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At least 937 records · Page 52Linked to original sources
PubMed2003

Phenotypic differences between peripheral myelin protein-22 (PMP22) and myelin protein zero (P0) mutations associated with Charcot-Marie-Tooth-related diseases.

Mutations in the genes for peripheral myelin protein-22 (PMP22) and myelin protein zero (P0) cause human hereditary neuropathies with varying clinical and pathological phenotypes. In this study, we examine the effects of representative disease-causing mutations on the subcellular distribution of their corresponding PMP22- and P0-enhanced green fluorescent protein (EGFP) fusion proteins. In transiently transfected HeLa and 293 cells, we find that wild-type P0-EGFP and PMP22-EGFP are efficiently synthesized and transported through the secretory pathway to the plasma membrane. The P0-EGFP and PMP22-EGFP mutants can be classified into several groups: those that are transported to the plasma membrane as in the majority of P0 mutants; those that are retained in the endoplasmic reticulum as in the majority of PMP22 mutants; and those that are a mixture of the two. In addition, several of these disease-causing mutations are associated with the development of abnormal intracellular cytoplasmic structures that we have previously identified as either intracellular myelin figures or aggresomes. Our studies indicate that different types of PMP22 and P0 mutations are associated with specific intracellular chaperone proteins, including calnexin and BiP, and that these associations can be altered by glycosylation. These findings indicate that the various P0 and PMP22 mutants may exert their pathogenic effects in different subcellular compartments and by different mechanisms in the mammalian cell.

Cell Compartmentation↗
PubMed1983

Recombinant DNA strategies in genetic neurological diseases.

The application of recombinant DNA techniques applied to the study of genetic neurological diseases will play a major role in the practice of neurology in upcoming years. Strategies are now available to develop useful and relatively simple biochemical diagnostic tests for heterozygous individuals with diseases inherited as autosomal dominant traits. In addition, molecular genetic methods will lead to the delineation of the genomic mutations responsible for these diseases. This review will update the current status of research in several neurological genetic diseases including myotonic muscular dystrophy, Huntington's disease, Charcot-Marie-Tooth disease and Duchenne muscular dystrophy (X-linked). An introduction and overview of the methodology is provided. Specific research strategies including random screening of libraries, chromosome walking, messenger RNA selection, and messenger RNA translation are described. These strategies are designed to provide heterozygote identification, prenatal diagnosis and gestational management, the development of rational therapies, and the understanding of the molecular basis of disease expression.

Charcot-Marie-Tooth Disease↗
PubMed1999

Molecular evolution of the CMT1A-REP region: a human- and chimpanzee-specific repeat.

The CMT1A-REP repeat consists of two copies of a 24-kb sequence on human chromosome 17p11.2-12 that flank a 1.5-Mb region containing a dosage-sensitive gene, peripheral nerve protein-22 (PMP22). Unequal meiotic crossover mediated by misalignment of proximal and distal copies of the CMT1A-REP in humans leads to a 1.5-Mb duplication or deletion associated with two common peripheral nerve diseases, Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). Previous molecular hybridization studies with CMT1A-REP sequences suggested that two copies of the repeat are also found in the chimpanzee, raising the possibility that this unique repeat arose during primate evolution. To further characterize the structure and evolutionary synthesis of the CMT1A-REP repeat, fluorescent in situ hybridization (FISH) analysis and heterologous PCR-based assays were carried out for a series of primates. Genomic DNA was analyzed with primers selected to differentially amplify the centromeric and telomeric ends of the human proximal and distal CMT1A-REP elements and an associated mariner (MLE) sequence. All primate species examined (common chimpanzee, pygmy chimpanzee, gorilla, orangutan, gibbon, baboon, rhesus monkey, green monkey, owl monkey, and galago) tested positive for a copy of the distal element. In addition to humans, only the chimpanzee was found to have a copy of the proximal CMT1A-REP element. All but one primate species (galago) tested positive for the MLE located within the CMT1A-REP sequence. These observations confirm the hypothesis that the distal CMT1A-REP element is the ancestral sequence which was duplicated during primate evolution, provide support for a human-chimpanzee clade, and suggest that insertion of the MLE into the CMT1A-REP sequence occurred in the ancestor of anthropoid primates.

Animals↗
PubMed2006

Hand function in Charcot Marie Tooth: test retest reliability of some measurements.

