Molecular cell biology of Charcot-Marie-Tooth disease

Abstract

Charcot-Marie-Tooth disease (CMT), also named hereditary motor and sensory neuropathies, includes a clinically and genetically heterogeneous group of disorders affecting the peripheral nervous system. Traditionally, the different classes of CMT have been divided into demyelinating forms (CMT1, CMT3, and CMT4) and axonal forms (CMT2), a clinically very useful distinction. However, investigations of the underlying molecular and cellular disease mechanisms, mainly accomplished using cell culture and animal models, as well as specific re-examination of appropriate patient cohorts, have revealed that the pathological signs of myelinopathies and axonopathies are often intermingled. These findings, although only recently fully appreciated, are not surprising given the dependence and intimate cellular interactions of Schwann cells and neurons, mainly during nerve development and, as indicated by the pathology of CMT, also in the adult organism. This review is intended to summarize our current knowledge about the molecular and cellular basis of CMT, with a particular emphasis on the role of Schwann cell/axon interactions. Such a view is particularly timely since approximately ten genes have now been identified as culprits in different forms of CMT. This collection revealed novel crucial players in the interplay between Schwann cells and neurons. The analysis of these genes and their encoded proteins will provide additional insights into the molecular and cellular basis of neuropathies and valuable information about the biology and interactions of Schwann cells, their associated neurons, endoneurial fibroblasts, and the nerve-surrounding and protecting perineurial sheath.

Mutational analysis ofPMP22, MPZ, GJB1, EGR2 andNEFL in Korean Charcot-Marie-Tooth neuropathy patients

“…The primary defect of CMT2 patients is neuronal (Harding and Thomas, 1980). CMT is a genetically heterogeneous disorder of the peripheral nervous system, thus many genes have been identified as CMT-causative genes (Berger et al, 2002). Tandem duplication of the CMT1A region within chromosome 17p11.2-p12 including peripheral myelin protein 22 (PMP22) gene is the most frequent cause of CMT type 1.…”

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

“…NDRG1 is involved in a diversity of cellular characteristics such as specific stress responses, hormone responses, cell growth and differentiation. NDRG1 gene mutations cause the neuropathy Charcot-MarieTooth disease type 4D (10). Its expression may also possess the potential to be used as a prognostic factor for some types of cancer (11).…”

Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module

“…2-5; see ref. 6 for review), which is characterized by reduced nerve conduction velocity and focally folded myelin sheets in peripheral nerves (7). Mutations in sbf2͞MTMR13 lead to a disease with identical pathology in the peripheral nervous system called CMT4B2, and are associated with early onset glaucomas in some families (8,9).…”