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)

The triple A or Allgrove's syndrome (MIM*231550) is an autosomal recessive disease characterized by the triad of adrenocorticotropic hormone (ACTH) resistant adrenal insufficiency, achalasia and alacrima. Since its first description by Allgrove et al. (1978) more than 70 cases from all over the world have been reported. The syndrome manifests itself during the first decade of life with severe hypoglycaemic episodes which can cause sudden death. The frequent association with neurological disorders presenting as a mixed pattern of upper and lower motor neuropathy, sensory impairment, autonomic neuropathy and mental retardation may result in a severely disabling disease. As an additional feature some patients have hyperkeratosis of their palms and soles. We have performed a systematic genome linkage scan in eight triple A families of which three were consanguineous [including the large highly inbred kindred described by Moore et al. (1991)]. We obtained conclusive evidence for linkage of the triple A syndrome locus to markers on chromosome 12q13 (D12S368, theta max = 0, Zmax = 10.81) with no indication of genetic heterogeneity. Haplotype and multipoint analyses suggest that the gene is located on a chromosomal segment flanked by the markers D12S1629 and D12S312 which are 6 cM apart. This region harbors the type II keratin gene cluster, and potential candidate genes include SCN8A and HOXC genes.
Hum Mol Genet 1996 Dec
PMID:Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. 896 64

Acrylamide and carbon disulfide produce central-peripheral distal axonopathy in experimental animals and humans. The main feature of this disease is the focal swellings containing neurofilaments in distal axons, followed by nerve degeneration beyond these swellings. We studied the possible role of tubulin assembly kinetics in this disease. The rats were either administered acrylamide (50 mg/kg, ip, saline) or exposed to carbon disulfide (700 ppm, 9 h) via inhalation for 12 and 15 d, respectively. Tubulin, purified from both acrylamide-(10.37 +/- 0.3 vs 11.3 +/- 0.15) and carbon disulfide-treated (9.72 +/- 0.5 vs 11.18 +/- 0.25) rat brains showed increase in Vmax (OD/min x 10(3)) of its polymerization. However, only acrylamide treatment showed a decrease in time to Vmax, when brain supernatant was used for tubulin polymerization. In vitro addition of acrylamide (0.1-1 mM) to bovine brain tubulin also showed a decrease in time to Vmax (16-21%) of its polymerization. Carbon disulfide treatment of rats, on the other hand, showed a decrease in MAP-2 and an increase in a 120-kDa peptide concentration. The latter showed immunoreactivity with anti-MAP-2. The increase in the rate of tubulin polymerization by acrylamide and carbon disulfide treatment may alter the rate of transport of axonal constituents, including neurofilament, and contribute toward their accumulation in the focal swellings observed in this neuropathy.
Mol Chem Neuropathol 1997 Apr
PMID:Acrylamide and carbon disulfide treatments increase the rate of rat brain tubulin polymerization. 916 88

Diabetes mellitus associated with mitochondrial tRNA mutation at position 3243(DM-Mt3243) is a new disease. Patients have a distinctly different picture from MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). During observations at the Saiseikai Central Hospital, the following findings were noted in DM-Mt3243 patients: DM-Mt3243 patients are diagnosed earlier with diabetes, compared to NIDDM (non-insulin dependent diabetes mellitus) controls without family history. DM-Mt3243 patients often need insulin more often than NIDDM controls without family history. Post-treatment neuropathy and insulin edema are often found in DM-Mt3243, and the two phenomena possibly have a similar pathophysiology related to mitochondrial dysfunction. Ambiguous psychiatric disorders of functional psychosis are observed frequently in DM-Mt3243. Mild headache is common in DM-Mt3243 cases. Ambiguous neuromuscular abnormalities such as sleep disturbance, paresthesia of the legs, edema of the legs, and palpitation may be symptoms associated with mitochondrial dysfunction in DM-Mt3243. Coenzyme Q may be effective in the relief of these neuromuscular symptoms.
Mol Aspects Med 1997
PMID:Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation: clinical features and coenzyme Q10 treatment. 926 20

Charcot-Marie-Tooth disease type 1A is most commonly caused by a duplication of a 1.5 Mb region of chromosome 17 which includes the peripheral myelin protein 22 gene (PMP22). Over-expression of this gene leads to a hypomyelinating/demyelinating neuropathy and to severely reduced nerve conduction velocity. Previous mouse and rat models have had relatively high levels of expression of the mouse or human PMP22 gene leading to severe demyelination. Here we describe five lines of transgenic mice carrying increasing copies of the human PMP22 gene (one to seven) and expressing increasing levels of the transgene. From histological and electrophysiological observations there appears to be a threshold below which expression of PMP22 has virtually no effect; below a ratio of human/mouse mRNA expression of approximately 0.8, little effect is observed. Between a ratio of 0.8 and 1.5, histological and nerve conduction velocity abnormalities are observed, but there are no behavioural signs of neuropathy. An expression ratio >1.5 leads to a severe neuropathy. A second observation concerns the histology of the different lines; the level of expression does not affect the type of demyelination, but influences the severity of involvement.
Hum Mol Genet 1998 Mar
PMID:Correlation between varying levels of PMP22 expression and the degree of demyelination and reduction in nerve conduction velocity in transgenic mice. 946 3

