• PMID: 15557122
• Gene Name: MTMR2
• Condition: Impaired spermatogenesis
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Impaired spermatogenesis

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.

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-null 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. FAU - Bolino, Alessandra AU - Bolino A AD - Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy. bolino.alessandra@hsr.it FAU - Bolis, Annalisa AU - Bolis A FAU - Previtali, Stefano Carlo AU - Previtali SC FAU - Dina, Giorgia AU - Dina G FAU - Bussini, Simona AU - Bussini S FAU - Dati, Gabriele AU - Dati G FAU - Amadio, Stefano AU - Amadio S FAU - Del Carro, Ubaldo AU - Del Carro U FAU - Mruk, Dolores D AU - Mruk DD FAU - Feltri, Maria Laura AU - Feltri ML FAU - Cheng, C Yan AU - Cheng CY FAU - Quattrini, Angelo AU - Quattrini A