Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Replication defective adenoviral vectors have been demonstrated as an effective method for delivering genes into a variety of cell types and tissues both in vivo and in vitro. Transfecting genes into neuronal cells has proven to be difficult because of their lack of cell division. Since the major problem in neurological disease is the degeneration of the terminally differentiated neuronal cells, the adenoviral vector's ability to transfer genes into differentiated post-mitotic cells makes them advantageous for a gene delivery system for the nervous system. Here we showed that a replication defective recombinant adenovirus carrying the lacZ gene could infect the neuronal stem cells and even the differentiated neuronal cells derived from the central nervous system. The lacZ gene delivered into the neuronal cells was expressed efficiently. In addition, the recombinant virus also infected Schwann cells in intact and injured nerves in vivo. The expression of the lacZ gene lasted for 5 weeks, within which nerve regeneration is accomplished in the rat. Adenoviral vectors might thus be used to modulate Schwann cell gene expression for treating peripheral nerve injury or peripheral neuropathy.
Mol Cells 2000 Oct 31
PMID:Effective gene transfer into regenerating sciatic nerves by adenoviral vectors: potentials for gene therapy of peripheral nerve injury. 1110 Nov 45

Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disease mainly characterized by familial diabetes mellitus and optic atrophy. WS patients frequently present with other clinical features such as diabetes insipidus, renal abnormalities, psychiatric disorders, and a variety of neurologic symptoms: deafness, ataxia, peripheral neuropathy. A gene responsible for Wolfram Syndrome (WFS1) has been recently identified on chromosome 4p16.1. Twenty-two Wolfram patients from 16 Spanish families were screened for mutations in the WFS1 coding region by SSCP analysis and direct sequencing. Since WS has been considered a mitochondrial disorder for some time, mitochondrial DNA (mtDNA) in these families was also examined. WFS1 mutations were detected in 75% of families (12 of 16). One of these mutations, an insertion of 16 base pairs in exon 4, turned out to be notably frequent in Spanish pedigrees. As many as 50% of pedigrees with WFS1 mutations harbored this insertion, either in one (33% of cases) or in two chromosomes (67%). Ten other mutations were identified: 7 missense changes, 2 deletions, and 1 nonsense mutation. Only 3 of these changes had been previously described in non-Spanish pedigrees. Large mtDNA rearrangements and LHON point mutations were detected in four and six families, respectively. No correlation could be established between WFS1 gene mutations and specific point mutations or rearrangements in mtDNA. We would suggest first screening for the 16-bp insertion in exon 4 when a new Spanish WS case is reported.
Mol Genet Metab 2001 Jan
PMID:Presence of a major WFS1 mutation in Spanish Wolfram syndrome pedigrees. 1116 32

Mutations in the connexin 31 (GJB3) gene have been found in subjects with dominant and recessive deafness and in patients with erythrokeratodermia variabilis. We report here a dominant mutation in the GJB3 gene (D66del) in a family affected with peripheral neuropathy and sensorineural hearing impairment. A wide range of disease severity for peripheral neuropathy, from asymptomatic cases to subjects with chronic skin ulcers in their feet and osteomyelitis leading to amputations, was detected in D66del patients. Mild, often asymmetrical, hearing impairment was found in all but one patient with mutation D66del of this family and the same mutation was present in an independent family ascertained because of hearing impairment. We have found mouse connexin 31 (Gjb3) gene expression in the cochlea and in the auditory and sciatic nerves, showing a pattern similar to that of Gjb1 (connexin 32), of which the human ortholog (GJB1) is involved in X-linked peripheral neuropathy. This expression pattern, together with auditory-evoked brainstem anomalous response in D66del patients, indicates that hearing impairment due to GJB3 mutations involves alterations in both the cochlea and the auditory nerve. Peripheral neuropathy is the third phenotypic alteration linked to GJB3 mutations, which enlarges the list of genes that cause this group of heterogeneous disorders.
Hum Mol Genet 2001 Apr 15
PMID:Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. 1130 68

