velocities, demyelination with myelin outfolding, and subsequently axonal loss. The disease gene has been recently identified as myotubularin-related 2 (MTMR2), encoding a protein phosphatase (Bolino et al., Nature Genetics 25: 17–19; 2000). Although this phosphatase is widely expressed, the disorder is restricted to the peripheral nervous system, just as mutations to the related and broadly expressed phosphatase MTM1 produce only myotubular myopathy. The function of MTMR2 and the pathogenetic mechanism of CMT4B are still unknown. We produced several new polyclonal antibodies to MTMR2 in order to better dissect the expression and potential function of MTMR2 in the peripheral nervous system. Although CMT4B manifests primarily as demyelinating neuropathy, our expression data show that MTMR2 protein is present in both Schwann cells and axons in peripheral nerve. In Schwann cells, MTMR2 is localized in the cytoplasm and, at lower level, in the nucleus, while no major differences were observed between non-myelin forming and myelin-forming Schwann cells. DRG sensory neurons and motor neurons, as well as their axons, show MTMR2 expression in their cytoplasm. Thus, it remains unclear whether demyelination in CMT4B is the consequence of a cell-autonomous or a cell-extrinsic defect, the latter possibly due to a defective interaction between Schwann cells and axons. |
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