Article

Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene.

Department of Neurophysiopathology, University of Cagliari, Italy.
Neurology (Impact Factor: 8.3). 06/1998; 50(5):1397-401. DOI: 10.1212/WNL.50.5.1397
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ABSTRACT Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), is a clinically and genetically heterogeneous condition. Mutations of the myelin protein zero (MPZ) gene have been associated with CMT1B, Dejerine-Sottas disease, and congenital hypomyelination, which are inherited demyelinating neuropathies characterized by different clinical severity. HMSN type II (HMSN II) or CMT2, the axonal form of CMT, is genetically heterogeneous. Linkage to 1p35-p36 (CMT2A), 3q (CMT2B), and 7p (CMT2D) chromosomes has been reported in the disease; however, most HMSN II families do not link to any of the reported loci. In a large HMSN II Sardinian family, we found a missense mutation in the chromosome 1q MPZ gene. This Ser44Phe mutation was located in exon 2 and was present in the heterozygous state in all affected individuals. This is the first example of an HMSN II family showing an MPZ point mutation. The MPZ gene Ser44Phe mutation found in the HMSN II family presented in this study suggests that genetic analysis of HMSN II families should also include the MPZ gene, previously not considered to be involved in the axonal form of HMSN.

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    • "DNM2 dynamin 2 GTPase endocytosis/cytoskeletal remodeling Fabrizi et al., 2007 CMT2C TRPV4 transient receptor potential cation channel, subfamily V, member 4 calcium channel calcium homeosthasis Klein et al., 2011; Landouré et al., 2010 CMT2I/2J MPZ myelin protein zero structural myelin protein myelin assembly Marrosu et al., 1998; Chapon et al., 1999; De Jonghe et al., 1999 "
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    ABSTRACT: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders of the peripheral nervous system, mainly characterized by distal muscle weakness and atrophy leading to motor handicap. With an estimated prevalence of 1 in 2,500, this condition is one of the most commonly inherited neurological disorders. Mutations in more than 30 genes affecting glial and/or neuronal functions have been associated with different forms of CMT leading to a substantial improvement in diagnostics of the disease and in the understanding of implicated pathophysiological mechanisms. However, recent data from systematic genetic screening performed in large cohorts of CMT patients indicated that molecular diagnosis could be established only in ∼50-70% of them, suggesting that additional genes are involved in this disease. In addition to providing an overview of genetic and functional data concerning various CMT forms, this review focuses on recent data generated through the use of highly parallel genetic technologies (SNP chips, sequence capture and next-generation DNA sequencing) in CMT families, and the current and future impact of these technologies on gene discovery and diagnostics of CMTs.
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    • "While there are examples of axonal neuropathy caused by different mutations in Schwann cell proteins, e.g. myelin basic protein zero and connexion 32 in CMT2 (Marrosu et al., 1998; Timmerman et al., 1996), human CMT4D patients, str mice and mutant Greyhound dogs have identical molecular defects, namely total NDRG1 deficiency. The link between demyelination and axonal loss remains poorly understood and the inter-species phenotype variation in NDRG1 mutants points to possible differences in PNS physiology and the role of genetic backgrounds. "
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    • "By definition, all demyelinating neuropathies exhibit morphological signs of myelin pathology as the underlying cause of slowed NCV, which suggests that myelin per se could be required to maintain axonal integrity. It was therefore a major advance when specific mutations in the Schwann cell–specific MPZ gene were identified that caused CMT type 2 with normal NCV (i.e., the axonal form of CMT disease ) rather than CMT1B (Marrosu et al. 1998, Senderek et al. 2000, Boerkoel et al. 2002). Although they are mechanistically not well understood , separate functions of Schwann cells in myelination (preserved in CMT2) and in axonal support (lost in all CMT forms) may have been uncoupled, reminiscent of Cnp1 and Plp null mutations in myelinating oligodendrocytes . "
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