Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Adult female rats received a constant i.v. infusion of oleoyl-estrone (3.5 pmol/kg day) in a lipidic suspension for 14 days. On days 0 (no treatment), 3, 6, 10 and 14, as well as on day 14 for controls (receiving only the lipid); the rats were killed and the expression of the beta1-, beta2- and beta3-adrenoceptor genes, in brown adipose tissue and in subcutaneous and periovaric white adipose tissue, were measured by RNA protection assay, and compared with that of cyclophyllin. The beta3-adrenoceptor was the most expressed in all adipose tissues, whereas beta2 was the less expressed in brown adipose tissue. Oleoyl-estrone significantly, but moderately, increased the expression of beta-adrenoceptors in the three adipose tissues: beta1 increased in subcutaneous, beta2 and beta3 in periovaric and beta3 in brown adipose tissue. Oleoyl-estrone also decreased beta3 expression in subcutaneous white adipose tissue. On day 10, adipocytes isolated from periovaric white adipose tissue of oleoyl-estrone-treated rats showed higher cAMP response to an isoproterenol challenge than the controls. The mechanism by which oleoyl-estrone elicits the wasting of fat reserves could be mediated by adrenergic pathways, at least in part.
Mol Cell Biochem 2001 May
PMID:Effect of oleoyl-estrone treatment on the expression of beta1- beta2- and beta3-adrenoreceptors in rat adipose tissues. 1150 72

Here, we describe a novel spontaneous autosomal recessive mutation in the mouse that is characterized by skeletal and cardiac muscle degeneration. We have named this mutant degenerating muscle (dmu). At birth, mutant mice are indistinguishable from their normal littermates. Thereafter, the disease progresses rapidly and a phenotype is first observed at approximately 11 days after birth; the dmu mice are weak and have great difficulty in moving. The principal cause of the lack of mobility is muscle atrophy and wasting in the hindquarters. Affected mice die at or around the time of weaning of unknown causes. Histopathological observations and ultrastructural analysis revealed muscle degeneration in both skeletal and cardiac muscle, but no abnormalities in sciatic nerves. Using linkage analysis, we have mapped the dmu locus to the distal portion of mouse chromosome 15 in a region syntenic to human chromosome 12q13. Interestingly, scapuloperoneal muscular dystrophy (SPMD) in humans has been linked to this region. SPMD patients with associated cardiomyopathy have also been described in the past. Initial analysis of candidate genes on mouse chromosome 15 reveal that although intact transcripts for Scn8a, the gene encoding the sodium channel 8a subunit, are present in dmu mice, their levels are dramatically reduced. Furthermore, genetic complementation crosses between dmu and med (mutation in Scn8a) mice revealed that they are allelic. Our results suggest that at least a portion of the dmu phenotype is caused by a down-regulation of Scn8a, making dmu a new allele of Scn8a.
Hum Mol Genet 2001 Aug 15
PMID:Pathological and genetic analysis of the degenerating muscle (dmu) mouse: a new allele of Scn8a. 1153 91

Charcot-Marie-Tooth disease (CMT) is characterized by distal muscle weakness and wasting, often resulting in foot deformities and gait disturbances, distal sensory impairment and by more or less typical changes in sural nerve biopsy. CMT type 1 is also characterized by reduced nerve conduction velocities. For these demyelinating subtypes, most frequently a 1.5 Mb tandem duplication in chromosome 17p11.2-12 comprising the gene for the peripheral myelin protein 22 (PMP22) is observed (CMT1A), but point mutations in PMP22 have also rarely been reported. X-linked, dominant CMTX1 disease is the second most common type of these hereditary motor and sensory neuropathies (HMSN). Mutations in the X chromosomal gene Connexin32 (Cx32) synonymous gap junction beta-1 (GJB1) are detectable in most X-linked CMT families. We report a novel missense mutation--Tyr65His--in the first extracelullar domain of the Cx32 gene in a Czech CMTX1 family. The mutation was not detectable in 50 healthy controls. The clinical phenotype in both the male proband and his mother was moderate with pronounced peroneal weakness and foot drop. Nerve conduction velocities were intermediately decreased (31-38 m/s) in both patients and slowing of central acoustic conduction (BAEP) was found in both the son and the mother whereas visual central conduction slowing (VEP) was detectable only in the son.
Int J Mol Med 2001 Oct
PMID:Charcot-Marie-Tooth type X: A novel mutation in the Cx32 gene with central conduction slowing. 1156 88

