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Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.

Bolino A, Bolis A, Previtali SC, Dina G, Bussini S, Dati G, Amadio S, Del Carro U, Mruk DD, Feltri ML, Cheng CY, Quattrini A, Wrabetz L - J. Cell Biol. (2004)

Bottom Line: We also identified a novel physical interaction in Schwann cells, between Mtmr2 and discs large 1 (Dlg1)/synapse-associated protein 97, a scaffolding molecule that is enriched at the node/paranode region.Dlg1 homologues have been located in several types of cellular junctions and play roles in cell polarity and membrane addition.We propose that Schwann cell-autonomous loss of Mtmr2-Dlg1 interaction dysregulates membrane homeostasis in the paranodal region, thereby producing outfolding and recurrent loops of myelin.

View Article: PubMed Central - PubMed

Affiliation: Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy. bolino.alessandra@hsr.it

ABSTRACT
Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomal recessive Charcot-Marie-Tooth (CMT) type 4B1, a demyelinating neuropathy with myelin outfolding and azoospermia. MTMR2 encodes a ubiquitously expressed phosphatase whose preferred substrate is phosphatidylinositol (3,5)-biphosphate, a regulator of membrane homeostasis and vesicle transport. We generated Mtmr2- mice, which develop progressive neuropathy characterized by myelin outfolding and recurrent loops, predominantly at paranodal myelin, and depletion of spermatids and spermatocytes from the seminiferous epithelium, which leads to azoospermia. Disruption of Mtmr2 in Schwann cells reproduces the myelin abnormalities. We also identified a novel physical interaction in Schwann cells, between Mtmr2 and discs large 1 (Dlg1)/synapse-associated protein 97, a scaffolding molecule that is enriched at the node/paranode region. Dlg1 homologues have been located in several types of cellular junctions and play roles in cell polarity and membrane addition. We propose that Schwann cell-autonomous loss of Mtmr2-Dlg1 interaction dysregulates membrane homeostasis in the paranodal region, thereby producing outfolding and recurrent loops of myelin.

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Gait and electrophysiological analysis of Mtmr2- mice. (A) Gait analysis revealed that right stride (R) (F[1, 18] = 9.96; P = 0.0055); left stride (L) (F[1, 18] = 10.97; P = 0.0039); and base (F[1, 18] = 16.746; P = 0.0007) were significantly increased in mutant mice as compared with wild-type mice, at 6 mo old. Values on the y axis refer to the measures normalized for the length of the animals (from the nape of the neck to the insertion of the tail). (B) Traces show the control and Mtmr2- profiles of compound motor action potential recorded after stimulation at the ankle (distal) and at the sciatic notch (proximal). The onset and end of the compound motor action potential and the onset of the F-wave are indicated by flags.
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fig2: Gait and electrophysiological analysis of Mtmr2- mice. (A) Gait analysis revealed that right stride (R) (F[1, 18] = 9.96; P = 0.0055); left stride (L) (F[1, 18] = 10.97; P = 0.0039); and base (F[1, 18] = 16.746; P = 0.0007) were significantly increased in mutant mice as compared with wild-type mice, at 6 mo old. Values on the y axis refer to the measures normalized for the length of the animals (from the nape of the neck to the insertion of the tail). (B) Traces show the control and Mtmr2- profiles of compound motor action potential recorded after stimulation at the ankle (distal) and at the sciatic notch (proximal). The onset and end of the compound motor action potential and the onset of the F-wave are indicated by flags.

Mentions: At 6 mo old, Mtmr2- animals and wild-type littermates showed no significant difference on rotarod testing (not depicted). Instead, gait analysis revealed significantly wider base and longer stride in Mtmr2- mice (Fig. 2 A), suggesting a neuromuscular abnormality. Consistent with this, Mtmr2- mice also showed reduced nerve conduction velocities (30.8 ± 0.8(8) m/s vs. 38.7 ± 0.5(20) m/s, P ≪ 0.001) and prolonged F-wave latencies (5.30 ± 0.13(8) ms vs. 4.99 ± 0.04(20) ms, P < 0.005). The amplitudes of proximal and distal compound motor action potentials were normal (Fig. 2 B). These findings are consistent with a peripheral neuropathy in Mtmr2- mice.


Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.

