Alternative titles; symbols
HGNC Approved Gene Symbol: MPZ
SNOMEDCT: 42986003, 45853006, 717013009, 717014003, 765747004; ICD10CM: G60.0;
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:161,303,600-161,309,968 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | Charcot-Marie-Tooth disease, dominant intermediate D | 607791 | Autosomal dominant | 3 |
| Charcot-Marie-Tooth disease, type 1B | 118200 | Autosomal dominant | 3 | |
| Charcot-Marie-Tooth disease, type 2I | 607677 | Autosomal dominant | 3 | |
| Charcot-Marie-Tooth disease, type 2J | 607736 | Autosomal dominant | 3 | |
| Dejerine-Sottas disease | 145900 | Autosomal dominant; Autosomal recessive | 3 | |
| Hypomyelinating neuropathy, congenital, 2 | 618184 | Autosomal dominant | 3 | |
| Roussy-Levy syndrome | 180800 | Autosomal dominant | 3 |
Myelin protein-zero is the major structural protein of peripheral myelin.
Hayasaka et al. (1991) isolated a full-length MPZ cDNA from a fetal spinal cord cDNA library. The deduced 248-amino acid protein was highly homologous to the P0 protein from other species.
Hayasaka et al. (1993) stated that the MPZ gene contains 6 exons.
You et al. (1991) found that the Mpz gene in the mouse, like that in the rat, contains 6 exons that span about 7 kb of genomic DNA.
In connection with the construction of a physical map of human 1q21-q23, Oakey et al. (1992) assigned the human gene, which they symbolized MPP, to a position close to FCGR2A (146790) and APOA2 (107670). By spot-blot hybridization of flow-sorted chromosomes and by fluorescence in situ hybridization, Hayasaka et al. (1993) mapped the MPZ gene to 1q22-q23 in the region of the CMT1B locus (118200). Su et al. (1993) mapped the MPZ gene physically 130 kb centromeric to the Fc receptor immunoglobulin gene cluster in band 1q22. By in situ hybridization, Pham-Dinh et al. (1993) assigned the MPZ gene to 1q21.3-q23, probably 1q22, and also demonstrated that the MPZ gene and the FCGR2A gene are located on the same YAC fragment within about 130 kb of each other.
You et al. (1991) mapped the mouse Mpz gene to chromosome 1 by Southern analysis of a Chinese hamster/mouse somatic cell hybrid panel. Using polymorphic restriction enzyme sites in the study of recombinant inbred strains, they linked the gene to genes in a region corresponding to band 1H3.
Myelin protein-zero is the major structural protein of peripheral myelin, accounting for more than 50% of the protein present in the sheath of peripheral nerves. Expression of the MPZ gene is restricted to Schwann cells; MPZ is not found in the CNS. An integral membrane glycoprotein of 28 kD, MPZ is thought to link adjacent lamellae and thereby stabilize the myelin assembly. The other 3 major components of myelin are myelin basic protein (MBP; 159430), myelin proteolipid protein (PLP1; 300401), and myelin-associated glycoprotein (MAG; 159460); see reviews of Lemke (1986) and Sutcliffe (1987).
Mutations in the MPZ gene are associated with the autosomal dominant form of Charcot-Marie-Tooth disease type 1 (CMT1B; 118200), which is characterized by progressive slowing of nerve conduction and hypertrophy of Schwann cells. Mutations in MPZ can also produce the more severe polyneuropathies, Dejerine-Sottas syndrome (DSS; 145900) and congenital hypomyelinating neuropathy-2 (CHN2; 618184), as well as several types of axonal CMT2 (see, e.g., 607677).
In 2 families with CMT1B, Hayasaka et al. (1993) identified mutations in the MPZ gene (159440.0001-159440.0002). Roa et al. (1996) surveyed 70 unrelated patients with demyelinating polyneuropathy for mutations in the MPZ gene. The 1.5-Mb DNA duplication on chromosome 17p12-p11.2 associated with Charcot-Marie-Tooth disease type 1A (118220) was not present. An ile135-to-thr substitution (159440.0007) in MPZ exon 3 was found in a family with clinically severe early-onset CMT1, and an exon 3 mutation encoding a gly137-to-ser (159440.0008) substitution was identified in a second CMT1 family. The mutations predicted amino acid substitutions in the extracellular domain of the MPZ protein. The observations confirmed the role of MPZ in CMT1B, but suggested to Roa et al. (1996) that MPZ coding region mutations account for only a limited percentage of disease-causing mutations in nonduplication CMT1 patients.
In 2 sibs with autosomal recessive DSS, Warner et al. (1996) identified homozygosity for a gly74 frameshift mutation in the MPZ gene (159440.0025). Ikegami et al. (1996) likewise observed the DSS phenotype with homozygosity for mutation in the MPZ gene. The findings are parallel to those found with homozygosity for the PMP22 gene (601097) in the cases reported by Killian and Kloepfer (1979), Lupski et al. (1991), and Kaku et al. (1993). The heterozygous parents presented with CMT1, whereas the homozygous children were more severely affected with DSS. These findings indicated the dosage sensitivity of the MPZ and PMP22 myelin genes and also supported the hypothesis that these clinical entities, CMT1 and DSS, represent variants of the same disease.
Marrosu et al. (1998) and Boerkoel et al. (2002) reported mutations in the MPZ gene (159440.0017 and 159440.0020) in patients with classic axonal CMT2 (CMT2I; 607677). Senderek et al. (2000) reported 2 MPZ point mutations in 2 families with classic axonal CMT2I with late onset. De Jonghe et al. (1999), Chapon et al. (1999), Misu et al. (2000), and Senderek et al. (2000) found that the thr124-to-met (T124M) mutation (159440.0016) was associated with a distinct CMT2 axonal phenotype with pupillary anomalies and deafness (CMTJ; 607736). Boerkoel et al. (2002) pointed that at least 6 mutations in the MPZ gene had been reported in patients with Charcot-Marie-Tooth disease type 2.
In affected members of a 4-generation Macedonian family with autosomal dominant HMSN characterized by variable severity and motor nerve conduction velocities in the intermediate range (CMTDID; 607791), Mastaglia et al. (1999) identified a heterozygous mutation in the MPZ gene (159440.0018).
Nelis et al. (1999) tabulated 56 distinct mutations in the MPZ gene that had been identified in association with hereditary peripheral neuropathy.
Among 214 Italian patients with CMT, Mandich et al. (2009) identified mutations in the MPZ gene in 7 (7.9%) of 89 patients with demyelinating neuropathy and in 6 (4.8%) of 125 patients with axonal neuropathy. Phenotypic variability ranged from severe Dejerine-Sottas syndrome to adult-onset axonal neuropathy.
Maeda et al. (2012) reported a 3-generation Taiwanese family in which 6 individuals had classic autosomal dominant early-onset demyelinating CMT1B. Array comparative genomic hybridization of 13 known CMT genes identified increased dosage of MPZ that segregated with the phenotype. The 118-kb duplication included the entire MPZ gene as well as the flanking genes SDHC (602413) and C1ORF192; both breakpoints occurred within Alu sequences. MPZ mRNA levels were increased in patient lymphoblasts and sural nerves, and the gene dosage was estimated to be 5 copies. There was striking intrafamilial variability in the phenotype, with variation in nerve conduction velocities and age at onset. Copy number changes of the MPZ gene were not found in 192 control individuals. Maeda et al. (2012) noted that mice with overexpression of the MPZ gene developed a dysmyelinating neuropathy (Wrabetz et al., 2000). The findings indicated that overexpression of wildtype MPZ may disturb myelination during development, similar to that observed with duplication of PMP22 (601097.0001) and PLP1 (300401.0021).
