Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot‐Marie‐Tooth disease)

Abstract

Over the last 15 years, a number of mutations in a variety of genes have been identified that lead to inherited motor and sensory neuropathies (HMSN), also called Charcot-Marie-Tooth disease (CMT). In this review we will focus on the molecular and cellular mechanisms that cause the Schwann cell pathologies observed in dysmyelinating and demyelinating forms of CMT. In most instances, the underlying gene defects alter primarily myelinating Schwann cells followed by secondary axonal degeneration. The first set of proteins affected by disease-causing mutations includes the myelin components PMP22, P0/MPZ, Cx32/GJB1, and periaxin. A second group contains the regulators of myelin gene transcription EGR2/Krox20 and SOX10. A third group is composed of intracellular Schwann cells proteins that are likely to be involved in the synthesis, transport and degradation of myelin components. These include the myotubularin-related lipid phosphatase MTMR2 and its regulatory binding partner MTMR13/SBF2, SIMPLE, and potentially also dynamin 2. Mutations affecting the mitochondrial fission factor GDAP1 may indicate an important contribution of mitochondria in myelination or myelin maintenance, whereas the functions of other identified genes, including NDRG1, KIAA1985, and the tyrosyl-tRNA synthase YARS, are not yet clear. Mutations in GDAP1, YARS, and the pleckstrin homology domain of dynamin 2 lead to an intermediate form of CMT that is characterized by moderately reduced nerve conduction velocity consistent with minor myelin deficits. Whether these phenotypes originate in Schwann cells or in neurons, or whether both cell types are directly affected, remains a challenging question. However, based on the advances in systematic gene identification in CMT and the analyses of the function and dysfunction of the affected proteins, crucially interconnected pathways in Schwann cells in health and disease have started to emerge. These networks include the control of myelin formation and stability, membrane trafficking, intracellular protein sorting and quality control, and may extend to mitochondrial dynamics and basic protein biosynthesis.

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

“…Disease-causing genes of demyelinating forms have been identified as follows: genes encoding myelin components, genes encoding regulators of myelin gene transcription and genes encoding intracellular Schwann cell proteins that are likely associated with the synthesis, transport and degradation of myelin components. [1][2][3][4] Regarding the causes of axonal forms, genes encoding cytoskeletal proteins, genes associated with axonal transport or with mitochondrial dynamics and genes encoding several aminoacyl-tRNA synthetases have been identified. 5 To identify the genetic background of Japanese CMT cases, we previously screened for gene mutations using single-strand conformation polymorphism [6][7][8][9] or denaturing gradient gel electrophoresis 10,11 and recently performed such screening by denaturing high performance liquid chromatography (DHPLC).…”

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

“…Myelin biogenesis and maintenance is a complex process involving coordinated exocytosis, endocytosis, and cytoskeletal dynamics. Perturbations in the myelin protein trafficking and/or turnover are associated with major myelin pathologies (16,17). Current hypotheses suggest that recycling endosomes play a central role in protein sorting and trafficking, both during plasma membrane recycling and as an intermediate step during cargo transport from the trans-Golgi network to the plasma membrane (18).…”

Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21.3 as novel candidate genes for autism

“…Taken together, also genes more distant to chromosomal breakpoints should be considered as candidate genes, even when they are separated from the aberration by unaffected genes. Therefore, although unlikely, for the two additional genes within the 1 Mb-region proximal to the 10q21.3 breakpoint, EGR2 (involved in Charcot -Marie -Tooth disease 52 ) at 650 kb and C10orf22 at 655 kb, a silencing effect cannot be completely excluded. Unfortunately, the absence of polymorphisms in de coding sequence of these genes together with low expression levels in EBV cell lines make it currently impossible to investigate this further.…”