Chediak Higashi syndrome (CHS) is a rare, autosomal recessive disorder that affects multiple systems of the body. Patients with CHS exhibit hypopigmentation of the skin, eyes and hair, prolonged bleeding times, easy bruisability, recurrent infections, abnormal NK cell function and peripheral neuropathy. Morbidity results from patients succumbing to frequent bacterial infections or to an "accelerated phase" lymphoproliferation into the major organs of the body. Current treatment for the disorder is bone marrow transplant, which alleviates the immune problems and the accelerated phase, but does not inhibit the development of neurologic disorders that grow increasingly worse with age. There are several animal models of CHS, the beige mouse being the most characterized. Positional cloning and YAC complementation resulted in the identification of the Beige and CHS1/LYST genes. These genes encode a cytosolic protein of 430,000 Da. Sequence analysis identified three conserved regions in the protein: a HEAT repeat motif at the amino-terminus that contains several a helices, a BEACH domain containing the amino acid sequence WIDL, and a WD40 repeat motif, which is described as a protein-protein interaction domain. The presence of the BEACH and WD40 domains defines a family of genes that encode extremely large proteins.
Curr Mol Med 2002 Aug
PMID:Chediak-Higashi syndrome: a clinical and molecular view of a rare lysosomal storage disorder. 1212 12

Distinct germline mutations in the gene (GJB3) encoding connexin 31 (Cx31) underlie the skin disease erythrokeratoderma variabilis (EKV) or sensorineural hearing loss with/without peripheral neuropathy. Here we describe a number of functional analyses to investigate the effect of these different disease-associated Cx31 mutants on connexon trafficking and intercellular communication. Immunostaining of a biopsy taken from an EKV patient harbouring the R42P mutation revealed sparse epidermal staining of Cx31, and, when present, it had a perinuclear localization. Transfection and microinjection studies in both keratinocytes and fibroblast cell lines also demonstrated that R42P and four other EKV-associated mutant Cx31 proteins displayed defective trafficking to the plasma membrane. The deafness/neuropathy only mutant 66delD had primarily a cytoplasmic localization, but some protein was visualized at the plasma membrane in a few transfected cells. Both 66delD- and R32W-Cx31/EGFP proteins had significantly impaired dye transfer rates compared to wild-type Cx31/EGFP protein. A striking characteristic feature observed with the dominant skin disease Cx31 mutations was a high incidence of cell death. This was not observed with wild-type, R32W 66delD Cx31 proteins. In conclusion, we have identified some key cellular phenotypic differences with respect to disease-associated Cx31 mutations.
Hum Mol Genet 2002 Aug 15
PMID:Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations. 1216 62

The term acanthocytosis is derived from the Greek for "thorn" and is used to describe a peculiar spiky appearance of erythrocytes. Acanthocytosis is found to be associated with at least three hereditary neurological disorders that are generally referred to as neuroacanthocytosis. Abetalipoproteinaemia is an autosomal recessive condition, characterised by absence of serum apolipoprotein B containing lipoproteins leading to fat intolerance and fat-soluble vitamin deficiency. This results in a progressive spinocerebellar ataxia with peripheral neuropathy and retinitis pigmentosa. Chorea-acanthocytosis is also an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysphagia, dysarthria, areflexia, seizures and dementia. Some of its features, including choreic movements, peripheral neuropathy with areflexia, elevated serum creatine kinase levels and myopathy are shared by another form of neuroacanthocytosis, McLeod syndrome. Patients affected by this X-linked disorder also show abnormal expression of Kell blood group antigens and a permanent haemolytic state. In addition to these cases, acanthocytosis is occasionally associated with other neurological disorders, such as Hallervorden-Spatz disease. For each of the neuroacanthocytosis syndromes we review the main clinical features and their molecular bases. The recent molecular genetics findings are the first step towards the understanding of the pathogenetic mechanisms and eventually the search for effective treatments.
J Mol Med (Berl) 2002 Aug
PMID:Clinical features and molecular bases of neuroacanthocytosis. 1218 48

We have identified and characterized a new peripheral myelin protein 22 (Pmp22) mouse mutant. The mutation results in a serine to threonine amino acid substitution at residue 72, which is a hot spot for mutation in human PMP22, leading to the peripheral neuropathy Dejerine-Sottas syndrome. We have previously described two other Pmp22 mutants, providing an allelic series for gene function analysis. Pmp22 mutations generally lead to abnormal intracellular trafficking of Pmp22, and we show that each mutant protein in the allelic series has a unique pattern of intracellular localization in transfected cell lines. The mutant protein from the less severely affected mutants occurs in large aggregates, while the mutant protein from the most severely affected mutant occurs in a diffuse perinuclear pattern that largely colocalizes with wild-type protein. This suggests that large Pmp22 aggregates may be protective in this form of peripheral neuropathy.
Mol Cell Neurosci 2002 Sep
PMID:Identification of a new Pmp22 mouse mutant and trafficking analysis of a Pmp22 allelic series suggesting that protein aggregates may be protective in Pmp22-associated peripheral neuropathy. 1235 55

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive peripheral neuropathy reported in several Algerian families. The gene locus of this disease has been narrowed to 5q31-33. Recently, a missense mutation in the gene for the kinesin superfamily KIF1B was reported as the cause of Charcot Marie Tooth disease type 2A (CMT2A). We suspected that Rab6KIFL, one of the kinesin superfamily proteins, might be involved in the pathophysiology of CMT4C, because Rab6KIFL gene is located in 5q31. The coding regions of the Rab6KIFL gene of genomic DNA derived from one Algerian family with CMT4C were analyzed by direct sequencing. No mutation in Rab6KIFL gene was found in this family. Further investigation is necessary to identify the causative gene for CMT4C.
Int J Mol Med 2003 Jan
PMID:The kinesin superfamily protein Rab6KIFL is not involved in the pathophysiology of Charcot-Marie-Tooth disease type 4C. 1246 16

Currently, there is no therapy for men with androgen-refractory prostate cancer that substantially extends survival. This report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains a peptide bond that can be hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as vinblastine-conjugate) is minimally toxic to cells in culture which do not express PSA. In the presence of PSA, the peptide moiety is hydrolyzed, generating several highly toxic metabolites that contain vinblastine. Animals bearing PSA-positive human prostate tumors that were treated with the vinblastine-conjugate experienced a >99% reduction in PSA serum level. In contrast, animals bearing PSA-positive human prostate tumors treated with the cytotoxic metabolites derived from the PSA hydrolysis of the vinblastine-conjugate showed a nonsignificant change in both PSA and tumor weight values. The cell killing activity of the vinblastine-conjugate is PSA dependent because animals bearing non-PSA-producing human tumor xenografts had a nonsignificant increase in tumor weight after vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP tumor-bearing nude mice were conducted with animals treated for 5 consecutive days with various doses of either the vinblastine-conjugate or a PSA-generated toxic metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment resulted in 10-70% mortality with a very slight effect on tumor growth. In contrast, vinblastine-conjugate treatments resulted in no mortality, good to excellent antitumor efficacy, very slight to slight peripheral neuropathy and myelopathy, and slight to severe testicular degeneration. Similar treatment of beagle dogs with the vinblastine-conjugate showed even less toxicity. These data support the use of the PSA-hydrolyzable vinblastine-conjugate as an experimental therapy for prostate cancer in man.
Mol Cancer Ther 2002 May
PMID:A prostate-specific antigen (PSA)-activated vinblastine prodrug selectively kills PSA-secreting cells in vivo. 1247 63

Charcot-Marie-Tooth disease type 4B1, CMT4B1, is a severe, autosomal-recessive, demyelinating peripheral neuropathy, due to mutations in the Myotubularin-related 2 gene, MTMR2. MTMR2 is widely expressed and encodes a phosphatase whose substrates include phosphoinositides. However, this does not explain how MTMR2 mutants specifically produce demyelination in the peripheral nerve. Therefore, we analysed the cellular and subcellular distribution of Mtmr2 in nerve. Mtmr2 was detected in all cytoplasmic compartments of myelin-forming Schwann cells, as well as in the cytoplasm of non-myelin-forming Schwann cells and both sensory and motorneurons. In contrast, Mtmr2 was detected in the nucleus of Schwann cells and motorneurons, but not in the nucleus of sensory neurons. As Mtmr2 is diffusely present also within the nerve, a specific function could derive instead from nerve-specific interacting proteins. Therefore, we performed two yeast two-hybrid screenings, using either fetal brain or peripheral nerve cDNA libraries. The neurofilament light chain protein, NF-L, was identified repeatedly in both screenings, and found to interact with MTMR2 in both Schwann cells and neurons. Interestingly, NF-L, encoding NF-L, is mutated in CMT2E. These data may provide a basis for the nerve-specific pathogenesis of CMT4B1, and further support for the notion that hereditary demyelinating and axonal neuropathies may represent different clinical manifestations of a common pathological mechanism.
Hum Mol Genet 2003 Jul 15
PMID:Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve. 1283 94


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