Mutations in the MPZ gene cause distinct neurologic diseases, including CHN, DSS, and CMT1B. Inoue et al. (2004) presented evidence suggesting that truncating mutations in the 5-prime end of the gene result in a milder clinical phenotype than those in the 3-prime end of the gene. Northern blot analysis showed that the mutations associated with the milder phenotype are located in an internal exon and result in a decrease in mutant mRNA compared to most mutations associated with severe disease that are located in the last exon, and are not followed by an intron, which results in a larger accumulation of mutant mRNA. The decrease in mutant mRNA occurs via the nonsense-mediated decay (NMD) pathway, which typically degrades only transcripts containing nonsense mutations that are followed by at least 1 intron (Carter et al., 1996; Nagy and Maquat, 1998). Accordingly, the mutations associated with the more severe phenotype may escape NMD and express large amounts of dominant-negative protein. Similar results were obtained for truncating mutations in the SOX10 gene (602229). Inoue et al. (2004) suggested that, in general, the NMD mechanism may function protectively to functionally convert dominant-negative effects to haploinsufficiency.
Most MPZ-truncating mutations associated with severe forms of peripheral neuropathy result in premature termination codons within the terminal or penultimate exons that are not subject to nonsense-mediated decay and are stably translated into mutant proteins with potential dominant-negative activity. However, some truncating mutations at the 3-prime end of MPZ escape the nonsense-mediated decay pathway and cause a mild peripheral neuropathy phenotype. Khajavi et al. (2005) examined the functional properties of MPZ-truncating proteins that escaped nonsense-mediated decay, and found that frameshift mutations associated with severe disease cause an intracellular accumulation of mutant proteins, primarily within the endoplasmic reticulum (ER), which induces apoptosis. They found that curcumin, a chemical compound derived from the curry spice turmeric, releases the ER-retained MPZ mutants into the cytoplasm accompanied by a lower number of apoptotic cells. The findings suggested that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and has the potential of a therapeutic role in treating selected forms of inherited peripheral neuropathies.
Wrabetz et al. (2000) showed that normal peripheral nerve myelination depends on strict dosage of MPZ, the most abundantly expressed myelin gene. Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P0-glycoprotein. The findings suggested that Schwann cells may be susceptible to gene dosage during nerve development.
Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), which is associated with greatly reduced nerve conduction velocity, was mapped to 1q21.3-q23 by family linkage studies and by deletion mapping. Mapping of the MPZ gene to the same region suggested that it might be the site of the causative mutations. Hayasaka et al. (1993) proved this to be the case by the demonstration of separate mutations in 2 families with CMT1B: a lys96-to-glu mutation and an asp90-to-glu mutation (159440.0002). Both were located in the extracellular domain, which plays a significant role in myelin membrane adhesion.
Su et al. (1993) found the lys96-to-glu mutation in all of 18 affected members of the largest known Duffy-linked CMT1B family. The mutation occurred in a region of the MPZ protein conserved identically in human, rat, and cow since these species diverged.
Thomas et al. (1994) demonstrated by sural nerve biopsies from a father and son in this family that the changes were typical of tomaculous neuropathy with loss of myelinated fibers and frequent small onion bulbs. The resemblance of tomacula to myelin folding and loops during early development may reflect immature or abnormal axon-myelin interaction. Tomaculous neuropathy is characteristic particularly of hereditary neuropathy with liability to pressure palsies (162500), which has been shown to result from deletion of the gene for peripheral myelin protein-22; PMP22 is duplicated or the site of point mutations in Charcot-Marie-Tooth disease type 1A.
In affected members of a family segregating Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Hayasaka et al. (1993) identified an asp90-to-glu mutation in the MPZ gene. The mutation was located in the extracellular domain, which plays a significant role in myelin membrane adhesion.
Kulkens et al. (1993) showed that all affected members of a family with type 1B Charcot-Marie-Tooth disease (CMT1B; 118200) had a 3-bp deletion in exon 2 causing loss of the serine-34 codon. This residue is located in the extracellular domain of P0.
Hayasaka et al. (1993) found a mutation of the MPZ gene in a 7-year-old boy with delayed motor development, hypotonia, muscle weakness, and sensory disturbance thought to be typical of Dejerine-Sottas syndrome (145900), or hereditary motor and sensory neuropathy type III (HMSN3). The patient was case 1 of Tachi et al. (1984). Cysteine was substituted for serine-63 in the extracellular domain. The patient was heterozygous for the mutation, which was absent in the parents and in 100 unrelated healthy controls.
Hayasaka et al. (1993) identified a gly167-to-arg mutation in the transmembrane domain of MPZ in case 20 of Ouvrier et al. (1987); the patient was thought to have typical Dejerine-Sottas syndrome (145900) except that his spinal fluid protein level was not elevated. The patient was heterozygous for the mutation, which was absent in the parents and in 100 unrelated healthy controls.
In all of 3 tested affected patients in a family with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Su et al. (1993) found 5 nucleotide substitutions in the MPZ gene. These mutations disrupted the splice site between intron 5 and exon 6 and may have created a new splice site 3 bases earlier. The new putative splice site would replace a neutral threonine with a positively charged arginine and a negatively charged glutamic acid. This major charge change would be expected to interfere with serine phosphorylation 6 amino acids upstream. This mutant 9-bp sequence is identical to a mouse intron 1 sequence. Thus, a recombination between the homologous human MPZ intron 1 and the MPZ intron 5 splice acceptor site could have generated this CMT1B allele. The mutation was referred to as T216ER.
Roa et al. (1996) identified an ile135-to-thr mutation in a Charcot-Marie-Tooth disease type 1B (CMT1B; 118200) family of Spanish descent with at least 3 generations of affected family members and male-to-male transmission. The proband was diagnosed with CMT disease at 22 years of age. Episodes of cramps in the legs and arms were subsequently documented. Neuroconduction studies showed no response on stimulation of sensory nerves and severely reduced motor neuron conduction velocities were observed. The patient had been wheelchair-bound since age 37 years.
Roa et al. (1996) identified a gly137-to-ser mutation in a father and daughter with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200). The grandparents were unaffected. The father had not walked until age 2 years. At the age of 12 he showed a slapping gait, severe atrophy of leg muscles, pes cavus, and hammertoes. He also had weakness and wasting of intrinsic hand muscles and absent stretch reflexes in all 4 limbs. There were no visibly enlarged or palpable peripheral nerves. Sensory nerve conduction studies on the left sural nerve elicited no response upon stimulation. The patient's 4-year-old daughter walked at 21 months of age, had flat feet, walked on her toes, and had muscle weakness. Neurologic examination showed absence of stretch reflexes and no enlargement of peripheral nerves.
Among 20 unrelated French Charcot-Marie-Tooth disease type 1B (CMT1B; 118200) patients without 17p11.2 duplications, Rouger et al. (1996) found 3 different mutations at codon 98. No other mutation in exon 3 of the MPZ gene was detected. The mutation was demonstrated to be de novo in 1 of the cases and suspected of being de novo in the other 2, suggesting that mutations occur with a high rate at codon 98. In 1 patient an arg98-to-pro (R98P) mutation was caused by a 293G-C transversion, whereas in another patient an arg98-to-cys substitution (R98C; 159440.0010) was caused by a 292C-T transition. The third mutation was a 293G-A transition, resulting in an arg98-to-his substitution (R98H; 159440.0011). Rouger et al. (1996) noted that this mutation had previously been reported in a Japanese family by Hayasaka et al. (1993). The patient with the R98C mutation showed a more severe clinical and electrophysiologic phenotype than the others with a codon 98 mutation, partly compatible with Dejerine-Sottas syndrome with very early onset (1 year), and a very low nerve conduction velocity, but only mild functional disability at age 8 years. All 3 mutations in codon 98 implied a C-to-T transition (1 on the sense and 2 on the antisense strand), suggesting that they may result from the deamination of a methylcytosine to a thymine. The authors stated that this could explain the high rate of mutations on codon 98. The R98H mutation, characterized by direct sequencing in 2 cases, was not detected by the SSCP technique. Since SSCP analysis was used as the initial screening technique in most previous studies, the frequency of mutations at codon 98 may have been underestimated. The 3 codon 98 mutations represented 20% of the CMT1 patients without duplications and probably a much higher proportion of those with MPZ mutations. These mutations can be picked up by CfoI restriction of exon 3 of the MPZ gene; this approach should be the first step in screening CMT1 patients without duplications.
