Distinct roles for the Charcot–Marie–Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination

Abstract

The form of Charcot–Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET Binding Factor 1; SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination. Thus, it is unclear whether MTMR5 plays an analogous or distinct role from that of its homolog, MTMR13, in the peripheral nervous system (PNS). MTMR5 and MTMR13 are pseudophosphatases predicted to regulate endosomal trafficking by activating Rab GTPases and binding to the phosphoinositide 3-phosphatase MTMR2. In the mouse PNS, Mtmr2 was required to maintain wild type levels of Mtmr5 and Mtmr13, suggesting that these factors function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 in mice led to perinatal lethality, indicating that the two proteins have partially redundant functions during embryogenesis. Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adult Mtmr5−/− mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects. Consistently, Mtmr5 levels were highest during axon radial sorting and fell sharply after postnatal day seven. Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2. This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease.

Characterization of a novel zebrafish model ofMTMR5-associated CMT4B3

“…4G-L). The reduced overall body size is consistent with smaller body size reported in Mtmr5 -/-adult mice (Mammel et al, 2022).…”

“…3D-E). In all, the loss of mtmr5 does not affect survival or cause significant movement defects, similar to observations from Mtmr5 -/- mice (Mammel et al, 2022).…”

“…To date, no pre-clinical models of CMT4B3 recapitulate the key features of the human disease. Mtmr5 knockout mice have been generated; they have defective spermatogenesis (Firestein et al, 2002, Mammel et al, 2022), and peripheral axon demyelination without overt axon defects or brain involvement (Mammel et al, 2022). Zebrafish serve as an excellent alternative model organism for studying CMT4B3.…”

Identification of novel pathogenic genes of childhood epileptic encephalopathies

“…Similarly, Sbf1 homozygous knockout in mice causes postnatal lethality with incomplete penetrance 38 . The Sbf1 homozygous knockout mice did not present overt motor or gait deficiencies, although an approximately 10% reduction in the number of myelinated axons in the sciatic nerve was observed 39 . Therefore, the mechanism underlying the pathogenesis of CMT4B3 caused by SBF1 biallelic variants is unclear.…”

A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder

“…SBF1 is predominantly expressed in the brain and skeletal muscle, and the protein encoded by this gene is a member of the myotubularin family. Myotubularin-related proteins, namely MTMR2, MTMR13/SBF2 and MTMR5/SBF1 are mainly involved in regulating endolysosomal trafficking 33 and mitochondrial functioning 34 . Dysregulation of SBF1 is linked to late-onset NCDs such as AD 17 , which is also indicated by the observed genotype anomalies in the NCD group versus controls in our study.…”