Myelin Protein Zero Gene Mutations Research Articles

Genetic variants, structural, and functional changes of Myelin Protein Zero and Mannose-Binding Lectin 2 protein involved in immune response and its allelic transmission in families of patients with leprosy in Colombia

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Genetic factors associated with immune response contribute to infection development and disease. M. leprae has the capacity to invade Schwann cells in the peripheral nervous system and cause neuropathy. However, while the responsible molecular mechanisms remain to be fully unveiled, they have begun being elucidated. We studied genetic variants Myelin Protein Zero (MPZ), a major structural component of the myelin sheath, and Mannose Binding Lectin 2 (MBL2), a protein involved in immune response, in 112 family groups of 114 leprosy patients using PCR-RFLP, aiming to calculate the association and allelic transmission of variants associated in first, second and third-degree relatives. Polymorphisms found in MPZ and MBL2 showed association with leprosy. Different probabilities for allelic transmission were found for first and second-degree relatives, a fact that is important to take into account when evaluating risk in contacts of leprosy patients. Structural analysis allows the study of putative amino acids and their possible effect on protein structure and function, as well as on the assembly of a protein homotetramer. Our results suggest that the identified MPZ and MBL2 gene mutations are associated with leprosy in a Colombian population, which correlates with MPZ and MBL2 protein function, and increase the risk of M. leprae infection in leprosy-patients' family members. Additionally, structural analyses were carried out specifically for MPZ protein using information available in databases, and analyzing the substitutions in wildtype and mutant protein. The results show significant structural changes, which may be associated to infection and pathogenicity.

Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene.

We aimed to characterize genotype-phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot-Marie-Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and the Charcot-Marie-Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot-Marie-Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3-84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot-Marie-Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for ambulation. Our results demonstrate that virtually all MPZ mutations are associated with specific phenotypes. Early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotype reflects axonal degeneration without antecedent demyelination. Data from this cohort of patients will provide the baseline data necessary for clinical trials of patients with Charcot-Marie-Tooth disease caused by MPZ gene mutations.

Dysmyelinating and demyelinating Charcot–Marie–Tooth disease associated with two myelin protein zero gene mutations

Mutations in the myelin protein zero (MPZ) gene are the third most frequent cause of hereditary motor and sensory neuropathies (HMSN), also called Charcot-Marie-Tooth disorders (CMT). Only in case of recurrent mutations occurring in the MPZ gene is it possible to draw phenotype-genotype correlations essential for establishing the prognosis and outcomes of CMT1. We have surveyed a cohort of 67 Polish patients from CMT families with demyelinating neuropathy for mutations in the MPZ gene. In this study, we report two CMT families in which the Ile135Thr and Pro132Leu mutations have been identified for the MPZ gene. These MPZ gene mutations had not been identified hitherto in the Polish population. The Pro132Leu mutation segregates with a severe early-onset dysmyelinating-hypomyelinating neuropathy, whereas the Ile135Thr substitution is associated with the classical phenotype of CMT1. To the best of our knowledge, we present here, for the first time, morphological data obtained in two sural nerve biopsies pointing to a hypomyelination-dysmyelination process in a family harboring the Pro132Leu mutation in the MPZ gene.

Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations

Duplication within the chromosome 17p11.2 (CMT1Adup), peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and gap junction beta1-protein (GJB1) gene mutations are frequent causes of the Charcot-Marie-Tooth disease (CMT). A large number of mutations in these genes are listed in databases. Sequence variants identified in patients are frequently reported as mutations without further evaluation. We analyzed 250 consecutively recruited unrelated Austrian CMT patients for CMT1Adup by microsatellite marker typing, real-time PCR or MLPA, and found 79 duplications (31.6%). The coding regions of the PMP22, MPZ and GJB1 genes were analyzed by direct sequencing in the remaining patients; 28 patients showed mutations, 14 of which were novel. We scored the pathogenicity of novel missense mutations by segregation studies and by their exclusion in control samples. Our comprehensive literature study found that up to 60% of the reported mutations in these genes had not been evaluated regarding their pathogenicity, and the PANTHER bioinformatics tool was used to score novel and published missense variants. The PANTHER program scored known polymorphisms as such, but scored approximately 82-88% only of the published and novel mutations as most likely deleterious. Mutations associated with axonal CMT were less likely to be classified as deleterious, and the PMP22 S72L mutation repeatedly associated with severe CMT was classified as a polymorphism using default parameters. Our data suggest that this in silico analysis tool could be useful for assessing the functional impact of DNA variations only as a complementary approach. The CMT1Adup, GJB1, MPZ and PMP22 mutation frequencies were in the range of those described in other CMT patient collectives with different ethnical backgrounds.

Rapid progression of late onset axonal Charcot–Marie–Tooth disease associated with a novel MPZ mutation in the extracellular domain

Myelin protein zero (MPZ) is a major component of compact myelin in peripheral nerves where it plays an essential role in myelin formation and adhesion. MPZ gene mutations are usually...