Among 20 unrelated French Charcot-Marie-Tooth disease type 1B (CMT1B; 118200) patients without 17p11.2 duplications, Rouger et al. (1996) found 3 different mutations at codon 98. No other mutation in exon 3 of the MPZ gene was detected. The mutation was demonstrated to be de novo in 1 of the cases and suspected of being de novo in the other 2, suggesting that mutations occur with a high rate at codon 98. In 1 patient an arg98-to-pro (R98P; 159440.0009) mutation was caused by a 293G-C transversion, whereas in another patient an arg98-to-cys substitution (R98C) was caused by a 292C-T transition. The third mutation was a 293G-A transition, resulting in an arg98-to-his substitution (R98H; 159440.0011). Rouger et al. (1996) noted that this mutation had previously been reported in a Japanese family by Hayasaka et al. (1993). The patient with the R98C mutation showed a more severe clinical and electrophysiologic phenotype than the others with a codon 98 mutation, partly compatible with Dejerine-Sottas syndrome with very early onset (1 year), and a very low nerve conduction velocity, but only mild functional disability at age 8 years. All 3 mutations in codon 98 implied a C-to-T transition (1 on the sense and 2 on the antisense strand), suggesting that they may result from the deamination of a methylcytosine to a thymine. The authors stated that this could explain the high rate of mutations on codon 98. The R98H mutation, characterized by direct sequencing in 2 cases, was not detected by the SSCP technique. Since SSCP analysis was used as the initial screening technique in most previous studies, the frequency of mutations at codon 98 may have been underestimated. The 3 codon 98 mutations represented 20% of the CMT1 patients without duplications and probably a much higher proportion of those with MPZ mutations. These mutations can be picked up by CfoI restriction of exon 3 of the MPZ gene; this approach should be the first step in screening CMT1 patients without duplications.
Among 20 unrelated French Charcot-Marie-Tooth disease type 1B (CMT1B; 118200) patients without 17p11.2 duplications, Rouger et al. (1996) found 3 different mutations at codon 98. No other mutation in exon 3 of the MPZ gene was detected. The mutation was demonstrated to be de novo in 1 of the cases and suspected of being de novo in the other 2, suggesting that mutations occur with a high rate at codon 98. In 1 patient an arg98-to-pro (R98P; 159440.0009) mutation was caused by a 293G-C transversion, whereas in another patient an arg98-to-cys substitution (R98C; 159440.0010) was caused by a 292C-T transition. The third mutation was a 293G-A transition, resulting in an arg98-to-his substitution. Rouger et al. (1996) noted that this mutation had previously been reported in a Japanese family by Hayasaka et al. (1993). The patient with the R98C mutation showed a more severe clinical and electrophysiologic phenotype than the others with a codon 98 mutation, partly compatible with Dejerine-Sottas syndrome with very early onset (1 year), and a very low nerve conduction velocity, but only mild functional disability at age 8 years. All 3 mutations in codon 98 implied a C-to-T transition (1 on the sense and 2 on the antisense strand), suggesting that they may result from the deamination of a methylcytosine to a thymine. The authors stated that this could explain the high rate of mutations on codon 98. The R98H mutation, characterized by direct sequencing in 2 cases, was not detected by the SSCP technique. Since SSCP analysis was used as the initial screening technique in most previous studies, the frequency of mutations at codon 98 may have been underestimated. The 3 codon 98 mutations represented 20% of the CMT1 patients without duplications and probably a much higher proportion of those with MPZ mutations. These mutations can be picked up by CfoI restriction of exon 3 of the MPZ gene; this approach should be the first step in screening CMT1 patients without duplications.
Watanabe et al. (2002) reported partial symptom relief with corticosteroid treatment in a patient with demyelinating CMT1B and a heterozygous R98H mutation in the MPZ gene. Although this response is rare in such patients, Watanabe et al. (2002) hypothesized that poor myelin compaction by the MPZ protein, caused by the mutation, may have allowed circulating immune elements access to normally sequestered endoneurial components, thus accounting for the response to corticosteroid treatment.
In a 54-year-old mother and her 22-year-old daughter, Blanquet-Grossard et al. (1995) found that type 1B Charcot-Marie-Tooth disease (CMT1B; 118200) was associated with a ser63-to-phe mutation. This was the third mutation to be described at this codon; a ser63-to-del mutation (159440.0003) led to CMT1B.
In a patient (patient 987) with congenital hypomyelination-2 (CHN2; 618184), Warner et al. (1996) identified a de novo heterozygous 643C-T transition in exon 5 of the MPZ gene, resulting in a gln186-to-ter (GLN186TER; Q186X) substitution.
Mandich et al. (1999) identified the same de novo heterozygous nonsense mutation, referred to as a c.643C-T transition resulting in a gln215-to-ter (Q215X) substitution, in an unrelated patient with CHN2.
In a family in South Wales in which 13 members were affected by Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Sorour et al. (1997) found a 242A-G transition in exon 3 of the MPZ gene, resulting in a his81-to-arg substitution. The family was unusual in that several members had severe distal lower limb weakness and foot deformities from early childhood, including 3 born with clubfoot. One had undergone bilateral below-knee amputations for severe foot deformities. All affected individuals had distal muscle weakness and wasting of upper and lower limbs, tendon stretch hypo/areflexia, and distal sensory impairment. The median nerve motor conduction velocity of affected family members was 11.1 m/s and median sensory nerve action potentials (SNAPs) were consistently absent. The disorder in this family was significantly more severe than in other families with HMSN type I in this study.
In a sporadic case of Dejerine-Sottas syndrome (DSS; 145900), Warner et al. (1997) identified 3 de novo point mutations in exon 3 of the MPZ gene. The point mutations occurred on the same allele and resulted in 3 amino acid substitutions: ile85 to thr, asn87 to his, and asp99 to asn. They were all novel mutations; therefore, it was difficult to predict what the phenotype of these mutations would be individually. The mechanism by which they produced a severe phenotype was also unclear. None of the mutations occurred at a CpG dinucleotide and there were no known similar sequences to participate in a gene conversion event. The spacing between the mutations (5 bp and 36 bp) suggested the occurrence of sequence alterations on different faces of the double helix, which may be less likely to result from a single contact by an interacting exogenous chemical mutagen. The patient was the offspring of a 36-year-old mother and a 46-year-old father. He was noted at 9 weeks of age to have moderate to severe hypotonia and weak tendon reflexes. At 2 years, he showed delay in motor development. He sat without support and could stand with assistance, but could not walk. He appeared to be advanced in mental development. Motor nerve conduction velocities at 1 year of age were markedly delayed with significantly low amplitude. There was no response from the medial plantar and sural nerves on sensory nerve conduction tests. Nerve biopsy showed variation in fiber size with reduced number of axons, hypomyelination, and sporadic onion bulb formation.
In a man with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Schiavon et al. (1998) identified a 371C-T transition in exon 3 of the MPZ gene, resulting in a thr124-to-met (T124M) substitution. The patient had a relatively mild clinical course, with onset of generalized asthenia at age 42 years and a slightly decreased motor NCV of 37 m/s.
