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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The diagnostic term congenital adrenal hyperplasia (CAH) applies to a family of inherited disorders of steroidogenesis caused by an abnormality in one of the five enzymatic steps necessary in the conversion of cholesterol to cortisol. The enzyme defects are translated as autosomal recessive traits, with the enzyme deficient in more than 90% of CAH cases being 21-hydroxylase. In the classical forms of CAH (simple virilizing and salt wasting), owing to 21-hydroxylase deficiency (21-OHD), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Non-classical 21-OHD (NC21OHD) refers to the condition in which partial deficiencies of 21-hydroxylation produce less extreme hyperandrogenemia and milder symptoms. Females do not demonstrate genital ambiguity at birth. The gene for adrenal 21-hydroxylase, CYP21, is located on chromosome 6p in the area of HLA genes. Specific mutations may be correlated with a given degree of enzymatic compromise and the clinical form of 21-OHD. NC21OHD patients are predicted to have mild mutations on both alleles or one severe and one mild mutation of the 21-OH locus (compound heterozygote). In most cases the mutation groups represent one diagnosis (e.g., Del/Del with SW CAH), however we have found several non-correlations of genotype to phenotype. Non-classical and classical patients were found within the same mutation group. Phenotypic variability within each mutation group has important implications for prenatal diagnosis and treatment. Prenatal treatment of 21-OHD with dexamethasone has been utilized for a decade. An algorithm has been developed for prenatal diagnosis and treatment, which, when followed closely, has been safe for both the mother and the fetus, and has been effective in preventing ambiguous genitalia in the affected female newborn. This is an instance of an inborn metabolic error successfully treated prenatally. Since 1986, prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) has been carried out in 403 pregnancies in The New York Hospital Cornell Medical Center. In 280, diagnoses were made by amniocentesis, while 123 were diagnosed using chorionic villus sampling. Of the 403 pregnancies evaluated, 84 babies were affected with classical 21-OHD. Of these, 52 were females, 36 of whom were treated prenatally with dexamethasone. Dexamethasone administered at or before 10 weeks of gestation (23 affected female fetuses) was effective in reducing virilization. Thirteen cases had affected female sibs (Prader stages 1-4); 6 of these fetuses were born with entirely normal female genitalia, while 6 were significantly less virilized (Prader stages 1-2) than their sibs, and one was Prader stage 3. Eight newborns had male sibs: 4 were born with normal genitalia, 3 were Prader stages 1-2, and 3 were born Prader stages 3-4. No significant or enduring side effects were noted in either the mothers or the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight, length, or head circumference from untreated, unaffected newborns. Based on our experience, proper prenatal diagnosis and treatment of 21-OHD is effective in significantly reducing or eliminating virilization in the newborn female. This spares the affected female the consequences of genital ambiguity of genital surgery, sex misassignment, and gender confusion.
J Steroid Biochem Mol Biol
PMID:Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. 1041 77

Androgens have significant and varied actions in women and there is now acknowledgment that women may experience symptoms secondary to androgen deficiency. There is also substantial evidence that prudent androgen replacement can be effective in relieving both the physical and psychological symptoms of androgen insufficiency, and is indicated for clinically affected women. Testosterone replacement for women is now available in a variety of formulations. It appears to be safe, with the caveat that doses are restricted to the 'therapeutic' window for androgen replacement in women, such that the beneficial effects on wellbeing and quality of life are achieved without incurring undesirable virilizing side effects. The predominant symptom of women with androgen deficiency is loss of sexual desire. This is not limited to women experiencing a surgical menopause but may also be a feature of women who have either undergone premature or natural menopause. There is increasing interest in other uses of androgen replacement in women that include premenopausal iatrogenic androgen deficiency states, glucocorticosteroid-induced bone loss, management of wasting syndromes and possibly premenopausal bone loss, premenopausal loss of libido and the treatment of the premenstrual syndrome.
J Steroid Biochem Mol Biol
PMID:The therapeutic use of androgens in women. 1041 91

Arterial blood pressure is critically dependent on sodium balance. The kidney is the key player in maintaining sodium homeostasis. Aldosterone-dependent epithelial sodium transport in the distal nephron is mediated by the highly selective, amiloride-sensitive epithelial sodium channel (ENaC). Direct evidence that dysfunction of ENaC participates in blood pressure regulation has come from the molecular analysis of two human genetic diseases, Liddle's syndrome and pseudohypoaldosteronism type 1 (PHA-1). Both, increased sodium reabsorption despite low aldosterone levels in Liddle's patients and decreased sodium reabsorption despite high aldosterone levels in PHA-1 patients, demonstrated that ENaC is an effector for aldosterone action. Gene-targeting and classical transgenic technology enable the generation of mouse models for these diseases and the analysis of the involvement of the epithelial sodium channel (ENaC) in the progress of these diseases. A first mouse model using alphaENaC transgenic knockout mice [alphaENaC(-/-)Tg] mimicked several clinical features of PHA-1, like salt-wasting, metabolic acidosis, high aldosterone levels, growth retardation and increased early mortality. Such mouse models will be necessary in testing the involvement of genetic and/or environmental factors like salt-intake in hypertension.
J Steroid Biochem Mol Biol
PMID:Implication of ENaC in salt-sensitive hypertension. 1041 16