Prostaglandin D synthetase (PGD-S; prostaglandin-H2 D-isomerase, EC 5,3,99,2), a 30 kDa glycoprotein also known as beta-trace protein that catalyzes the formation of prostaglandin D2 (PGD2) from PGH2, was purified to apparent homogeneity from human cerebrospinal fluid (CSF) using a two-step procedure involving HPLC on a Vydac C8 reversed-phase column and high performance electrophoresis chromatography (HPEC) using a 10% T SDS-polyacrylamide gel. The purity of PGD-S isolated from CSF was confirmed by silver stained SDS-polyacrylamide gel and direct protein microsequencing (NH2-APEAQVSVQPNFQ). A highly specific polyclonal antibody was prepared against this protein for immunoassay development. Using an ELISA, it was found that the concentration of PGD-S in CSF did not alter significantly in different pathological conditions of the central nervous system (CNS). These include dementia (n = 9), hydrocephalus (n = 4), neuropathy (n = 11), optic neuritis (n = 4), multiple sclerosis (n = 11), and demyelinating syndrome (n = 11), when compared to normal individuals (n = 12); however, the level of PGD-S in the CSF obtained from patients with brain tumor (n = 11), was reduced by as much as 2-fold when compared to control samples (n = 12) illustrating PGD-S is a potentially useful marker for brain tumor.
Biochem Mol Biol Int 1998 Nov
PMID:Quantification of prostaglandin D synthetase in cerebrospinal fluid: a potential marker for brain tumor. 984 24

A 1.5 Mb duplication on chromosome 17p11.2 is typical for the great majority of patients suffering from Charcot-Marie-Tooth type 1A (CMT1A) disease. A female child of 4 years with clinical signs and symptoms of a demyelinating neuropathy was examined for the presence of this duplication. Analysis of MspI polymorphisms in DNA extracted from peripheral blood failed due to homozygosity for probes pVAW409R3a and pEW401HE. Also, no EcoRI/SacI 3.2 kb junction fragment or dosage difference with probe pLR7.8, characteristic of the CMT1A duplication, was found. However, fluorescence in situ hybridization (FISH) analysis with the PMP22 specific probe c132G8 revealed in peripheral blood lymphocytes 60% of interphase nuclei with CMT1A duplication indicating the probability of mosaicism. In interphase nuclei extracted from nerve tissue the duplication was detectable in 88%, in muscle tissue in 72% of the analyzed nuclei. This suggests the presence of a somatic CMT1A duplication mosaicism that can only be reliably detected by FISH. The early onset and severity of the phenotype indicates that the hypothesized somatic reversion is probably fixed to early developmental stages.
Int J Mol Med 1998 Feb
PMID:Mosaicism for Charcot-Marie-Tooth disease type 1A: onset in childhood suggests somatic reversion in early developmental stages. 985 34

We have previously reported on a novel autoantibody in a patient with paraneoplastic sensory-dominant neuropathy. This autoantibody immunostains the rat primary sensory system and reacts with a 47 kDa protein on immunoblotting. Here, we report on the isolation from rat spinal cord of a molecule that is recognized by this autoantibody. By ammonium sulfate cut and gel filtration, affinity and ion exchange chromatographies, the immunoreactive protein was purified to homogeneity and identified as brain-type creatine kinase (B-CK). Our study revealed that the autoantibody of the patient reacted with B-CK in the primary sensory system.
Int J Mol Med 1998 Mar
PMID:A novel autoantibody in paraneoplastic sensory-dominant neuropathy reacts with brain-type creatine kinase. 985 70