In 7 Charcot-Marie-Tooth families and in 2 isolated CMT patients of Belgian ancestry, De Jonghe et al. (1999) found the T124M mutation. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the T124M mutation had 1 common ancestor. The mutation was associated with a clinically distinct phenotype characterized by axonal involvement, late onset, marked sensory abnormalities, and, in some families, deafness and pupillary abnormalities (CMT2J; 607736). Nerve conduction velocities of the motor median nerve varied from less than 38 m/s to normal values in these patients. Clusters of remyelinating axons in the sural nerve biopsy demonstrated an axonal involvement, with axonal regeneration. Phenotype/genotype correlations in 30 patients with the mutation indicated that, based on nerve conduction velocity criteria, these patients were difficult to classify as CMT1 or CMT2. De Jonghe et al. (1999) concluded that CMT patients with slightly reduced or nearly normal nerve conduction velocity should be screened for MPZ mutations, particularly when additional clinical features such as marked sensory disturbances, pupillary abnormalities, or deafness are also present.
Chapon et al. (1999) and Misu et al. (2000) likewise found a distinct CMT type 2 axonal phenotype with pupillary anomalies, deafness, and sensory abnormalities associated with the T124M mutation.
Senderek et al. (2000) suggested that T124M reflects a mutation hotspot.
Baloh et al. (2004) reported a family in which multiple members spanning 3 generations had severe chronic recurring coughing spasms, beginning in their teens and lasting for 20 to 30 minutes and ending in retching or vomiting. All affected members had tonic pupils and most developed late-onset axonal peripheral neuropathy. The features resembled CMT with hearing loss and pupillary abnormalities reported by De Jonghe et al. (1999) and Misu et al. (2000), but hearing loss was not a feature in this family. The proband also reported gastrointestinal symptoms diagnosed as irritable bowel syndrome, occasional urinary incontinence, and erectile dysfunction. The proband and his affected sister and mother were heterozygous for the T124M mutation; 4 unaffected family members tested did not have the mutation. Baloh et al. (2004) concluded that the T124M mutation results in dysfunction of the autonomic nervous system.
Triggs et al. (2006) described a family with the characteristic features of CMT2J and the T124M mutation.
In a patient with a classic CMT2 phenotype (CMT2I; 607677), Boerkoel et al. (2002) found heterozygosity for 3 missense mutations in the MPZ gene: ile89-to-asn, val92-to-met, and ile162-to-met. The first 2 mutant amino acids are in the extracellular domain of the P0 protein; ile162-to-met is in the transmembrane domain. Boerkoel et al. (2002) pointed to another report of a patient with 3 MPZ mutations (Warner et al., 1997); see 159440.0015.
Mastaglia et al. (1999) reported a 4-generation Macedonian family with autosomal dominant HMSN characterized by variable severity and motor nerve conduction velocities in the intermediate range (CMTDID; 607791). Affected members displayed a symmetric pattern of distal muscle atrophy, weakness, and sensory impairment in the lower limbs and to a lesser extent in the upper limbs. Motor NCVs ranged from 24-41 m/s for the median nerve and from 33-48 m/s for the ulnar nerve. Nerve biopsy of 2 patients showed primarily axonal degeneration, but also areas of segmental demyelination and remyelination without onion bulb formation. All affected members had a heterozygous G-to-T transversion in the MPZ gene, resulting in an asp6-to-tyr (D6Y) substitution in the extracellular domain of the protein. Mastaglia et al. (1999) called the disorder in this family an 'intermediate' form of HMSN between types 1 and 2.
In 3 unrelated patients with axonal CMT2 with pupillary abnormalities and deafness (CMT2J; 607736), Misu et al. (2000) identified an A-to-T change in exon 2 of the MPZ gene, resulting in an asp75-to-val (D75V) substitution. Age of onset was relatively late (37 to 61 years) and the presenting symptom was paresthesia in the distal legs. There was also distal leg weakness and atrophy and distal sensory impairment. Two patients had pupillary abnormalities, and 1 also had deafness. NCVs were consistent with axonal neuropathy. The authors noted that the distinctive phenotype, with pupillary abnormalities and deafness, was similar to that reported in some patients with the T124M mutation (159440.0016).
In a large Sardinian family with a classic CMT2 phenotype (CMT2I; 607677), Marrosu et al. (1998) identified a heterozygous mutation in exon 2 of the MPZ gene, resulting in a ser44-to-phe (S44F) substitution.
In 3 individuals with Roussy-Levy syndrome (180800) from the original family described by Roussy and Levy (1926), Plante-Bordeneuve et al. (1999) identified a heterozygous 727C-A transition in exon 3 of the MPZ gene, resulting in an asn131-to-lys (N131K) substitution in the extracellular domain of the protein. The authors concluded that the Roussy-Levy family falls into the CMT1B (118200) subgroup of the hereditary demyelinating polyneuropathies.
In 2 sisters with a severe early-onset form of demyelinating Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Fabrizi et al. (2001) identified a heterozygous 308G-A change in exon 3 of the MPZ gene, resulting in a gly74-to-glu (G74E) substitution. Because both parents were asymptomatic, the disorder at first appeared to be autosomal recessive. However, molecular analysis showed that the mother was a mosaic for the mutation in somatic cells and presumably in germline cells, thus confirming autosomal dominant inheritance.
In 2 pedigrees with a late-onset, relatively mild form of Charcot-Marie-Tooth disease 1B with focally folded myelin sheaths (CMT1B; 118200), Fabrizi et al. (2000) identified a heterozygous 233C-T transition in exon 2 of the MPZ gene, resulting in a ser49-to-leu (S49L) substitution in the extracellular domain of the protein. Pathology showed a characteristic demyelinating process, but also revealed irregular myelin outfoldings and infoldings and tomacula. Fabrizi et al. (2000) noted that the mutation exchanges a polar amino acid with a hydrophobic amino acid, and suggested that the change would result in myelin uncompaction which could lead to out- or infoldings. The authors also noted that myelin outfoldings have been described in other CMT patients with mutations in MPZ, EGR2 (129010.0004), and PMP22 (601097.0016), and that the finding is not restricted to CMT4B (see CMT4B1; 601382).
In a family with Charcot-Marie-Tooth disease 1B with focally folded myelin sheaths (CMT1B; 118200) first reported by Umehara et al. (1993), Nakagawa et al. (1999) identified a heterozygous 184A-T transversion in exon 2 of the MPZ gene, resulting in an ile62-to-phe (I62F) substitution.
In 2 sibs with autosomal recessive Dejerine-Sottas syndrome (DSS; 145900), Warner et al. (1996) identified homozygosity for a gly74 frameshift mutation in the MPZ gene. The mutation, a 1-bp deletion, led to premature termination that predicted a truncated protein of only 87 amino acids. This truncated protein was presumably degraded and never reached the membrane. Therefore, this mutation probably constituted a loss-of-function allele. The consanguineous parents, who were heterozygous for the 1-bp deletion, had a mild neuropathy with features of CMT1B. The children presented with the phenotype of Dejerine-Sottas syndrome which behaved as a recessive trait in this family, as compared to the dominant inheritance in other families (e.g., 159440.0004). This phenotypic variation between the heterozygous and the homozygous state closely resembled that seen in Mpz knockout mice (Martini et al., 1995).
In affected members of a Costa Rican family with Charcot-Marie-Tooth disease (CMT1B; 118200), Leal et al. (2003) identified a tyr145-to-ser (Y145S) mutation in the MPZ gene. Four affected members were heterozygous for the mutation; 2 offspring of 2 heterozygous carrier parents were homozygous for the mutation. On neurologic examination, the heterozygous parents and their homozygous children all showed distal sensory deficits. The mother and the offspring displayed impaired deep tendon reflexes and mild sensory ataxia. The homozygous individuals were more severely affected with an earlier age at onset, distal motor weakness, and pupillary abnormalities. Electrophysiologic studies revealed signs of demyelination and axonal nerve degeneration. The sural nerve biopsy of 1 offspring showed thinly myelinated nerve fibers, onion bulb formation, and clusters of regenerating fibers.
