Gene/Protein Disease Symptom Drug Enzyme Compound
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Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.
Hum Mol Genet 2004 Apr 15
PMID:A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. 1497 60

Lyme borreliosis is a systemic infection caused by the spirochaete Borrelia burgdorferi, which is transmitted by tick bites and maintained in a delicately balanced ecological cycle. Recent increases in the population densities of tick hosts, the abundance of ticks and the proximity of man to natural tick habitats have led to an escalating worldwide incidence of Lyme borreliosis, and nonspecific clinical manifestations have yielded significant misunderstanding of the disease. After entry, B. burgdorferi activates local inflammation, yet evades host defences and facilitates dissemination by potentially masquerading with host components such as plasmin and complement. The extent of tissue injury is determined by the aggressiveness of host inflammation and immunological reactions, as well as by genetic attributes of the spirochaete. The clinical presentation can be highly varied, including early manifestations that are limited to erythema migrans and ranging to disseminated infection with arthritis, carditis, cranial nerve palsy, peripheral neuropathy, meningitis, or other manifestations. Diagnostic tests have improved, but are unhelpful during certain stages of infection. Therapy varies depending on the degree of involvement, and recovery is usually rapid and complete. Post-treatment clinical manifestations in the absence of evidence for active infection are still poorly understood. The understanding of how B. burgdorferi survives in the environment and interacts with human and mammalian hosts has improved. However, further advances in prevention and therapy depend on continued investigation of the ecological risks and improved understanding of the pathobiology of this obligate bacterial parasite.
Expert Rev Mol Med 2004 Jan 19
PMID:Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment. 1498 14

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.
Mol Cell Biol 2004 May
PMID:Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves. 1508 88

The vascular targeting agent ZD6126 is a water-soluble prodrug of N-acetylcolchinol that acts by disrupting the cytoskeleton of tumor endothelial cells. It is currently undergoing clinical evaluation in man. As peripheral neuropathy is a major dose-limiting toxicity associated with tubulin binding agents, the neurotoxic potential of ZD6126 was investigated in male and female Wistar rats. ZD6126 was administered i.v. at up to maximum tolerated doses using subacute (0 to 20 mg/kg/d for 5 days) and chronic (0 to 10 mg/kg/d for 5 days, repeated monthly for 6 months) dosing regimens. A separate study examined a combination of ZD6126 (three cycles of ZD6126 given as in the chronic dosing regimen) and paclitaxel (12 mg/kg/wk for 9 weeks) to assess whether coadministration of ZD6126 altered the time course or magnitude of a paclitaxel-induced neuropathy. Neurotoxic potential was examined using a comprehensive series of tests including a functional observation battery, measurements of muscle strength (forelimb and hind limb grip strength), nociception (tail flick test), locomotor activity, neuropathology, and whole nerve electrophysiology. There was no evidence that ZD6126 induced neurotoxicity in the rat following either subacute or chronic i.v. dosing. In a chronic electrophysiology study, ZD6126 produced a slight slowing of the maturational increase of caudal nerve amplitude, with some evidence of reversibility. However, this was not associated with any changes in caudal nerve conduction velocity, motor nerve conduction velocity or amplitude, functional observation battery behavioral and function parameters (including no effects on tail flick latency), and neuropathology. As expected, paclitaxel administration was associated with a significant decrease in caudal nerve conduction velocity (P = 0.0001). Coadministration of ZD6126 did not increase the neurotoxicity of paclitaxel. These studies suggest that ZD6126 should not induce the peripheral neuropathy associated with other antitubulin chemotherapeutic agents and that ZD6126 may not exacerbate the neurotoxicity of other agents with dose-limiting neuropathies.
Mol Cancer Ther 2004 Jul
PMID:Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat. 1525 39

Inherited peripheral neuropathies comprise a wide variety of diseases primarily affecting the peripheral nervous system. The best-known peripheral neuropathy is Charcot-Marie-Tooth disease (CMT) described in 1886 by J.-M. Charcot, P. Marie and H.H. Tooth. In 1980, A.E. Harding and P.K. Thomas showed that in a large group of individuals with CMT, several only had motor abnormalities on clinical and electrophysiological examination, whereas sensory abnormalities were absent. This exclusively motor variant of CMT was designated as spinal CMT or hereditary distal spinal muscular atrophy, and included in the distal hereditary motor neuropathies (distal HMN). The distal HMN are clinically and genetically heterogeneous and are subdivided according to the mode of inheritance, age at onset and clinical evolution. Since the introduction of positional cloning, 12 chromosomal loci and seven disease-causing genes have been identified for autosomal dominant and recessive distal HMN. Most of the genes involved have housekeeping functions, as in RNA processing, translation synthesis, glycosylation, stress response, apoptosis, but also axonal trafficking and editing. Functional characterization of the mutations will help to unravel the cellular processes that underlie the specificity of motor neuropathies leading to neurogenic muscular atrophy of distal limb muscles. Here we review the recent progress of the molecular genetics of distal HMN and discuss the genes implicated.
Hum Mol Genet 2004 Oct 01
PMID:Molecular genetics of distal hereditary motor neuropathies. 1535 25

