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
Source: PubMed

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.
    Molecular syndromology 11/2012; 3(5):204-14. DOI:10.1159/000343487
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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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    ABSTRACT: CMT4D disease is a severe autosomal recessive demyelinating neuropathy with extensive axonal loss leading to early disability, caused by mutations in the N-myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly high levels in the Schwann cell (SC), but its physiological function(s) are unknown. To help with their understanding, we characterise the phenotype of a new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display normal initial myelination and a transition to overt pathology between weeks 3 and 5, the markedly more severe str phenotype suggests that even low Ndrg1 expression results in significant phenotype rescue. Neither model replicates fully the features of CMT4D: although axon damage is present, regenerative capacity is unimpaired and the mice do not display the early severe axonal loss typical of the human disease. The widespread large fibre demyelination coincides precisely with the period of rapid growth of the animals and the dramatic (160-500-fold) increase in myelin volume and length in large fibres. This is followed by stabilisation after week 10, while small fibres remain unaffected. Gene expression profiling of str peripheral nerve reveals non-specific secondary changes at weeks 5 and 10 and preliminary data point to normal proteasomal function. Our findings do not support the proposed roles of NDRG1 in growth arrest, terminal differentiation, gene expression regulation and proteasomal degradation. Impaired SC trafficking failing to meet the considerable demands of nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency.
    Neurobiology of Disease 02/2011; 42(3):368-80. DOI:10.1016/j.nbd.2011.01.030 · 5.20 Impact Factor
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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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    ABSTRACT: Oligodendrocytes and Schwann cells are highly specialized glial cells that wrap axons with a multilayered myelin membrane for rapid impulse conduction. Investigators have recently identified axonal signals that recruit myelin-forming Schwann cells from an alternate fate of simple axonal engulfment. This is the evolutionary oldest form of axon-glia interaction, and its function is unknown. Recent observations suggest that oligodendrocytes and Schwann cells not only myelinate axons but also maintain their long-term functional integrity. Mutations in the mouse reveal that axonal support by oligodendrocytes is independent of myelin assembly. The underlying mechanisms are still poorly understood; we do know that to maintain axonal integrity, mammalian myelin-forming cells require the expression of some glia-specific proteins, including CNP, PLP, and MAG, as well as intact peroxisomes, none of which is necessary for myelin assembly. Loss of glial support causes progressive axon degeneration and possibly local inflammation, both of which are likely to contribute to a variety of neuronal diseases in the central and peripheral nervous systems.
    Annual Review of Neuroscience 02/2008; 31:535-61. DOI:10.1146/annurev.neuro.30.051606.094309 · 22.66 Impact Factor
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