In a patient with congenital hypomyelinating neuropathy-2 (CHN2; 618184), Szigeti et al. (2003) identified a heterozygous 3-bp deletion (550delCTA) and a 1-bp insertion (550insG) in the MPZ gene, predicted to result in a protein in which the last 65 amino acids are replaced with a 49-amino acid novel sequence. The authors noted that the mutation may result in decreased adhesion capacity of the protein.
In 4 affected members of a family with very late onset axonal Charcot-Marie-Tooth disease (CMT2I; 607677), Auer-Grumbach et al. (2003) identified a 178G-C transversion in exon 2 of the MPZ gene, resulting in an asp60-to-his (D60H) substitution, which they incorrectly reported as ASN60HIS. Kamholz and Shy (2004) reported the correct mutation as D60H. The patients had onset of symptomatic disease, primarily gait abnormalities, at the ages of 70, 60, 68, and 70 years. The phenotype was consistent with axonal CMT with prominent sensory involvement. Five asymptomatic family members with the mutation were younger than 57 years. The authors noted that patients with very late onset may appear to have an acquired neuropathy.
In a patient with late-onset axonal Charcot-Marie-Tooth disease (CMT2I; 607677), Auer-Grumbach et al. (2003) identified a 186C-G transversion in the MPZ gene, resulting in an ile62-to-met (I62M) substitution. The patient first noted weakness and reduced sensation in the toes at age 65 years. The disorder was progressive within the next few years, leading to marked disability. The authors noted that patients with late onset may appear to have an acquired neuropathy.
In 3 affected members spanning 3 generations of a Czech family with Charcot-Marie-Tooth disease type 2J (CMT2J; 607736), Seeman et al. (2004) identified a heterozygous 290A-T transversion in exon 3 of the MPZ gene, resulting in a glu97-to-val (E97V) substitution. The mutation was not identified in 100 control chromosomes. Seeman et al. (2004) noted that sensorineural hearing loss and slowed pupillary reactions occurred at least 10 years before the onset of distal muscle weakness.
In a Polish patient with congenital hypomyelinating neuropathy-2 (CHN2; 618184), Kochanski et al. (2004) identified a de novo heterozygous 704C-A transversion in exon 3 of the MPZ gene, resulting in a thr124-to-lys (T124K) substitution. The patient had a severe disease course, becoming wheelchair-bound by age 12 years. The authors noted that another mutation at the same codon, T124M (159440.0016), had been identified in patients with axonal forms of CMT.
In affected members of a family with Charcot-Marie-Tooth disease 1B (CMT1B; 118200), Sabet et al. (2006) identified a heterozygous T-to-G transversion at the +2 position of intron 4 of the MPZ gene. The mutation was predicted to alter the conserved splice site and result in the skipping of exon 4. The phenotype was a late-onset, relatively mild, and slowly progressive lower limb neuropathy. RT-PCR analysis of skin biopsies from the proband showed that the mutant protein lacked the transmembrane domain encoded by exon 4. Quantitative immunoelectron microscopy demonstrated normal levels of MPZ within the myelin, indicating that the mutant protein had been transported to compact myelin. Sabet et al. (2006) postulated a dominant-negative or gain-of-function effect.
In multiple affected members of a Chinese family with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Lee et al. (2008) identified a heterozygous 367G-A transition in the MPZ gene, resulting in a gly123-to-ser (G123S) substitution in the extracellular domain of the protein. In vitro functional expression studies found that most of the mutant protein was localized in the cytosol and associated with the endoplasmic reticulum or Golgi apparatus, with very little protein on the plasma membrane. Cultured cells carrying the mutation showed decreased adhesiveness compared to cells with wildtype MPZ, and sural nerve biopsy revealed severe loss of myelinated fibers. Lee et al. (2008) hypothesized that the mutation resulted in defective adhesion, which could compromise myelin compaction and result in peripheral demyelination.
In affected members of a family with late-onset axonal CMT and progressive hearing loss (CMT2J; 607736), Kabzinska et al. (2007) identified a heterozygous 647C-A transversion in exon 3 of the MPZ gene, resulting in a pro105-to-thr (P105T) substitution in a conserved residue in the extracellular domain. Although none of the patients presented with hearing loss, all had some evidence of hearing loss on audiometric studies. The mutation was not identified in 100 control chromosomes.
In 4 affected members of a family with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Crehalet et al. (2010) identified a heterozygous 306G-A transition in exon 3 of the MPZ gene, resulting in a synonymous val102-to-val (V102V) change. In silico analysis predicted that the G-to-A transition would result in increased strength of a cryptic donor splice site, and in vitro cellular studies showed that the 306A variant resulted in a truncated protein. The variant created a sequence that better matched the binding domain for U1 snRNA (RNU1A; 180680), which is required for correct splicing. The phenotype was an adult-onset neuropathy with moderately decreased NCVs, consistent with haploinsufficiency. The findings were important in demonstrating that so-called 'silent' mutations may be disease-causing.
In an Italian father and daughter with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Fabrizi et al. (2006) identified a homozygous 670G-T transversion in the MPZ gene, resulting in an asp195-to-tyr (D195Y) substitution in a conserved residue in the intracellular domain of the protein. The mutation was absent in 200 control chromosomes. The father and daughter had classic features of the disorder, including severely decreased NCVs (less than 30 m/s). In contrast, the 41-year-old sister and 75-year-old mother of the proband, who were both heterozygous for the mutation, showed no clinical features except for mildly decreased vibration sense in the distal legs in the mother. Electrophysiologic diffuse mild slowing of NCV in the mother (41 m/s) and daughter (44 m/s). Fabrizi et al. (2006) speculated that the mutation may interfere with a functional phosphorylation site and affect molecular adhesions. Since only the homozygous individuals had an overt phenotype, Fabrizi et al. (2006) concluded that the mutation showed semidominant inheritance in this family. The authors suggested that mutation in the intracellular domain of MPZ, which is a rare occurrence, results in a gene dosage effect.
In a father and daughter with congenital hypomyelinating neuropathy-2 (CHN2; 618184), Smit et al. (2008) identified a heterozygous 1-bp insertion (c.549_550insG, NM_000539) in exon 4 of the MPZ gene, resulting in a frameshift and premature termination (Leu184AlafsTer51). The mutation was not found in 900 control chromosomes. Functional studies of the variant were not performed, but it was predicted to interfere with adhesion properties of the protein.