Bolino A, Bolis A, Previtali SC, Dina G, Bussini S, Dati G, Amadio S, Del Carro U, Mruk DD, Feltri ML, Cheng CY, Quattrini A, Wrabetz L - J. Cell Biol. (2004)

Gait and electrophysiological analysis of Mtmr2- mice. (A) Gait analysis revealed that right stride (R) (F[1, 18] = 9.96; P = 0.0055); left stride (L) (F[1, 18] = 10.97; P = 0.0039); and base (F[1, 18] = 16.746; P = 0.0007) were significantly increased in mutant mice as compared with wild-type mice, at 6 mo old. Values on the y axis refer to the measures normalized for the length of the animals (from the nape of the neck to the insertion of the tail). (B) Traces show the control and Mtmr2- profiles of compound motor action potential recorded after stimulation at the ankle (distal) and at the sciatic notch (proximal). The onset and end of the compound motor action potential and the onset of the F-wave are indicated by flags.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172586&req=5

fig2: Gait and electrophysiological analysis of Mtmr2- mice. (A) Gait analysis revealed that right stride (R) (F[1, 18] = 9.96; P = 0.0055); left stride (L) (F[1, 18] = 10.97; P = 0.0039); and base (F[1, 18] = 16.746; P = 0.0007) were significantly increased in mutant mice as compared with wild-type mice, at 6 mo old. Values on the y axis refer to the measures normalized for the length of the animals (from the nape of the neck to the insertion of the tail). (B) Traces show the control and Mtmr2- profiles of compound motor action potential recorded after stimulation at the ankle (distal) and at the sciatic notch (proximal). The onset and end of the compound motor action potential and the onset of the F-wave are indicated by flags.
Mentions: At 6 mo old, Mtmr2- animals and wild-type littermates showed no significant difference on rotarod testing (not depicted). Instead, gait analysis revealed significantly wider base and longer stride in Mtmr2- mice (Fig. 2 A), suggesting a neuromuscular abnormality. Consistent with this, Mtmr2- mice also showed reduced nerve conduction velocities (30.8 ± 0.8(8) m/s vs. 38.7 ± 0.5(20) m/s, P ≪ 0.001) and prolonged F-wave latencies (5.30 ± 0.13(8) ms vs. 4.99 ± 0.04(20) ms, P < 0.005). The amplitudes of proximal and distal compound motor action potentials were normal (Fig. 2 B). These findings are consistent with a peripheral neuropathy in Mtmr2- mice.

Bottom Line: We also identified a novel physical interaction in Schwann cells, between Mtmr2 and discs large 1 (Dlg1)/synapse-associated protein 97, a scaffolding molecule that is enriched at the node/paranode region.Dlg1 homologues have been located in several types of cellular junctions and play roles in cell polarity and membrane addition.We propose that Schwann cell-autonomous loss of Mtmr2-Dlg1 interaction dysregulates membrane homeostasis in the paranodal region, thereby producing outfolding and recurrent loops of myelin.

View Article: PubMed Central - PubMed

Affiliation: Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy. bolino.alessandra@hsr.it

ABSTRACT
Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomal recessive Charcot-Marie-Tooth (CMT) type 4B1, a demyelinating neuropathy with myelin outfolding and azoospermia. MTMR2 encodes a ubiquitously expressed phosphatase whose preferred substrate is phosphatidylinositol (3,5)-biphosphate, a regulator of membrane homeostasis and vesicle transport. We generated Mtmr2- mice, which develop progressive neuropathy characterized by myelin outfolding and recurrent loops, predominantly at paranodal myelin, and depletion of spermatids and spermatocytes from the seminiferous epithelium, which leads to azoospermia. Disruption of Mtmr2 in Schwann cells reproduces the myelin abnormalities. We also identified a novel physical interaction in Schwann cells, between Mtmr2 and discs large 1 (Dlg1)/synapse-associated protein 97, a scaffolding molecule that is enriched at the node/paranode region. Dlg1 homologues have been located in several types of cellular junctions and play roles in cell polarity and membrane addition. We propose that Schwann cell-autonomous loss of Mtmr2-Dlg1 interaction dysregulates membrane homeostasis in the paranodal region, thereby producing outfolding and recurrent loops of myelin.

Show MeSH
Related in: MedlinePlus