Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain.

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.

SUBMITTER: Ramirez JD

PROVIDER: S-EPMC3399778 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Myelin protein zero gene mutated in Charcot-Marie-tooth type 1B patients.

Project description:Autosomal dominant of Charcot-Marie-Tooth disease (CMT), whose gene is type 1B (CMT1B), has slow nerve conduction with demyelinated Schwann cells. In this study the abundant peripheral myelin protein zero (MPZ) gene, MPZ, was mapped 130 kb centromeric to the Fc receptor immunoglobulin gene cluster in band 1q22, and a major MPZ point mutation was found to cosegregate with CMT1B in one large CMT1B family. 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. The same MPZ locus cosegregates with the CMT1B disease gene in a second CMT1B family [total multipoint logarithm of odds (lod) = 11.4 at theta = 0.00] with a splice junction mutation. Both mutations occur in MPZ protein regions otherwise conserved identically in human, rat, and cow since these species diverged 100 million years ago. MPZ protein, expressed exclusively in myelinated peripheral nerve Schwann cells, constitutes > 50% of myelin protein. These mutations are anticipated to disrupt homophilic MPZ binding and result in CMT1B peripheral nerve demyelination.

| S-EPMC47877 | biostudies-other

Intermediate Charcot-Marie-Tooth disease.

Project description:Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria: very slow motor nerve conduction velocity (MNCV) (<15 m/s), slow MNCV (15-25 m/s), intermediate MNCV (25-45 m/s), and normal MNCV (>45 m/s). Based on the inheritance pattern, intermediate CMT can be divided into dominant (DI-CMT) and recessive types (RI-CMT). GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.

| S-EPMC5562560 | biostudies-other

Upregulation of large myelin protein zero leads to Charcot-Marie-Tooth disease-like neuropathy in mice.

Project description:Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy mainly caused by gene mutation of peripheral myelin proteins including myelin protein zero (P0, MPZ). Large myelin protein zero (L-MPZ) is an isoform of P0 that contains an extended polypeptide synthesized by translational readthrough at the C-terminus in tetrapods, including humans. The physiological role of L-MPZ and consequences of an altered L-MPZ/P0 ratio in peripheral myelin are not known. To clarify this, we used genome editing to generate a mouse line (L-MPZ mice) that produced L-MPZ instead of P0. Motor tests and electrophysiological, immunohistological, and electron microscopy analyses show that homozygous L-MPZ mice exhibit CMT-like phenotypes including thin and/or loose myelin, increased small-caliber axons, and disorganized axo-glial interactions. Heterozygous mice show a milder phenotype. These results highlight the importance of an appropriate L-MPZ/P0 ratio and show that aberrant readthrough of a myelin protein causes neuropathy.

| S-EPMC7070019 | biostudies-literature

Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan.

Project description:We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.

| S-EPMC7898366 | biostudies-literature

Genetic and clinical spectrums in Korean Charcot-Marie-Tooth disease patients with myelin protein zero mutations.

Project description:BackgroundCharcot-Marie-Tooth disease (CMT) is the most common disorder of inherited peripheral neuropathies characterized by distal muscle weakness and sensory loss. CMT is usually classified into three types, demyelinating, axonal, and intermediate neuropathies. Mutations in myelin protein zero (MPZ) gene which encodes a transmembrane protein of the Schwann cells as a major component of peripheral myelin have been reported to cause various type of CMT.MethodsThis study screened MPZ mutations in Korean CMT patients (1,121 families) by whole exome sequencing and targeted sequencing.ResultsWe identified 22 pathogenic or likely pathogenic MPZ mutations in 36 families as the underlying cause of the CMT1B, CMTDID, or CMT2I subtypes. Among them, five mutations were novel. The frequency of CMT patients with the MPZ mutations was similar or slightly lower compared to other ethnic groups.ConclusionsWe showed that the median onset ages and clinical phenotypes varied by subtypes: the most severe in the CMT1B group, and the mildest in the CMT2I group. This study also observed a clear correlation that earlier onsets cause more severe symptoms. We believe that this study will provide useful reference data for genetic and clinical information on CMT patients with MPZ mutations in Korea.

| S-EPMC8222852 | biostudies-literature

Two novel missense mutations in the myelin protein zero gene causes Charcot-Marie-Tooth type 2 and Dejerine-Sottas syndrome.