OBJECTIVE: To evaluate the reliability of some measurements of hand function in people with Charcot Marie Tooth disease. DESIGN: Test retest study. SETTING: University, hospitals/clinics in northern Sweden. SUBJECTS: Twenty people with Charcot Marie Tooth disease. MAIN OUTCOME MEASURES: Measures of (1) dexterity; Box and Block Test and Nine-Hole Peg Test, (2) strength; Grippit instrument (grip and pinch), (3) tactile sensation; Shape Texture Identification Test. Statistics used: intraclass correlation (ICC 2.1), limits of agreement, coefficient of repeatability, coefficient of variation, and linear weighted kappa. RESULTS: The ICC for the Box and Block Test was very high (0.95). The limits of agreement, coefficient of repeatability (CR) (11.5 blocks/min) and coefficient of variation (CV) (8.4%) were acceptable. There was bias towards a better result on the second occasion. For the Nine-Hole Peg Test, the reliability was good if performance was within 2 min (ICC =0.99, CR = 4.3 s, CV = 3.9%). Grip strength proved to be reliable (ICC = 0.99, CR = 26.7 N, CV = 6.6%), while pinch strength was less reliable. The kappa value of the Shape Texture Identification Test was 0.87, which was considered very good although the test has limitations in terms of how well it can describe patients either performing very well or very poorly. CONCLUSIONS: The tested instruments can all be used to evaluate hand function in people with Charcot Marie Tooth. Certain factors, however, like limited time aspects for the Nine-Hole Peg Test and the number of trials used, should be taken into consideration. Pinch strength evaluation should be interpreted with caution.

Adult↗
PubMed1998

Common themes in peripheral neuropathy disease genes.

After a century of study, mutations in connexin32, peripheral myelin protein22, and protein zero are now known to culminate in the prototypical phenotype of Charcot-Marie-Tooth disease. Many of these mutations have been modeled in rodents and in tissue culture. Consequently, structure-function predictions for these mutations are now possible and detailed analyses of many of them are ongoing. Despite the marked differences in the functions of these three proteins, it is profitable to consider the many similarities between them, including the types of mutational mechanisms and their effects on myelin structure and function. Accordingly, the biology and genetics of Charcot-Marie-Tooth disease and other inherited peripheral neuropathies due to mutations in these proteins are reviewed.

Amino Acid Sequence↗
PubMed2005

[Localized aggressive periodontitis: a possible site-specific rather than tooth-specific disease?].

The diagnosis of localized aggressive periodontitis includes first molar attachment loss as an obligatory criterion. This tooth-specific based diagnosis has never been questioned or tested previously. We present a rare case of aggressive periodontitis that developed during orthodontic treatment, which included extraction of right lower first molar and bodily movement of the second molar to the original first molar site. At the end of the orthodontic therapy, localized periodontal disease was diagnosed at the site of the lower left first molar and the second lower right molar that was now occupying the site of the former first lower molar. The patient's periodontal condition was stabilized, and the bony defects were filled following periodontal treatment. This report shows that bacterial induced aggressive periodontitis developed during orthodontic treatment in a site-specific manner and suggest the hypothesis that localized aggressive periodontitis was targeted to a specific alveolar site rather than a tooth-specific site.

Acute Disease↗
PubMed1997

Clinical and electrophysiological phenotype of a homozygously duplicated Charcot-Marie-Tooth (type 1A) disease.

Type 1A of Charcot-Marie-Tooth disease (CMT1A) is associated with a microduplication of chromosome 17 (region 17p11.2) which contains PMP22, an important gene for peripheral nerve myelination. Patients carrying two duplications are expected to have a more severe phenotype, close to the Dejerine-Sottas syndrome. In this article, we report a family of 5 CMT1A patients in whom the unrelated father and mother carry a 17p11.2 duplication. The 2 daughters carry only one duplication (one given by the father, the other given by the mother), but the son carries two 17p11.2 duplications. Interestingly, the clinical phenotype of the son is more severe (scoliosis) compared to those of his sisters, but his motor nerve conduction velocities are in the range of a heterozygote CMT1A patient. The mechanisms leading to a more severe phenotype for CMT1A are discussed and may not be strictly related to lower nerve conduction velocities.

Adult↗
PubMed2006

Phenotypic and cellular expression of two novel connexin32 mutations causing CMT1X.

