Loss of Mtmr2 phosphatase in Schwann cells but not in motor neurons causes Charcot-Marie-Tooth type 4B1 neuropathy with myelin outfoldings.
Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomal recessive Charcot-Marie-Tooth type 4B1 (CMT4B1). This disorder is characterized by childhood onset of weakness and sensory loss, severely decreased nerve conduction velocity, demyelination in the nerve with myelin outfoldings, and severe functional impairment of affected patients, mainly resulting from loss of myelinated fibers in the nerve. We recently generated Mtmr2-null(neo) mice, which show a dysmyelinating neuropathy with myelin outfoldings, thus reproducing human CMT4B1. Mtmr2 is detected in both Schwann cells and neurons, in which it interacts with discs large 1/synapse-associated protein 97 and neurofilament light chain, respectively. Here, we specifically ablated Mtmr2 in either Schwann cells or motor neurons. Disruption of Mtmr2 in Schwann cells produced a dysmyelinating phenotype very similar to that of the Mtmr2-null(neo) mouse. Disruption of Mtmr2 in motor neurons does not provoke myelin outfoldings nor axonal defects. We propose that loss of Mtmr2 in Schwann cells, but not in motor neurons, is both sufficient and necessary to cause CMT4B1 neuropathy. Thus, therapeutical approaches might be designed in the future to specifically deliver the Mtmr2 phospholipid phosphatase to Schwann cells in affected nerves.
Bolis
Annalisa
A
Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy.
Coviello
Silvia
S
Bussini
Simona
S
Dina
Giorgia
G
Pardini
Celia
C
Previtali
Stefano Carlo
SC
Malaguti
Mariachiara
M
Morana
Paolo
P
Del Carro
Ubaldo
U
Feltri
Maria Laura
ML
Quattrini
Angelo
A
Wrabetz
Lawrence
L
Bolino
Alessandra
A
D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000201:enzymology* / Q000502:physiology; D009186:Myelin Sheath / Q000473:pathology*; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D012583:Schwann Cells / Q000201:enzymology*
C498717:Mtmr2 protein, mouse; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor