Disease relevance of MPZ

• Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity [1].
• Dejerine-Sottas disease, also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene of the P0 gene [2].
• The understanding of the molecular basis of CMT1 and related disorders has allowed accurate DNA diagnosis and genetic counseling of inherited peripheral neuropathies and will make it possible to develop rational strategies for therapy [3].
• Probably a fourth locus (CMT1C) exists since some autosomal dominant HMSN I families have been excluded for linkage with the CMT1A and CMT1B loci [4].
• Although demyelination is the hallmark of CMT1, the clinical signs and symptoms of this disease are probably produced by axonal degeneration, not demyelination [5].

Psychiatry related information on MPZ

• CONCLUSIONS: MPZ mutation His39Pro may be associated with acute-onset neuropathy, early-onset hearing loss and restless legs [6].
• In simple medical classification tasks this dynamic self-learning system can be used to create a DSS that can assist in the quality control of clinical decision making [7].
• The dynamic range of current, the pitch variation with repetition rate, and the difference limens for repetition rate were found to be similar to MPP and SPP [8].

High impact information on MPZ

• PMP22 Thr(118)Met: recessive CMT1 mutation or polymorphism [9]?
• Deletion of the serine 34 codon from the major peripheral myelin protein P0 gene in Charcot-Marie-Tooth disease type 1B [10].
• We have investigated P0 as a candidate gene in two pedigrees with CMT1B and found point mutations which are completely linked with the disease (Z = 5.5, theta = 0) [11].
• We have investigated the myelin P0 gene on chromosome 1 as a candidate gene in two sporadic cases with Dejerine-Sottas disease or hereditary motor and sensory neuropathy (HMSN) type III [12].
• P0 is a 28 kDa glycoprotein involved in the compaction of the multilamellar myelin sheet and accounts for more than half of the peripheral myelin protein content [10].

Chemical compound and disease context of MPZ

• Adie's pupil and deafness were often present, and serum creatine kinase concentrations were often raised irrespective of which MPZ mutation was present [13].
• We now show that point mutations in the cytoplasmic domain that modify a PKC target motif (RSTK) or an adjacent serine residue abolish P0 adhesion function and can cause peripheral neuropathy in humans [14].
• Two myelin proteins, P2 basic protein and P0 glycoprotein, can induce experimental autoimmune neuritis (EAN), a model of human inflammatory neuropathy [15].
• CONCLUSIONS: This broadens the range of familial neuropathy associated with MPZ mutations to include steroid responsive neuropathy, initially diagnosed as chronic inflammatory demyelinating polyneuropathy [16].
• This model predicts that agents which compete with MPP+ binding to neuromelanin should partially protect the dopamine neurons from MPTP-induced toxicity [17].

Biological context of MPZ

• These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes [18].
• We conclude that the clinical and electrophysiological heterogeneity among CMT patients carrying point mutations in MPZ and GJB1 is similar [1].
• OBJECTIVES: To expand our understanding of the characteristics of nerve conduction velocity (NCV) in patients with different MPZ mutations, the authors collected and analysed the NCV values from patients with MPZ mutations [19].
• Subsequent analysis of the coding regions of the MPZ gene was performed with single-strand-conformation polymorphism (SSCP), which was then followed by nucleotide sequencing [20].
• Here, we demonstrate for the first time that P0 and PMP22 proteins form complexes in the myelin membrane, as shown by coimmunoprecipitation experiments, and that glycosylation is not involved in mediating these interactions [21].

Anatomical context of MPZ

• In the nonduplicated CMT1 patients, several different mutations were identified in the myelin genes PMP22, MPZ and Cx32 [22].
• In transfected cells, P0 and PMP22 are recruited and colocalize at the apposed plasma membranes of expressors as shown by confocal microscopy [21].
• In this study, we determined the ultrastructural distribution of PMP22 and other myelin proteins in normal human peripheral nervous system (PNS) nerves and in CMT1 patients with or without the CMT1A duplication on chromosome 17 [23].
• Median nerve motor conduction velocity is concordant with myelin protein zero gene mutation [19].
• Human Cx32 was expressed in transgenic mice using a rat myelin protein zero (Mpz) promoter, which is exclusively expressed by myelinating Schwann cells [24].

Associations of MPZ with chemical compounds

• The G308-->A transition was a nonconservative mutation that changed a glycine into a glutamate at the amino acid residue 74 in the extracellular domain of the mature MPZ/P(0) [25].
• As shown for the animal model of globoid cell dystrophy, it is conceivable that increased expression of MHC class II molecules in CMT1 and HNPP accelerates nerve pathology [26].
• The MPZ point mutation in 18 of 18 related CMT1B pedigree 1 patients converts a positively charged lysine in codon 96 to a negatively charged glutamate [27].
• Daily administration of progesterone elevated the steady-state levels of Pmp22 and Mpz mRNA in the sciatic nerve, resulting in enhanced Schwann cell pathology and a more progressive clinical neuropathy [28].
• The mutation, a methionine substitution for isoleucine at amino acid position 30, is located in the extracellular domain, which constitutes an immunoglobulin domain responsible for the function of P0 as an adhesion molecule [29].

Regulatory relationships of MPZ

• Known inducers of Mpz expression such as forskolin and insulin-like growth factor-1 also activate the element in an Egr2-dependent manner [30].
• Three months after bone marrow transplantation, P0+/- mice expressing M-CSF showed a substantial upregulation and activation of both GFP- and GFP+ macrophages in femoral nerves when compared to P0+/+ mice [31].
• Doxy and CMT-1 also inhibited the inactivation of alpha1-proteinase inhibitor (serpinolytic activity) by a collagenolytic fraction of P. gingivalis [32].

Other interactions of MPZ

• We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations [18].
• Here the authors report a family with a Pro22Ser mutation in the neurofilament-light gene (NF-L; CMT2E) manifesting electrophysiologically as the demyelinating type 1 CMT (CMT1) and pathologically as an axonopathy with giant axons and accumulation of disorganized NF [33].
• The unrelated CMT patients included 108 clinically and electrophysiologically diagnosed CMT1 cases, 32 CMT2 cases, and 34 cases with unspecified CMT [34].
• Our results demonstrate that PMP22, P0 protein, and myelin basic protein are present in compact myelin of all patients examined [23].
• Genetic loci for CMT1 map to chromosome 17 (CMT1A), chromosome 1 (CMT1B), and another unknown autosome (CMT1C) [35].

Analytical, diagnostic and therapeutic context of MPZ

• By DNA heteroduplex analysis, four base mismatches were detected in three exons of MPZ [36].
• The peripheral myelin proteins P0 and PMP22 are associated in preparations of compact myelin and in cell cultures coexpressing both molecules [37].
• Thirty-eight Norwegian patients with CMT1, 4 patients with HNPP, 15 asymptomatic family members, and 45 normal controls were studied using the ABI 7700 sequence detection system and the TaqMan method of real-time quantitative polymerase chain reaction (PCR) [38].
• The extent of nerve pathology as assessed by teased fiber preparations or electron microscopy was not predictive for the degree of MHC class II expression in CMT1/HNPP [26].
• The S140T mutation in myelin P0 can be associated with conduction block and Charcot-Marie-Tooth should be part of the differential diagnosis of that phenomenon [39].

References