Mtmr13/Sbf2-Deficient Mice: An Animal Model for CMT4B2

[Guest guest]

Mtmr13/Sbf2-Deficient Mice: An Animal Model for CMT4B2

http://hmg.oxfordjournals.org/cgi/content/short/ddm257v1

Kristian Tersar1,*, Matthias Boentert2,*, Philipp Berger1,3, Sonja

Bonneick1, Carsten Wessig4, Klaus V. Toyka4, Young2 and Ueli

Suter1,

1 Institute of Cell Biology, Department of Biology, ETH Zürich, CH-

8093 Zurich, Switzerland 2 Department of Neurology and

Interdisciplinary Center of Clinical Research, University of

Münster, Münster, Germany 3 Molecular Cell Biology, Scherrer

Institut, Villigen, Switzerland 4 Department of Neurology,

University of Wurzburg, Würzburg, Germany

Corresponding author: Dr. Ueli Suter Institute of Cell Biology, ETH

Charcot-Marie-Tooth disease (CMT) 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.