Auer-Grumbach, M., Strasser-Fuchs, S., Robl, T., Windpassinger, C., Wagner, K. Late onset Charcot-Marie-Tooth 2 syndrome caused by two novel mutations in the MPZ gene. Neurology 61: 1435-1437, 2003. Note: Erratum: Neurology 62: 678 only, 2004. [PubMed: 14638973] [Full Text: https://doi.org/10.1212/01.wnl.0000094197.46109.75]
Baloh, R. H., Jen, J. C., Kim, G., Baloh, R. W. Chronic cough due to thr124met mutation in the peripheral myelin protein zero (MPZ gene). Neurology 62: 1905-1906, 2004. [PubMed: 15159512] [Full Text: https://doi.org/10.1212/01.wnl.0000125287.98456.23]
Blanquet-Grossard, F., Pham-Dinh, D., Dautigny, A., Latour, P., Bonnebouche, C., Corbillon, E., Chazot, G., Vandenberghe, A. Charcot-Marie-Tooth type 1B neuropathy: third mutation of serine 63 codon in the major peripheral myelin glycoprotein P0 gene. Clin. Genet. 48: 281-283, 1995. [PubMed: 8835320] [Full Text: https://doi.org/10.1111/j.1399-0004.1995.tb04109.x]
Boerkoel, C. F., Takashima, H., Garcia, C. A., Olney, R. K., Johnson, J., Berry, K., Russo, P., Kennedy, S., Teebi, A. S., Scavina, M., Williams, L. L., Mancias, P., Butler, I. J., Krajewski, K., Shy, M., Lupski, J. R. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann. Neurol. 51: 190-201, 2002. [PubMed: 11835375] [Full Text: https://doi.org/10.1002/ana.10089]
Carter, M. S., Li, S., Wilkinson, M. F. A splicing-dependent regulatory mechanism that detects translation signals. EMBO J. 15: 5965-5975, 1996. [PubMed: 8918474]
Chapon, F., Latour, P., Diraison, P., Schaeffer, S., Vandenberghe, A. Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene. J. Neurol. Neurosurg. Psychiat. 66: 779-782, 1999. [PubMed: 10329755] [Full Text: https://doi.org/10.1136/jnnp.66.6.779]
Crehalet, H., Latour, P., Bonnet, V., Attarian, S., Labauge, P., Bonello, N., Bernard, R., Millat, G., Rousson, R., Bozon, D. U1 snRNA mis-binding: a new cause of CMT1B. Neurogenetics 11: 13-19, 2010. [PubMed: 19475438] [Full Text: https://doi.org/10.1007/s10048-009-0199-8]
De Jonghe, P., Timmerman, V., Ceuterick, C., Nelis, E., De Vriendt, E., Lofgren, A., Vercruyssen, A., Verellen, C., Van Maldergem, L., Martin, J.-J., Van Broeckhoven, C. The thr124-to-met mutation in peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot-Marie-Tooth phenotype. Brain 122: 281-290, 1999. [PubMed: 10071056] [Full Text: https://doi.org/10.1093/brain/122.2.281]
Fabrizi, G. M., Ferrarini, M., Cavallaro, T., Jarre, L., Polo, A., Rizzuto, N. A somatic and germline mosaic mutation in MPZ/P0 mimics recessive inheritance of CMT1B. Neurology 57: 101-105, 2001. [PubMed: 11445635] [Full Text: https://doi.org/10.1212/wnl.57.1.101]
Fabrizi, G. M., Pellegrini, M., Angiari, C., Cavallaro, T., Morini, A., Taioli, F., Cabrini, I., Orrico, D., Rizzuto, N. Gene dosage sensitivity of a novel mutation in the intracellular domain of P0 associated with Charcot-Marie-Tooth disease type 1B. Neuromusc. Disord. 16: 183-187, 2006. [PubMed: 16488608] [Full Text: https://doi.org/10.1016/j.nmd.2006.01.006]
Fabrizi, G. M., Taioli, F., Cavallaro, T., Rigatelli, F., Simonati, A., Mariani, G., Perrone, P., Rizzuto, N. Focally folded myelin in Charcot-Marie-Tooth neuropathy type 1B with ser49leu in the myelin protein zero. Acta Neuropath. 100: 299-304, 2000. [PubMed: 10965800] [Full Text: https://doi.org/10.1007/s004019900175]
Harati, Y., Butler, I. J. Congenital hypomyelinating neuropathy. J. Neurol. Neurosurg. Psychiat. 48: 1269-1276, 1985. [PubMed: 4087003] [Full Text: https://doi.org/10.1136/jnnp.48.12.1269]
Hayasaka, K., Himoro, M., Sato, W., Takada, G., Uyemura, K., Shimizu, N., Bird, T. D., Conneally, P. M., Chance, P. F. Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P(0) gene. Nature Genet. 5: 31-34, 1993. [PubMed: 7693129] [Full Text: https://doi.org/10.1038/ng0993-31]
Hayasaka, K., Himoro, M., Sawaishi, Y., Nanao, K., Takahashi, T., Takada, G., Nicholson, G. A., Ouvrier, R. A., Tachi, N. De novo mutation of the myelin P(0) gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III). Nature Genet. 5: 266-268, 1993. [PubMed: 7506095] [Full Text: https://doi.org/10.1038/ng1193-266]
Hayasaka, K., Himoro, M., Wang, Y., Takata, M., Minoshima, S., Shimizu, N., Miura, M., Uyemura, K., Takada, G. Structure and chromosomal localization of the gene encoding the human myelin protein zero (MPZ). Genomics 17: 755-758, 1993. [PubMed: 7503936] [Full Text: https://doi.org/10.1006/geno.1993.1400]
Hayasaka, K., Nanao, K., Tahara, M., Sato, W., Takada, G., Miura, M., Uyemura, K. Isolation and sequence determination of cDNA encoding the major structural protein of human peripheral myelin. Biochem. Biophys. Res. Commun. 180: 515-518, 1991. [PubMed: 1719967] [Full Text: https://doi.org/10.1016/s0006-291x(05)81094-0]
Hayasaka, K., Ohnishi, A., Takada, G., Fukushima, Y., Murai, Y. Mutation of the myeline (sic) P0 gene in the Charcot-Marie-Tooth neuropathy type 1. Biochem. Biophys. Res. Commun. 194: 1317-1322, 1993. [PubMed: 7688964] [Full Text: https://doi.org/10.1006/bbrc.1993.1968]
Ikegami, T., Nicholson, G., Ikeda, H., Ishida, A., Johnston, H., Wise, G., Ouvrier, R., Hayasaka, K. A novel homozygous mutation of the myelin P(0) gene producing Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III). Biochem. Biophys. Res. Commun. 222: 107-110, 1996. [PubMed: 8630052] [Full Text: https://doi.org/10.1006/bbrc.1996.0705]
Inoue, K., Khajavi, M., Ohyama, T., Hirabayashi, S., Wilson, J., Reggin, J. D., Mancias, P., Butler, I. J., Wilkinson, M. F., Wegner, M., Lupski, J. R. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nature Genet. 36: 361-369, 2004. [PubMed: 15004559] [Full Text: https://doi.org/10.1038/ng1322]
Kabzinska, D., Korwin-Piotrowska, T., Dreschler, H., Drac, H., Hausmanowa-Petrusewicz, I., Kochanski, A. Late-onset Charcot-Marie-Tooth type 2 disease with hearing impairment associated with a novel Pro105Thr mutation in the MPZ gene. (Letter) Am. J. Med. Genet. 143A: 2196-2199, 2007. [PubMed: 17663472] [Full Text: https://doi.org/10.1002/ajmg.a.31908]
Kaku, D. A., Parry, G. J., Malamut, R., Lupski, J. R., Garcia, C. A. Nerve conduction studies in Charcot-Marie-Tooth polyneuropathy associated with a segmental duplication of chromosome 17. Neurology 43: 1806-1808, 1993. [PubMed: 8414036] [Full Text: https://doi.org/10.1212/wnl.43.9.1806]
Kamholz, J., Shy, M. E. Late onset Charcot-Marie-Tooth 2 syndrome caused by two novel mutations in the MPZ gene. Neurology 63: 194 only, 2004. [PubMed: 15249646] [Full Text: https://doi.org/10.1212/wnl.63.1.194]
Khajavi, M., Inoue, K., Wisniewski, W., Ohyama, T., Snipes, G. J., Lupski, J. R. Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants. Am. J. Hum. Genet. 77: 841-850, 2005. [PubMed: 16252242] [Full Text: https://doi.org/10.1086/497541]
Killian, J. M., Kloepfer, H. W. Homozygous expression of a dominant gene for Charcot-Marie-Tooth neuropathy. Ann. Neurol. 5: 515-522, 1979. [PubMed: 475348] [Full Text: https://doi.org/10.1002/ana.410050604]
Kochanski, A., Drac, H., Kabzinska, D., Ryniewicz, B., Rowinska-Marcinska, K., Nowakowski, A., Hausmanowa-Petrusewicz, I. A novel MPZ gene mutation in congenital neuropathy with hypomyelination. Neurology 62: 2122-2123, 2004. [PubMed: 15184631] [Full Text: https://doi.org/10.1212/01.wnl.0000127606.93772.3a]
Kulkens, T., Bolhuis, P. A., Wolterman, R. A., Kemp, S., te Nijenhuis, S., Valentijn, L. J., Hensels, G. W., Jennekens, F. G. I., de Visser, M., Hoogendijk, J. E., Baas, F. Deletion of the serine 34 codon from the major peripheral myelin protein P(0) gene in Charcot-Marie-Tooth disease type 1B. Nature Genet. 5: 35-39, 1993. [PubMed: 7693130] [Full Text: https://doi.org/10.1038/ng0993-35]
Leal, A., Berghoff, C., Berghoff, M., Del Valle, G., Contreras, C., Montoya, O., Hernandez, E., Barrantes, R., Schlotzer-Schrehardt, U., Neundorfer, B., Reis, A., Rautenstrauss, B., Heuss, D. Charcot-Marie-Tooth disease: a novel tyr145ser mutation in the myelin protein zero (MPZ, PO) gene causes different phenotypes in homozygous and heterozygous carriers within one family. Neurogenetics 4: 191-197, 2003. [PubMed: 12845552] [Full Text: https://doi.org/10.1007/s10048-003-0153-0]
Lee, Y. C., Yu, C. T. R., Lin, K. P., Chang, M. H., Hsu, S. L., Liu, Y. F., Lu, Y. C., Soong, B. W. MPZ mutation G123S characterization: evidence for a complex pathogenesis in CMT disease. Neurology 70: 273-277, 2008. [PubMed: 18209201] [Full Text: https://doi.org/10.1212/01.wnl.0000296828.66915.bf]
Lemke, G., Axel, R. Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell 40: 501-508, 1985. [PubMed: 2578885] [Full Text: https://doi.org/10.1016/0092-8674(85)90198-9]
Lemke, G. Molecular biology of the major myelin genes. Trends Neurosci. 9: 266-270, 1986.