The extra-intestinal manifestations of celiac disease (CD), including ataxia and peripheral neuropathy, are increasingly being recognized as the presenting symptoms of this autoimmune disease. Although there is a greater understanding of the pathogenesis of the intestinal lesions in CD the mechanisms behind the neurologic manifestations of CD have not been elucidated. In this article, the authors review the cellular and molecular mechanisms behind the histopathologic changes in the intestine, discuss the presentation and characteristics of neurologic manifestations of CD, review the data on the mechanisms behind these manifestations, and discuss the diagnosis and treatment of CD. Molecular mimicry and intermolecular help may play a role in the development of neurologic complications.
Cell Mol Life Sci 2005 Apr
PMID:Mechanisms underlying celiac disease and its neurologic manifestations. 1586 4

Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological disorders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 cause hereditary sensory and autonomic neuropathy (type I) (HSAN1), an adult onset, autosomal dominant neuropathy. HSAN1 patients have reduced SPT activity. Expression of mutant SPTLC1 in yeast and mammalian cell cultures dominantly inhibits SPT activity. We created transgenic mouse lines that ubiquitously overexpress either wild-type (SPTLC1(WT)) or mutant SPTLC1 (SPTLC1(C133W)). We report here that SPTLC1(C133W) mice develop age-dependent weight loss and mild sensory and motor impairments. Aged SPTLC1(C133W) mice lose large myelinated axons in the ventral root of the spinal cord and demonstrate myelin thinning. There is also a loss of large myelinated axons in the dorsal roots, although the unmyelinated fibers are preserved. In the dorsal root ganglia, IB4 staining is diminished, whereas expression of the injury-induced transcription factor ATF3 is increased. These mice represent a novel mouse model of peripheral neuropathy and confirm the link between mutant SPT and neuronal dysfunction.
Hum Mol Genet 2005 Nov 15
PMID:Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy. 1621 Mar 80

The mas-related gene (Mrg) family is a large family of G-protein-coupled receptors which are variable in number depending on species. The so-called sensory-neuron-specific receptors (SNSRs) make up a subset of the Mrg family, and several of these have been implicated in nociceptive processes. To verify their specific localization in sensory ganglia, we have determined the expression patterns of two of them, rMrgA and rMrgC, in a panel of rat tissues. The quantitative PCR results in the rat tissue panel indicate that, while several non-neuronal tissues contain significant levels of mRNA for both receptors, these two receptors are most highly expressed in dorsal root ganglia and trigeminal ganglia. Given this, we have examined the effects of spinal nerve ligation (SNL) on the expression of these genes. Peripheral neuropathy induced by ligation of spinal nerves at L5 and L6 resulted in a pronounced mechanical allodynia. These behavioral changes in tactile sensitivity were accompanied by significant decreases (10- to 100-fold) in the mRNA expression of both rMrgA and rMrgC exclusively in the L5 and L6 dorsal root ganglia ipsilateral to the SNL. In situ hybridization studies demonstrated that this decrease did not result from neuronal loss but rather from a reduction in the hybridization signals for rMrgC over small-to-medium diameter L5 and L6 dorsal root ganglia neurons. While the functional implications of the altered regulation of rMrgA and rMrgC in neuropathic pain models remain unclear, the results suggest that therapeutics targeting these receptors may have limited utility.
Brain Res Mol Brain Res 2005 Dec 07
PMID:Regulation of two rat mas-related genes in a model of neuropathic pain. 1624 53

It is now well known that peripheral nerves are a target for the action of neuroactive steroids. This review summarizes observations obtained so far, indicating that through the interaction with classical and nonclassical steroid receptors, neuroactive steroids (e.g., progesterone, testosterone and their derivatives, estrogens, etc.) are able to influence several parameters of the peripheral nervous system, particularly its glial compartment (i.e., Schwann cells). Interestingly, some of these neuroactive steroids might be considered as promising neuroprotective agents. They are able to counteract neurodegenerative events of rat peripheral nerves occurring after experimental physical trauma, during the aging process, or in hereditary demyelinating diseases. On this basis, the hypothesis that neuroactive steroids might represent a new therapeutic strategy for peripheral neuropathy is proposed.
J Mol Neurosci 2006
PMID:Neuroactive steroids: A therapeutic approach to maintain peripheral nerve integrity during neurodegenerative events. 1663 76

Mutations in GJB1, the gene encoding the gap junction protein connexin32 (Cx32), cause X-linked Charcot-Marie-Tooth disease, an inherited demyelinating peripheral neuropathy. We generated transgenic mice that express the R142W mutation in myelinating Schwann cells. The R142W mutant protein was aberrantly localized to the Golgi, indicating that it does not traffic properly, but the molecular organization of the myelin sheath, including the localization of Cx29, another connexin expressed by myelinating Schwann cells, was not disrupted. In a wild type background, this mutation dramatically decreased the level of wild type mouse Cx32 in immunoblots of sciatic nerve and caused demyelination. The expression of wild type human Cx32 with the same transgenic construct had different effects-increased amounts of Cx32, normal localization of Cx32 at nodes and incisures, and split myelin sheaths. Thus, the R142W mutant protein has dominant effects that are distinct from overexpression.
Mol Cell Neurosci 2006 Jul
PMID:The effects of a dominant connexin32 mutant in myelinating Schwann cells. 1679 Mar 56


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