OBJECTIVE: To determine the phenotypic and cellular expression of two novel connexin32 (Cx32) mutations causing X-linked Charcot-Marie-Tooth disease (CMT1X). METHODS: The authors evaluated several members of two families with CMT1X clinically, electrophysiologically, pathologically, and by genetic testing. The Cx32 mutations were expressed in vitro and studied by immunocytochemistry. RESULTS: In both families, men were more severely affected than women with onset in the second decade of life. In the first family, the phenotype was that of demyelinating polyneuropathy with variable involvement of peripheral nerves. There was clinical evidence of CNS involvement in at least three of the patients, with extensor plantar responses and brisk reflexes. In the second family, the affected man presented with symmetric polyneuropathy and intermediate slowing of conduction velocities, whereas affected women had prominent asymmetric atrophy of the leg muscles. The authors identified two novel missense mutations resulting in L143P amino acid substitution in the first family and in V140E substitution in the second family, both located in the third transmembrane domain of Cx32. Expression of these Cx32 mutations in communication-incompetent HeLa cells and immunocytochemical analysis revealed that both mutants were retained intracellularly and were localized in the Golgi apparatus. In contrast to wild-type protein, they did not form gap junctions. CONCLUSION: These novel connexin32 (Cx32) mutations cause a spectrum of clinical manifestations characteristic of Charcot-Marie-Tooth disease (CMT1X), including demyelinating or intermediate polyneuropathy, which is often asymmetric, and CNS involvement in one family. The position and cellular expression of Cx32 mutations alone cannot fully predict these phenotypic variations in CMT1X.

Aged↗
PubMed2004

Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves.

NDRG1 is an intracellular protein that is induced under a number of stress and pathological conditions, and it is thought to be associated with cell growth and differentiation. Recently, human NDRG1 was identified as a gene responsible for hereditary motor and sensory neuropathy-Lom (classified as Charcot-Marie-Tooth disease type 4D), which is characterized by early-onset peripheral neuropathy, leading to severe disability in adulthood. In this study, we generated mice lacking Ndrg1 to analyze its function and elucidate the pathogenesis of Charcot-Marie-Tooth disease type 4D. Histological analysis showed that the sciatic nerve of Ndrg1-deficient mice degenerated with demyelination at about 5 weeks of age. However, myelination of Schwann cells in the sciatic nerve was normal for 2 weeks after birth. Ndrg1-deficient mice showed muscle weakness, especially in the hind limbs, but complicated motor skills were retained. In wild-type mice, NDRG1 was abundantly expressed in the cytoplasm of Schwann cells rather than the myelin sheath. These results indicate that NDRG1 deficiency leads to Schwann cell dysfunction, suggesting that NDRG1 is essential for maintenance of the myelin sheaths in peripheral nerves. These mice will be used for future analyses of the mechanisms of myelin maintenance.

Adult↗
PubMed1992

Food habits and dental disease in an iron-age population.

Tooth diseases and wear record valuable information on diet and methods of food preparation in past human populations. In this paper the teeth of an Iron-Age population (Monte Bibele, Bologna) are analyzed to reconstruct their nutritional situation. The analysis of caries frequency and distribution indicates a level of carbohydrate consumption which is consistent with an agricultural way of life. The presence of calculus indicates that proteins were present in the diet of the Monte Bibele population. The frequency of antemortem tooth loss and of dental abscesses is in harmony with the results of the analysis of caries and calculus. The examination of dental wear suggests the presence of a substantial vegetable component in the diet. From the analysis of the dental characteristics one can conclude that the population of Monte Bibele had a prevalent agricultural economy. The presence of some diachronic variations in the distribution of the examined characters suggest changes in the diet in the course of time.

Feeding Behavior↗
PubMed2002

Peripheral nerve extracellular matrix remodeling in Charcot-Marie-Tooth type I disease.

Charcot-Marie-Tooth type 1 disease (CMT1) is a group of inherited demyelinating neuropathies caused by mutations in genes expressed by myelinating Schwann cells. Rather than demyelination per se, alterations of Schwann cell-axon interactions have been suggested as the main cause of motor-sensory impairment in CMT1 patients. In an attempt to identify molecules that may be involved in such altered interactions, the extracellular matrix (ECM) remodeling occurring in CMT1 sural nerves was studied. For comparison, both normal sural nerves and sural nerves affected by neuropathies of different origin were used. The study was performed by immunohistochemical analysis using antibodies against collagen types I, III, IV, V, and VI and the glycoproteins fibronectin, laminin, vitronectin and tenascin. Up-regulation of collagens, fibronectin and laminin was commonly found in nerve biopsy specimens from patients affected by CMT1 and control diseases, but higher levels of overexpression were usually observed in CMT1 cases. On the other hand, vitronectin and tenascin appeared preferentially induced in CMT1 compared to other pathologies investigated here. Vitronectin, whose expression in normal nerves was limited to perineurial layers and to the walls of epineurial and endoneurial vessels, became strongly and diffusely expressed in the endoneurium in most CMT1 biopsy specimens. The expression of tenascin, confined to the perineurium, to vessel walls and to the nodes of Ranvier in normal nerves, was displaced and extended along the internodes of several nerve fibers in the majority of CMT1 nerves. Thus, compared with our pathological controls CMT1 seemed to determine the most extensive remodeling of peripheral nerve ECM.

Adolescent↗