Lupski, J. R., Montes de Oca-Luna, R., Slaugenhaupt, S., Pentao, L., Guzzetta, V., Trask, B. J., Saucedo-Cardenas, O., Barker, D. F., Killian, J. M., Garcia, C. A., Chakravarti, A., Patel, P. I. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66: 219-232, 1991. [PubMed: 1677316] [Full Text: https://doi.org/10.1016/0092-8674(91)90613-4]
Maeda, M. H., Mitsui, J., Soong, B.-W., Takahashi, Y., Ishiura, H., Hayashi, S., Shirota, Y., Ichikawa, Y., Matsumoto, H., Arai, M., Okamoto, T., Miyama, S., Shimizu, J., Inazawa, J., Goto, J., Tsuji, S. Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease. Ann. Neurol. 71: 84-92, 2012. [PubMed: 22275255] [Full Text: https://doi.org/10.1002/ana.22658]
Mandich, P., Fossa, P., Capponi, S., Geroldi, A., Acquaviva, M., Gulli, R., Ciotti, P., Manganelli, F., Grandis, M., Bellone, E. Clinical features and molecular modelling of novel MPZ mutations in demyelinating and axonal neuropathies. Europ. J. Hum. Genet. 17: 1129-1134, 2009. [PubMed: 19293842] [Full Text: https://doi.org/10.1038/ejhg.2009.37]
Mandich, P., Mancardi, G. L., Varese, A., Soriani, S., Di Maria, E., Bellone, E., Bado, M., Gross, L., Windebank, A. J., Ajmar, F., Schenone, A. Congenital hypomyelination due to myelin protein zero Q215X mutation. Ann. Neurol. 45: 676-678, 1999. [PubMed: 10319895] [Full Text: https://doi.org/10.1002/1531-8249(199905)45:5<676::aid-ana21>3.0.co;2-k]
Marrosu, M. G., Vaccargiu, S., Marrosu, G., Vannelli, A., Cianchetti, C., Muntoni, F. Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Neurology 50: 1397-1401, 1998. [PubMed: 9595994] [Full Text: https://doi.org/10.1212/wnl.50.5.1397]
Martini, R., Zielasek, J., Toyka, K. V., Giese, K. P., Schachner, M. Protein zero (P0)-deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies. Nature Genet. 11: 281-286, 1995. [PubMed: 7581451] [Full Text: https://doi.org/10.1038/ng1195-281]
Mastaglia, F. L., Nowak, K. J., Stell, R., Phillips, B. A., Edmondston, J. E., Dorosz, S. M., Wilton, S. D., Hallmayer, J., Kakulas, B. A., Laing, N. G. Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy. J. Neurol. Neurosurg. Psychiat. 67: 174-179, 1999. [PubMed: 10406984] [Full Text: https://doi.org/10.1136/jnnp.67.2.174]
Misu, K., Yoshihara, T., Shikama, Y., Awaki, E., Yamamoto, M., Hattori, N., Hirayama, M., Takegami, T., Nakashima, K., Sobue, G. An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (thr124met or asp75val). J. Neurol. Neurosurg. Psychiat. 69: 806-811, 2000. [PubMed: 11080237] [Full Text: https://doi.org/10.1136/jnnp.69.6.806]
Nagy, E., Maquat, L. E. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem. Sci. 23: 198-199, 1998. [PubMed: 9644970] [Full Text: https://doi.org/10.1016/s0968-0004(98)01208-0]
Nakagawa, M., Suehara, M., Saito, A., Takashima, H., Umehara, F., Saito, M., Kanzato, N., Matsuzaki, T., Takenaga, S., Sakoda, S., Izumo, S., Osame, M. A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheaths. Neurology 52: 1271-1275, 1999. [PubMed: 10214757] [Full Text: https://doi.org/10.1212/wnl.52.6.1271]
Nelis, E., Haites, N., Van Broeckhoven, C. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies. Hum. Mutat. 13: 11-28, 1999. [PubMed: 9888385] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:1<11::AID-HUMU2>3.0.CO;2-A]
Oakey, R. J., Watson, M. L., Seldin, M. F. Construction of a physical map on mouse and human chromosome 1: comparison of 13 Mb of mouse and 11 Mb of human DNA. Hum. Molec. Genet. 1: 613-620, 1992. [PubMed: 1301170] [Full Text: https://doi.org/10.1093/hmg/1.8.613]
Ouvrier, R. A., McLeod, J. G., Conchin, T. E. The hypertrophic forms of hereditary motor and sensory neuropathy: a study of hypertrophic Charcot-Marie-Tooth disease (HMSN type I) and Dejerine-Sottas disease (HMSN type III) in childhood. Brain 110: 121-148, 1987. [PubMed: 3467805] [Full Text: https://doi.org/10.1093/brain/110.1.121]
Pham-Dinh, D., Fourbil, Y., Blanquet, F., Mattei, M.-G., Roeckel, N., Latour, P., Chazot, G., Vandenberghe, A., Dautigny, A. The major peripheral myelin protein zero gene: structure and localization in the cluster of Fc-gamma receptor genes on human chromosome 1q21.3-q23. Hum. Molec. Genet. 2: 2051-2054, 1993. [PubMed: 7509228] [Full Text: https://doi.org/10.1093/hmg/2.12.2051]
Plante-Bordeneuve, V., Guiochon-Mantel, A., Lacroix, C., Lapresle, J., Said, G. The Roussy-Levy family: from the original description to the gene. Ann. Neurol. 46: 770-773, 1999. [PubMed: 10553995] [Full Text: https://doi.org/10.1002/1531-8249(199911)46:5<770::aid-ana13>3.0.co;2-u]
Roa, B. B., Warner, L. E., Garcia, C. A., Russo, D., Lovelace, R., Chance, P. F., Lupski, J. R. Myelin protein zero (MPZ) gene mutations in nonduplication type 1 Charcot-Marie-Tooth disease. Hum. Mutat. 7: 36-45, 1996. [PubMed: 8664899] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)7:1<36::AID-HUMU5>3.0.CO;2-N]
Rouger, H., LeGuern, E., Gouider, R., Tardieu, S., Birouk, N., Gugenheim, M., Bouche, P., Agid, Y., Brice, A. High frequency of mutations in codon 98 of the peripheral myelin protein Po gene in 20 French CMT1 patients. (Letter) Am. J. Hum. Genet. 58: 638-641, 1996. [PubMed: 8644725]
Roussy, G., Levy, G. Sept cas d'une maladie familiale particulaiere. Rev. Neurol. 45: 427-450, 1926.