The treatment of patients with type 1 diabetes mellitus has to focus on short-term and long-term risks of the disease which means to avoid hyperglycemic or hypoglycemic coma as well as late complications. As we know from the DCCT study metabolic control substantially lowers the risk for retinopathy, nephropathy and neuropathy. We also know, that keeping the blood glucose in a nearly normal range inevitably is connected with a marked increase of severe hypoglycemia, an event which occurs more frequently when normoglycemia has been reached and the further slow decline of blood glucose is not recognized by the patient (autonomous neuropathy, hypoglycemia unawareness of other origin, long duration of diabetes etc.). Furthermore, counterregulatory hormones as glucagon and epinephrine may be lacking due to diminished or even lost alpha cells within the islets and as recently observed due to fibrosis of the adrenal medulla in long-term diabetes. The consequences of severe hypoglycemia are manifold: in the actual situation of unconsciousness the risk of heavy injuries and as long-term consequences irreversible brain damage may occur. Finally, the effort of the patient to reach normoglycemia includes the burden of an intensive blood glucose self-control day by day. This broad scenario of all the achievements and of all the problems connected with an intensified insulin treatment has to be regarded when the indication for an islet transplant will be discussed. From our point of view as clinicians it seems adequate not to give definite recommendations but to express our considerations for islet transplantation in patients with type 1 diabetes mellitus with the following list (table 1). It must be clearly stated, that at present transplantation of isolated islets by no means can serve as a treatment for a larger number of patients and this may hold through also for the foreseeable future. In this context, also the many contraindications should be summarized (table 2). Consequently we have to deal with several questions and problems which can be subdivided into those regarding the possible benefit for the patients from an islet graft (full success = insulin independence, partial success = lower exogenous insulin requirement due to additional endogenous insulin, measured by C-peptide levels, more stable glucose metabolism) and those regarding possible side effects (primary risk of implantation, threat for rejection of the primarily transplanted kidney). Furthermore, one may ask for risks when islets are transplanted alone (ITA). We therefore will address the following areas: 1. Simultaneous islet and kidney transplants 2. Islet transplants after kidney transplantation alone (IAK) 3. Islet transplantation after pancreas transplantation failure (P-failure) 4. Defect hypoglycemia counterregulation--life threatening hypoglycemia unawareness as indication for islet transplantation? 5. Autonomous cardiac neuropathy as indication for islet transplantation? 6. Significant clinical problems with exogenous insulin therapy as indication for islet transplantation?
J Mol Med (Berl) 1999 Jan
PMID:Indications for clinical islet transplantation today and in the forseeable future--the diabetologist's point of view. 993 Sep 51

The effect of increasing extracellular calcium concentration on spontaneous transmitter release was studied at both soleus (slow) and fast extensor digitorum longus (EDL) nerve terminals of control and streptozotocin-induced diabetic (STZ-D) young C57 BL mice (7 months old) depolarized by high (20 mM) extracellular potassium [K]o. Diabetes was induced by i.p. injection with a single dose of streptozotocin (200 mg/kg) at the age 5 months and the electrophysiological studies were carried out after 8 more weeks. By using intracellular recording, miniature endplate potentials (MEPPs) were first recorded in a normal [K]o Krebs solution. Subsequently, MEPPs were recorded in high [K]o Krebs solution with 4 different Ca concentrations: Ca-free/ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetra acetic acid (EGTA), 0.5, 1.5 and 2 mM Ca. MEPP frequency was lower at STZ-D than control nerve terminals in EDL but not soleus. However, MEPP frequency was progressively higher at both EDL and soleus of STZ-D than control with increasing Ca concentration in Krebs that contained 20 mM [K]o. In STZ-D slow soleus muscle, depolarization produced 0.7, 4.3, 41.6 and 62.7 vs 1.4, 2.8, 20.7 and 31.6 Hz for control in the 4 different Ca concentrations. In STZ-D fast EDL muscle, depolarization produced 0.5, 4.9, 48.2 and 66.8 vs 1.2, 2.5, 27 and 35.4 Hz for control in the 4 different Ca concentrations. Bimodal and unimodal MEPP amplitude were present at both slow and fast nerve terminals. However, depolarization increased the percentage of bimodal MEPP amplitude in STZ-D compared to control (p<0.01) mice in EDL but not soleus. The results revealed that these changes in muscle firing pattern may provide a protective effect against diabetes-induced neuropathy at the neuromuscular junction.
Cell Mol Biol (Noisy-le-grand) 1999 Mar
PMID:Depolarization affects neuromuscular junction of streptozotocin-diabetic mice. 1023 Jul 36

Background: Charcot-Marie-Tooth disease, type 1A (CMT,1A) is a common autosomal dominant neuromuscular disorder, which affects both motor and sensory function and is characterized usually by duplication of a region on chromosome 17 through unequal crossover. As a result, affected patients carry three copies of this region. Individuals inheriting the other deleted chromosome involved in the crossover have one copy of the region and manifest herditary neuropathy with susceptibility to pressure palsies (HNPP). One diagnostic approach to CMT,1A exploits Southern blot hybridization and the relative intensity for three polymorphic MspI restriction fragment lenth polymorphism bands within the duplicated area to judge whether patients have two or three copies of this region using a probe such as VAW409R3A. This is usually straightfoward and works well for the majority of samples that display polymorphisms. However, it is difficult to judge dosage for this region in patients who do not demonstrate polymorphic bands. Methods and Results: An assay has been developed in which a simultaneously hybridized probe (pH15), which detects a nonpolymorphic band on chromosome 22 generated by the same restriction enzyme used to digest genomic DNA, is used to normalize the signal from the CMT,1A probe after phosphorimager analysis. Normalized ratios for VAW409R3A-hybridizing Southern bands fell within discrete ranges for patients with three copies (2.72-3.69), two copies (1.60-2.40) and one copy (0.75-1.30) of this region in over 45 patient and control samples studied. Conclusions: This assay appears to provide a reliable and consistent method of analysis.
Mol Diagn 1996 Jun
PMID:Normalized Southern Hybridization to Enhance Testing for Charcot-Marie-Tooth Disease, Type 1A. 1033 Jan 99


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