Phenotypic Clustering in MPZ mutations

Department of Neurology, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA.
Brain (Impact Factor: 9.2). 03/2004; 127(Pt 2):371-84. DOI: 10.1093/brain/awh048
Source: PubMed


Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily with single extracellular, transmembrane and cytoplasmic domains. Homotypic interactions between extracellular domains of MPZ adhere adjacent myelin wraps to each other. MPZ is also necessary for myelin compaction since mice which lack MPZ develop severe dysmyelinating neuropathies in which compaction is dramatically disrupted. MPZ mutations in humans cause the inherited demyelinating neuropathy CMT1B. Some mutations cause the severe neuropathies of infancy designated as Dejerine-Sottas disease, while others cause a 'classical' Charcot-Marie-Tooth (CMT) disease Type 1B (CMT1B) phenotype with normal early milestones but development of disability during the first two decades of life. Still other mutations cause a neuropathy that presents in adults, with normal nerve conduction velocities, designated as a 'CMT2' form of CMT1B. To correlate the phenotype of patients with MPZ mutations with their genotype, we identified and evaluated 13 patients from 12 different families with eight different MPZ mutations. In addition, we re-analysed the clinical data from 64 cases of CMT1B from the literature. Contrary to our expectations, we found that most patients presented with either an early onset neuropathy with signs and symptoms prior to the onset of walking or a late onset neuropathy with signs and symptoms at around age 40 years. Only occasional patients presented with a 'classical' CMT phenotype. Correlation of specific MPZ mutations with their phenotypes demonstrated that addition of either a charged amino acid or altering a cysteine residue in the extracellular domain caused a severe early onset neuropathy. Severe neuropathy was also caused by truncation of the cytoplasmic domain or alteration of an evolutionarily conserved amino acid. Taken together, these data suggest that early onset neuropathy is caused by MPZ mutations that significantly disrupt the tertiary structure of MPZ and thus interfere with MPZ-mediated adhesion and myelin compaction. In contrast, late onset neuropathy is caused by mutations that more subtly alter myelin structure and which probably disrupt Schwann cell-axonal interactions.

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    • "The median MNCV is always < 38 m/s [10-13]. Patients with MPZ mutations may have a grave demyelinating phenotype, Dejerine-Sottas syndrome/CMT3 (DSS, MIM 145900) or congenital hypomyelinating neuropathy (MIM 605253) with very slow MNCVs or they may have a milder CMT1 or CMT2 phenotype with MNCVs in the intermediate or axonal range [14]. MFN2 mutations may be coupled with the classical CMT2 phenotype, but individuals who experience an early disease onset (<10 years) also tend to have severe symptoms, sometimes also optic atrophy [15,16]. "
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    ABSTRACT: The identification of disease causing, or putative disease causing, mutations in index patients with Charcot-Marie-Tooth disease (CMT) allows for genetic testing of family members. Relevant variants identified in index patients are of either definite, likely or uncertain pathogenicity. The main objective of this study was to make an evaluation of the family investigations performed as part of the assessment of genetic variants of unknown clinical significance (VUS). Between 2004 and 2010 molecular genetic family investigations were requested for 87 family members from 41 families harbouring PMP22dup or genetic variants in GJB1, MPZ, MFN2 and NEFL. Relatives were tested for the family mutation and data from the requisitions were evaluated by means of statistical tools. The results within each indication category are presented and discussed in detail. Twenty-two relatives (9 affected) from eight families were included in the segregation analyses, which invoked reclassification of three MFN2 mutations, two of which were de novo substitutions (c.2146_2148dup, c.692C > T). One MFN2 substitution was downgraded due to non-segregation (c.1709 A > G), and a MPZ substitution (c.103 G > A) upgraded due to segregation with the phenotype in the family. The results allow for the evaluation of the patient phenotypes ascertained in families, as opposed to the phenotypic descriptions of index patients. They indicate that de novo MFN2 mutations are regularly found in patients with a classical CMT2 phenotype. They also demonstrate the importance of a precise clinical and neurophysiologic diagnosis of affected family members. This particularly applies for the examination of variants of uncertain clinical significance. Finally, the fact that 14,6 % of affected relatives tested for (probable or certain) pathogenic mutations were mutation negative, demonstrates that clinical evaluation alone is not always sufficient in order to determine their diagnosis. We believe that the results will aid in the estimation and planning of resources required for the various aspects of family evaluations in CMT.
    BMC Medical Genetics 01/2014; 15(1):12. DOI:10.1186/1471-2350-15-12 · 2.08 Impact Factor
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    • "Myelin protein zero (MPZ) is the major glycoprotein of peripheral nerve myelin, and homotypic interactions between the extracellular domains of MPZ are required for the compaction of myelin lamellae. A large number of different MPZ mutations have been reported in association with CMT and can include axonal, demyelinating, or intermediate forms of CMT, with differing levels of severity [29]. "
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    ABSTRACT: We report an English kindred affected across 4 generations with a hereditary neuropathy associated with debilitating neuropathic pain as the main clinical feature. The principal finding on clinical examination was sensory loss, and there was variable motor dysfunction. Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range. There was an autosomal-dominant pattern of inheritance, and genetic testing revealed a novel heterozygous Trp101X mutation in exon 3 coding for a portion of the extracellular domain of myelin protein zero. This is predicted to lead to premature termination of translation. Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity. Chronic pain is an increasingly recognised sequela of certain hereditary neuropathies and may be musculoskeletal or neuropathic in origin. In this kindred, the neuropathy was relatively mild in severity, however, neuropathic pain was an important and disabling outcome.
    Pain 06/2012; 153(8):1763-8. DOI:10.1016/j.pain.2012.05.015 · 5.21 Impact Factor
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    • "To date there are more than 150 different mutations in MPZ known to cause CMT1B in patients, which include missense, nonsense, small insertion/deletion, and splice site mutations. Based on clinical studies, Shy and coworkers' [36] patients fall into two distinct phenotype groups: one causing delayed motor development and marked slow nerve conduction and a second one usually associated with late-onset neuropathy, which allows developmental myelination, but eventually leads to axonal degeneration with minimal evidence of demyelination. It is difficult to make genotype-phenotype correlations because mutations in MPZ impair the adhesive function of myelin protein zero (P0), its subcellular trafficking, or both. "
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    ABSTRACT: In the peripheral nervous system disorders plasticity is related to changes on the axon and Schwann cell biology, and the synaptic formations and connections, which could be also a focus for therapeutic research. Charcot-Marie-Tooth disease (CMT) represents a large group of inherited peripheral neuropathies that involve mainly both motor and sensory nerves and induce muscular atrophy and weakness. Genetic analysis has identified several pathways and molecular mechanisms involving myelin structure and proper nerve myelination, transcriptional regulation, protein turnover, vesicle trafficking, axonal transport and mitochondrial dynamics. These pathogenic mechanisms affect the continuous signaling and dialogue between the Schwann cell and the axon, having as final result the loss of myelin and nerve maintenance; however, some late onset axonal CMT neuropathies are a consequence of Schwann cell specific changes not affecting myelin. Comprehension of molecular pathways involved in Schwann cell-axonal interactions is likely not only to increase the understanding of nerve biology but also to identify the molecular targets and cell pathways to design novel therapeutic approaches for inherited neuropathies but also for most common peripheral neuropathies. These approaches should improve the plasticity of the synaptic connections at the neuromuscular junction and regenerate cell viability based on improving myelin and axon interaction.
    Neural Plasticity 06/2012; 2012(2):171636. DOI:10.1155/2012/171636 · 3.58 Impact Factor
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