Spinal Deformities in Hereditary Motor and Sensory Neuropathy

Retrospective study of 175 patients with hereditary motor and sensory neuropathy (HMSN), i.e., Charcot-Marie-Tooth (CMT) disease. To investigate the frequency, age of onset, character, familial, and genotypical incidence of spinal deformities among HMSN patients. Prior studies addressing HMSN discuss the associated spinal deformities. However, these data vary significantly while inconsistently including genotypes within the classification framework. Plain-film radiographic spine studies of 175 HMSN patients were performed to determine the incidence, character, and severity of spinal deformity. The degree of the spinal deformity was evaluated measuring Cobb's angle of the main curve. The results of the entire cohort were initially assessed before being classified by genotype. The incidence of spinal deformity for the entire group was 26%. Of these, 58% demonstrated scoliosis, 31% had kyphoscoliosis, and 11% had thoracic hyperkyphosis; 73% of patients with spinal deformity were classified as HMSN Type I with confirmed duplication of the PMP 22 (peripheral myelin protein) gene on chromosome 17. The incidence of spinal deformity by genotype was: duplication of the PMP 22 gene: 29% (25 of 87); deletion of the PMP 22 gene: 0% (0 of 15); Cx32 (connexin 32) gene mutation: 24% (8 of 34); and MPZ (myelin protein zero) gene mutation: 100% (6 of 6). Familial incidence of spinal deformity was found in "MPZ gene mutation" and "duplication of PMP 22 gene" subgroups. This study demonstrates a 26% incidence of spinal deformity among HMSN patients. Spinal deformity was most frequently observed in patients with the MPZ gene mutation, where the most common familial incidence was also found.

Novel C59T leader peptide mutation in the MPZ gene associated with late‐onset, axonal, sensorimotor polyneuropathy

The objective of this study was to report a novel exon-1 mutation in the myelin protein zero (MPZ) gene, resulting in axonal Charcot-Marie-Tooth neuropathy with recurrent hyper-CK-emia. In a 64-year-old woman slowly progressive distal lower limb weakness, muscle cramps in the lower limb muscles, and stocking-type numbness had developed from the age of 61. Neurologic examination revealed discrete hip flexor weakness, weakness for foot extension, diffuse wasting of the distal lower limb muscles, reduced patella tendon reflexes, and absent Achilles tendon reflexes. There was recurrently elevated creatine kinase with a maximum of 607 U/l (n, <145 U/l). Stimulation of the peroneal and tibial nerves did not evoke a muscular response. Electromyography was neurogenic. Biopsy of the right sural nerve showed diffuse axonal degeneration and loss of axons of all diameters. Muscle biopsy showed increased fiber-size variability, angulated fibers, internalized nuclei, accumulations of nuclei, grouped atrophic muscle fibers, and fiber splitting. Molecular genetic analysis by PCR and direct nucleotide sequencing revealed the heterozygous C59T exon-1 MPZ gene mutation, resulting in the amino acid exchange S20F of the MPZ signal protein domain (leader peptide). The novel C59T mutation in the leader peptide of the MPZ gene is pathogenic and manifests as severe, late-onset, axonal, symmetric sensorimotor polyneuropathy (CMT2) and hyper-CK-emia.

Marked phenotypic variation in a family with a new myelin protein zero mutation

Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily, which has a role in myelin compaction. MPZ gene mutations cause mostly demyelinating neuropathies of the Charcot-Marie-Tooth 1B type (CMT1B), but axonal CMT have been described as well. There is a broad spectrum of phenotypic manifestation of neuropathies caused by MPZ mutations. Some mutations of MPZ cause severe early-onset neuropathies such as Dejerine-Sottas disease, while others cause the classical CMT phenotype with normal early milestones but development of disability during the first two decades of life. We describe a family in which five members of three consecutive generations had a heterozygous mutation in nucleotide position 143 with a T–C transition in exon 2 of the MPZ gene. The resulting substitution of Leu48 with proline has not been previously described. The age of onset of symptoms varied from 8 months to 41 years. The marked variation of the age of disease onset and clinical phenotype in this one family, related to the same MPZ mutation, suggests that in addition to the type and intragenic location of the mutation, other putative modifying gene(s) are regulating MPZ gene expression, mRNA stability and posttranslational protein modification and may have an important effect on the ultimate clinical phenotype.

Early onset Charcot-Marie-Tooth type 1B disease caused by a novel Leu190fs mutation in the myelin protein zero gene

The spectrum of Charcot-Marie-Tooth (CMT) phenotypes segregating with mutations in the Myelin Protein Zero (MPZ) gene is wide and ranges from congenital hypomyelinating neuropathy (CHN) through demyelinating form of CMT to the axonal type of CMT disease. Within 94 MPZ gene mutations reported up to now, only a few were identified in the exon 4 of the MPZ gene. In this study we have identified a novel Leu190fs mutation in the MPZ gene. The Leu190fs mutation was found in a 14-year-old girl suffering from Charcot-Marie-Tooth type 1 disease (CMT1) with onset in early infancy. Similarly to the other MPZ gene frame-shift mutations reported as far the Leu190fs seems to have a dominant negative effect.

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)

OBJECTIVES AND METHODSSeven families were studied with an axonal form of Charcot-Marie-Tooth disease (CMT) associated with mutations in the peripheral myelin protein zero (MPZ) gene—Thr124Met or Asp75Val.RESULTSPatients with these mutations...