Project description:BACKGROUND: The Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P0) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. The crystalline structure of the extracellular domain of the myelin protein zero (P0ex) is known, while the transmembrane and intracellular structure is unknown. FINDINGS: One novel missense mutation caused a milder late onset CMT type 2, while the second missense mutation caused a severe early onset phenotype compatible with Déjérine-Sottas syndrome. CONCLUSIONS: The phenotypic variation caused by different missense mutations in the MPZ gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and Déjérine-Sottas syndrome, while milder changes cause the phenotypes CMT type 1 and 2.

| S-EPMC2861067 | biostudies-literature

Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2.

Project description:The hereditary disorders of peripheral nerve form one of the most common groups of human genetic diseases, collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis we have identified a new locus for a form of CMT that we have called "dominant intermediate CMT" (DI-CMT). A genomewide screen using 383 microsatellite markers showed strong linkage to the short arm of chromosome 19 (maximum LOD score 4.3, with a recombination fraction (straight theta) of 0, at D19S221 and maximum LOD score 5.28, straight theta=0, at D19S226). Haplotype analysis performed with 14 additional markers placed the DI-CMT locus within a 16.8-cM region flanked by the markers D19S586 and D19S546. Multipoint linkage analysis suggested the most likely location at D19S226 (maximum multipoint LOD score 6.77), within a 10-cM confidence interval. This study establishes the presence of a locus for DI-CMT on chromosome 19p12-p13.2.

| S-EPMC1226074 | biostudies-literature

Charcot-Marie-Tooth disease.

Project description:Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity. Population based studies have determined the contributions of the various genes to disease burden enabling evidence-based approaches to genetic testing.

| S-EPMC2947101 | biostudies-literature

Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome 1p34-p35.

Project description:Dominant intermediate Charcot-Marie-Tooth (DI-CMT) neuropathy is a genetic and phenotypic variant of classical CMT, characterized by intermediate nerve conduction velocities and histological evidence of both axonal and demyelinating features. We report two unrelated families with intermediate CMT linked to a novel locus on chromosome 1p34-p35 (DI-CMTC). The combined haplotype analysis in both families localized the DI-CMTC gene within a 6.3-cM linkage interval flanked by markers D1S2787 and D1S2830. The functional and positional candidate genes, Syndecan 3 (SDC3), and lysosomal-associated multispanning membrane protein 5 (LAPTM5) were excluded for pathogenic mutations.

| S-EPMC1180404 | biostudies-literature

Membranous Nephropathy in a Patient with Charcot-Marie-Tooth Disease: Association of Myelin Mutations.

Project description:A 40-year-old female presented to the neurologist with gradually progressive weakness of distal and proximal muscles of both lower limbs and cramps for 2 years. She gave a history of similar illness in her paternal grandmother and her father. Her examination revealed bilateral foot drop and mild proximal muscle weakness. She was diagnosed to have peripheral neuropathy and subsequently treated conservatively. Over the next year, she noticed progressive swelling of both lower limb and frothy urine. A nephrology consultation was obtained, and a renal biopsy was done, which showed membranous nephropathy. She was started on steroids and subsequently on tacrolimus as the proteinuria progressively worsened. Her anti-phospholipase A2 receptor antibody was negative both in blood and in the kidney biopsy tissue. A search for a genetic basis of this rare clinical condition was made, and heterozygous mutation was detected in the myelin gene. This mutation was confirmed with genetic sequencing. The mutation is associated with MPZ gene and is associated with multiple hereditary sensorimotor neuropathy. MPZ knockout mice have been shown to have increased glomerular permeability and proteinuria.

| S-EPMC6146723 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data