Sabet, A., Li, J., Ghandour, K., Pu, Q., Wu, X., Kamholz, J., Shy, M. E., Cambi, F. Skin biopsies demonstrate MPZ splicing abnormalities in Charcot-Marie-Tooth neuropathy 1B. Neurology 67: 1141-1146, 2006. [PubMed: 17030746] [Full Text: https://doi.org/10.1212/01.wnl.0000238499.37764.b1]
Schiavon, F., Rampazzo, A., Merlini, L., Angelini, C., Mostacciuolo, M. L. Mutations of the same sequence of the myelin P0 gene causing two different phenotypes. Hum. Mutat. Suppl. 1: S217-S219, 1998. [PubMed: 9452091] [Full Text: https://doi.org/10.1002/humu.1380110170]
Seeman, P., Mazanec, R., Huehne, K., Suslikova, P., Keller, O., Rautenstrauss, B. Hearing loss as the first feature of late-onset axonal CMT disease due to a novel P0 mutation. Neurology 63: 733-735, 2004. [PubMed: 15326256] [Full Text: https://doi.org/10.1212/01.wnl.0000134605.61307.de]
Senderek, J., Hermanns, B., Lehmann, U., Bergmann, C., Marx, G., Kabus, C., Timmerman, V., Stoltenburg-Didinger, G., Schroder, J. M. Charcot-Marie-Tooth neuropathy type 2 and PO point mutations: two novel amino acid substitutions (Asp61Gly; Tyr119Cys) and a possible 'hotspot' on Thr124Met. Brain Path. 10: 235-248, 2000. [PubMed: 10764043] [Full Text: https://doi.org/10.1111/j.1750-3639.2000.tb00257.x]
Skre, H. Genetic and clinical aspects of Charcot-Marie-Tooth disease. Clin. Genet. 6: 98-118, 1974. [PubMed: 4430158] [Full Text: https://doi.org/10.1111/j.1399-0004.1974.tb00638.x]
Smit, L. S., Roofthooft, D., van Ruissen, F., Baas, F., van Doorn, P. A. Congenital hypomyelinating neuropathy, a long term follow-up study in an affected family. Neuromusc. Disord. 18: 59-62, 2008. [PubMed: 17825553] [Full Text: https://doi.org/10.1016/j.nmd.2007.07.011]
Sorour, E., MacMillan, J., Upadhyaya, M. Novel mutation of the myelin P0 gene in a CMT1B family. Hum. Mutat. 9: 74-77, 1997. [PubMed: 8990016] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)9:1<74::AID-HUMU16>3.0.CO;2-M]
Su, Y., Brooks, D. G., Li, L., Lepercq, J., Trofatter, J. A., Ravetch, J. V., Lebo, R. V. Myelin protein zero gene mutated in Charcot-Marie-Tooth type 1B patients. Proc. Nat. Acad. Sci. 90: 10856-10860, 1993. [PubMed: 7504284] [Full Text: https://doi.org/10.1073/pnas.90.22.10856]
Sutcliffe, J. G. The genes for myelin. Trends Genet. 3: 73-76, 1987.
Szigeti, K., Saifi, G. M., Armstrong, D., Belmont, J. W., Miller, G., Lupski, J. R. Disturbance of muscle fiber differentiation in congenital hypomyelinating neuropathy caused by a novel myelin protein zero mutation. Ann. Neurol. 54: 398-402, 2003. [PubMed: 12953275] [Full Text: https://doi.org/10.1002/ana.10681]
Tachi, N., Ishikawa, Y., Minami, R. Two cases of congenital hypomyelination neuropathy. Brain Dev. 6: 560-565, 1984. [PubMed: 6099985] [Full Text: https://doi.org/10.1016/s0387-7604(84)80101-1]
Thomas, F. P., Lebo, R. V., Rosoklija, G., Ding, X.-S., Lovelace, R. E., Latov, N., Hays, A. P. Tomaculous neuropathy in chromosome 1 Charcot-Marie-Tooth syndrome. Acta Neuropath. 87: 91-97, 1994. [PubMed: 7511317] [Full Text: https://doi.org/10.1007/BF00386259]
Triggs, W. J., Brown, R. H., Jr., Menkes, D. L. Case 18-2006: a 57-year-old woman with numbness and weakness of the feet and legs. New Eng. J. Med. 354: 2584-2592, 2006. [PubMed: 16775239] [Full Text: https://doi.org/10.1056/NEJMcpc069009]
Umehara, F., Takenaga, S., Nakagawa, M., Takahashi, K., Izumo, S., Matsumuro, K., Sakota, S., Nishimura, T., Yoshikawa, H., Osame, M. Dominantly inherited motor and sensory neuropathy with excessive myelin folding complex. Acta Neuropath. 86: 602-608, 1993. [PubMed: 8310815] [Full Text: https://doi.org/10.1007/BF00294299]
Warner, L. E., Hilz, M. J., Appel, S. H., Killian, J. M., Kolodny, E. H., Karpati, G., Carpenter, S., Watters, G. V., Wheeler, C., Witt, D., Bodell, A., Nelis, E., Van Broeckhoven, C., Lupski, J. R. Clinical phenotypes of different MPZ(P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron 17: 451-460, 1996. [PubMed: 8816708] [Full Text: https://doi.org/10.1016/s0896-6273(00)80177-4]
Warner, L. E., Shohat, M., Shorer, Z., Lupski, J. R. Multiple de novo MPZ (P0) point mutations in a sporadic Dejerine-Sottas case. Hum. Mutat. 10: 21-24, 1997. [PubMed: 9222756] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)10:1<21::AID-HUMU3>3.0.CO;2-P]
Watanabe, M., Yamamoto, N., Ohkoshi, N., Nagata, H., Kohno, Y., Hayashi, A., Tamaoka, A., Shoji, S. Corticosteroid-responsive asymmetric neuropathy with a myelin protein zero gene mutation. Neurology 59: 767-769, 2002. [PubMed: 12221176] [Full Text: https://doi.org/10.1212/wnl.59.5.767]
Wrabetz, L., Feltri, M. L., Quattrini, A., Imperiale, D., Previtali, S., D'Antonio, M., Martini, R., Yin, X., Trapp, B. D., Zhou, L., Chiu, S.-Y., Messing, A. P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves. J. Cell Biol. 148: 1021-1033, 2000. [PubMed: 10704451] [Full Text: https://doi.org/10.1083/jcb.148.5.1021]
You, K.-H., Hsieh, C.-L., Hayes, C., Stahl, N., Francke, U., Popko, B. DNA sequence, genomic organization, and chromosomal localization of the mouse peripheral myelin protein zero gene: identification of polymorphic alleles. Genomics 9: 751-757, 1991. [PubMed: 1709914] [Full Text: https://doi.org/10.1016/0888-7543(91)90370-t]