Human Molecular Genetics Advance Access originally published online on September 12, 2007
Human Molecular Genetics 2007 16(24):2991-3001; doi:10.1093/hmg/ddm257
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Mtmr13/Sbf2-deficient mice: an animal model for CMT4B2
1 Institute of Cell Biology, Department of Biology, ETH Zürich, Switzerland, 2 Department of Neurology and Interdisciplinary Center of Clinical Research, University of Münster, Münster, Germany, 3 Molecular Cell Biology, Paul Scherrer Institut, Villigen, Switzerland and 4 Department of Neurology, University of Wurzburg, Würzburg, Germany
* To whom correspondence should be addressed. Institute of Cell Biology, ETH Hönggerberg, CH-8093 Zürich, Switzerland. Tel: +41 446333432; Fax: +41 446331190; Email: usuter{at}cell.biol.ethz.ch
Received July 12, 2007; Accepted September 4, 2007
Charcot-Marie-Tooth (CMT) disease denotes a large group of genetically heterogeneous hereditary motor and sensory neuropathies and ranks among the most common inherited neurological disorders. Mutations in the Myotubularin-Related Protein-2 (MTMR2) or MTMR13/Set-Binding Factor-2 (SBF2) genes are associated with the autosomal recessive disease subtypes CMT4B1 or CMT4B2. Both forms of CMT share similar features including a demyelinating neuropathy associated with reduced nerve conduction velocity (NCV) and focally folded myelin. Consistent with a common disease mechanism, the homodimeric MTMR2 acts as a phosphoinositide D3-phosphatase with phosphatidylinositol (PtdIns) 3-phosphate and PtdIns 3,5-bisphosphate as substrates while MTMR13/SBF2 is catalytically inactive but can form a tetrameric complex with MTMR2, resulting in a strong increase of the enzymatic activity of complexed MTMR2. To prove that MTMR13/SBF2 is the disease-causing gene in CMT4B2 and to provide a suitable animal model, we have generated Mtmr13/Sbf2-deficient mice. These animals reproduced myelin outfoldings and infoldings in motor and sensory peripheral nerves as the pathological hallmarks of CMT4B2, concomitant with decreased motor performance. The number and complexity of myelin misfoldings increased with age, associated with axonal degeneration, and decreased compound motor action potential amplitude. Prolonged F-wave latency indicated a mild NCV impairment. Loss of Mtmr13/Sbf2 did not affect the levels of its binding partner Mtmr2 and the Mtmr2-binding Dlg1/Sap97 in peripheral nerves. Mice deficient in Mtmr13/Sbf2 together with known Mtmr2-deficient animals will be of major value to unravel the disease mechanism in CMT4B and to elucidate the critical functions of protein complexes that are involved in phosphoinositide-controlled processes in peripheral nerves.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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