The purpose of this study was to modify the amount of 22:4 n-6, 22:5 n-6 and 20:5 n-3 in cardiac phospholipids and to evaluate the influence of these changes on the functioning of working rat hearts and mitochondrial energy metabolism under normoxic conditions and during postischemic reperfusion. The animals were fed one of these four diets: (i) 10% sunflower seed oil (SSO); (ii) 10% SSO + 1% cholesterol; (iii) 5% fish oil (FO, EPAX 3000TG, Pronova) + 5% SSO; (iv) 5% FO + 5% SSO + 1% cholesterol. Feeding n-3 PUFA decreased n-6 PUFA and increased n-3 PUFA in plasma lipids. In the phospholipids of cardiac mitochondria, this dietary modification also induced a decrease in the n-6/n-3 PUFA ratio. Cholesterol feeding induced marked hepatic steatosis (HS) characterized by the whitish appearance of the liver. It also brought about marked changes in the fatty acid composition of plasma and mitochondrial phospholipids. These changes, characterized by the impairment of deltaS- and delta6-desaturases, were more obvious in the SSO-fed rats, probably because of the presence of the precursor of the n-6 family (linoleate) in the diet whereas the FO diet contained large amounts of eicosapentaenoic and docosahexaenoic acids. In the mitochondrial phospholipids of SSO-fed rats, the (22:4 n-6 + 22:5 n-6) to 18:2 n-6 ratio was decreased by HS, without modification of the proportion of 20:4 n-6. In the mitochondrial phospholipids of FO-fed rats, the amount of 20:5 n-3 tended to be higher (+56%). Cardiac functioning was modulated by the diets. Myocardial coronary flow was enhanced by HS in the SSO-fed rats, whereas it was decreased in the FO-fed animals. The rate constant k012 representing the activity of the adenylate kinase varied in the opposite direction, suggesting that decreased ADP concentrations could cause oxygen wasting through the opening of the permeability transition pore. The recovery of the pump function tended to be increased by n-3 PUFA feeding (+22%) and HS (+45%). However, the release of ascorbyl free radical during reperfusion was not significantly modified by the diets. Conversely, energy production was increased by ischemia/reperfusion in the SSO group, whereas it was not modified in the FO group. This supports greater ischemia/reperfusion-induced calcium accumulation in the SSO groups than in the FO groups. HS did not modify the mitochondrial energy metabolism during ischemia/reperfusion. Taken together, these data suggest that HS- and n-3 PUFA-induced decrease in 22:4 and 22:5 n-6 and increase in 20:5 n-3 favor the recovery of mechanical activity during post-ischemic reperfusion.
Mol Cell Biochem 2001 Aug
PMID:Effects of dietary polyunsaturated fatty acids and hepatic steatosis on the functioning of isolated working rat heart under normoxic conditions and during post-ischemic reperfusion. 1169 87

Increased whole-body proteolysis with muscle protein net degradation has been suggested as one of the causes of weight loss in patients infected with human immunodeficiency virus (HIV). We studied the exchange rates of amino acids and energy substrates across the lower extremity in 16 HIV patients and 16 age-matched controls with similar body cell mass. The patients had either opportunistic infections or chronic diarrhea but no signs of clinical malnutrition. The following findings were obtained in the HIV patients: an augmented peripheral net release of arginine and lysine; an increase in both the negative arterial-venous difference and the efflux of the nitrogen contained in nonmetabolized amino acids; diminished export of 3-methylhistidine; lowered plasma and erythrocyte amino acid concentrations; reduced output of glycerol and furthermore; and neither a net release nor a net uptake of free fatty acids. The findings concerning nitrogen metabolism support the hypothesis that, in the presence of a reduction in protein breakdown, peripheral protein synthesis is severely depressed, making a slow protein wasting process likely to occur. The balances of glycerol and free fatty acids are due not only to the leg tissues but perhaps also in part to increased net retention of these substrates by skeletal muscle.
J Mol Med (Berl) 2001 Nov
PMID:Flux of amino acids and energy substrates across the leg in weight-stable HIV-infected patients with acute opportunistic infections: indication of a slow protein wasting process. 1171 71

The autosomal dominant mutation causing myotonic dystrophy (DM1) is a CTG repeat expansion in the 3'-UTR of the DM protein kinase (DMPK) gene. This multisystemic disorder includes myotonia, progressive weakness and wasting of skeletal muscle and extramuscular symptoms such as cataracts, testicular atrophy, endocrine and cognitive dysfunction. The mechanisms underlying its pathogenesis are complex. Recent reports have revealed that DMPK gene haploinsufficiency may account for cardiac conduction defects whereas cataracts may be due to haploinsufficiency of the neighboring gene, the DM-associated homeobox protein (DMAHP or SIX5) gene. Furthermore, mice expressing the CUG expansion in an unrelated mRNA develop myotonia and myopathy, consistent with an RNA gain of function. We demonstrated that transgenic mice carrying the CTG expansion in its human DM1 context (>45 kb) and producing abnormal DMPK mRNA with at least 300 CUG repeats, displayed clinical, histological, molecular and electrophysiological abnormalities in skeletal muscle consistent with those observed in DM1 patients. Like DM1 patients, these transgenic mice show abnormal tau expression in the brain. These results provide further evidence for the RNA trans-dominant effect of the CUG expansion, not only in muscle, but also in brain.
Hum Mol Genet 2001 Nov 01
PMID:Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. 1172 59

Autosomal dominant medullary cystic kidney disease (ADMCKD) is an adult-onset heterogeneous genetic nephropathy characterized by salt wasting and end-stage renal failure. The gene responsible for ADMCKD-1 was mapped on chromosome 1q21 and it is flanked proximally by marker D1S498 and distally by D1S2125, encompassing a region of approximately 8 cm. Within this region there are a large number of transcribed genes including NPR1 that encodes the atrial natriuretic peptide receptor 1. This receptor plays a crucial role in regulation of blood pressure by facilitating salt excretion. Based on its function we hypothesized this gene as a reasonable candidate for the MCKD1 locus. DNA mutation screening was performed on the entire NPR1 gene-coding sequence and some of the 5' prime-UTR and 3'-UTR sequences. The samples investigated belonged to patients of five large ADMCKD-1 Cypriot families. The screening revealed two novel polymorphisms, one intragenic at amino acid position 939, which was occupied by either arginine or glutamine, and a second one located in the 3' prime-UTR, 29 nucleotides downstream of the NPR1 stop codon. The latter was a single nucleotide C insertion/deletion in a stretch of three or four Cs. No relationship was present between any allele of the two polymorphisms and the disease, as both alleles were observed in both affected and healthy subjects. In addition, no association was observed between the disease and another rare 8-bp deletion polymorphism at the 5' prime-UTR of NPR1 and the disease. Based on these findings it is unlikely that NPR1 is the same as the MCKD1 gene, although it is presently unknown whether it plays a disease modifying role.
Mol Cell Probes 2001 Dec
PMID:Novel NPR1 polymorphic variants and its exclusion as a candidate gene for medullary cystic kidney disease (ADMCKD) type 1. 1185 79

Duchenne muscular dystrophy is a debilitating muscle-wasting disease caused by mutations in the dystrophin gene - one of the largest genes identified thus far - and which ultimately results in premature death. With no current treatment available, the hopes of many sufferers lie in the establishment of an effective gene therapy. The adeno-associated virus is now emerging as a premium gene transfer vector eliciting minimal immune response from the host and allowing for long-term gene expression. It is the scope of this review to examine the recent efforts that have been made to develop ultra-truncated versions of the dystrophin gene that retain functionality, yet can still be cloned into recombinant adeno-associated viral vectors and other low-capacity vector systems.
Curr Opin Mol Ther 2002 Aug
PMID:The future of Duchenne muscular dystrophy gene therapy: shrinking the dystrophin gene. 1222 72

Clinically, celiac disease has always been regarded as a wasting, malabsorptive disorder due to disease of the small intestinal mucosa. It has been difficult for clinicians to recognize that this condition is primarily due to sensitization of mesenteric T lymphocytes to wheat protein (gluten) in genetically predisposed (DQ2+) individuals. On contact with dietary-derived gluten in the upper intestine, these sensitized T lymphocytes are activated leading to inflammation of and morphologically altered mucosal architecture: the latter reverts to normal with a gluten-free diet. The circulation of sensitized T lymphocytes to other parts of the intestinal mucosa explains why identical immunopathological inflammation can be induced in ileal and rectal mucosa. It appears, then, that in predisposed DQ2+ subjects, mesenteric T lymphocytes recognize gluten as foreign (non-self) antigen, thereby inducing mucosal pathology secondary to the initiating lymphocyte-protein interaction, analogously to the mucosal lesions that typify graft-vs-host reactions, or nematode or Giaraia infestations. Today, as this article describes, we recognize that celiac disease often exists in a subclinical, or "compensated-latent," form, or with symptoms that do not immediately suggest an origin in the gastrointestinal tract.
Mol Biotechnol 2002 Nov
PMID:Celiac disease. 1244 83

Dorsoventral patterning depends on the local concentrations of the morphogens. Twisted gastrulation (TSG) regulates the extracellular availability of a mesoderm inducer, bone morphogenetic protein 4 (BMP-4). However, TSG function in vivo is still unclear. We isolated a TSG cDNA as a secreted molecule from the mouse aorta-gonad-mesonephros region. Here we show that TSG-deficient mice were born healthy, but more than half of the neonatal pups showed severe growth retardation shortly after birth and displayed dwarfism with delayed endochondral ossification and lymphopenia, followed by death within a month. TSG-deficient thymus was atrophic, and phosphorylation of SMAD1 was augmented in the thymocytes, suggesting enhanced BMP-4 signaling in the thymus. Since BMP-4 promotes skeletogenesis and inhibits thymus development, our findings suggest that TSG acts as both a BMP-4 agonist in skeletogenesis and a BMP-4 antagonist in T-cell development. Although lymphopenia in TSG-deficient mice would partly be ascribed to systemic effects of runtiness and wasting, our findings may also provide a clue for understanding the pathogenesis of human dwarfism with combined immunodeficiency.
Mol Cell Biol 2003 Apr
PMID:Mammalian twisted gastrulation is essential for skeleto-lymphogenesis. 1266 93


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