Extracellular phosphate concentrations are maintained by coordinated regulation of specific homeostatic mechanisms. A novel gene, the type IIb sodium-phosphate cotransporter (Npt2b), was recently cloned and is expressed within intestinal tissues, indicating that the transporter may be an important regulator of phosphate reabsorption. Another gene, human stanniocalcin-2 (STC2), was previously shown to decrease phosphate uptake into kidney cells in vitro. Because of the important role that STC2 may play in phosphate homeostasis, we considered the peptide hormone a candidate for the phosphate wasting disease autosomal dominant hypophosphatemic rickets (ADHR), previously localized to chromosome 12p13. The purpose of our study was to determine the chromosomal localization of human NPT2b and STC2. In the present work, NPT2b was localized to human chromosome 4p15-p16, and STC2 to 5q33-tel. Because STC2 did not map to 12p13, the hormone was excluded as the ADHR gene, however it should be considered a candidate for other diseases involving phosphate homeostasis.
Somat Cell Mol Genet 1998 Nov
PMID:Chromosomal localization of two human genes involved in phosphate homeostasis: the type IIb sodium-phosphate cotransporter and stanniocalcin-2. 1076 14

Environmental, congenital, and acquired immunological insults perturbing neuromuscular junction (NMJ) activity may induce a variety of debilitating neuromuscular pathologies. However, the molecular elements linking NMJ dysfunction to long-term myopathies are unknown. Here, we report dramatically elevated levels of mRNA encoding c-Fos and the "readthrough" (R) variant of acetylcholinesterase (AChE) in muscles of transgenic mice overexpressing synaptic (S) AChE in motoneurons and in control mice treated with the irreversible cholinesterase inhibitor diisopropylfluorophosphonate (DFP). Tongue muscles from DFP-treated and AChE-S transgenic mice displayed exaggerated neurite branching and disorganized, wasting fibers. Moreover, diaphragm muscles from both transgenic and DFP-treated mice exhibited NMJ proliferation. 2'-O-methyl-protected antisense oligonucleotides targeted to AChE mRNA suppressed feedback upregulation of AChE and ameliorated DFP-induced NMJ proliferation. Our findings demonstrate common transcriptional responses to cholinergic NMJ stress of diverse origin, and implicate deregulated AChE expression in excessive neurite outgrowth, uncontrolled synaptogenesis, and myopathology.
J Mol Neurosci
PMID:Synaptogenesis and myopathy under acetylcholinesterase overexpression. 1085 41

Previously we reported carbon tetrachloride-induced body weight loss in rats as a new model of wasting disorders. The oral administration of a low dose of carbon tetrachloride to rats reduced the body weight and food intake at 24 h with a minimal effect on plasma alanine aminotransferase activity. Tumor necrosis factor-alpha, and cyclooxygenase-1 and -2 mRNA expression in the brain was not affected by carbon tetrachloride. Zaltoprofen, which is a non-steroidal anti-inflammatory drug, prevented the carbon tetrachloride-induced body weight decrease, without preventing the carbon tetrachloride-induced loss of food intake. The present results suggest the possible application of this drug for the treatment of wasting disorders.
Int J Mol Med 2001 Jan
PMID:Zaltoprofen prevents carbon tetrachloride-induced reduction of body weight in rats. 1111 17

Administration of exogenous Ach to isolated in situ saline-perfused hearts of Anguilla australis via the perfusate, resulted in reduction in cardiac frequency (F). This reduction in F became significant at Ach concentrations of 10(-11) M or greater. A weak inotropic effect of Ach at the lowest concentration tested (10(-13) M) was also observed. Maximum power output of preparations was 2.94+/-0.26 mW gVM(-1). The mechanical efficiency of A. australis hearts working at 25 and 50% of maximum power under different conditions of stroke volume (SV) and F was investigated. Cardiac frequency was manipulated using a combination of temperature and Ach administration. Stroke volume was manipulated by regulating input pressure of the perfusate supplying the preparations (pre-load). Values of MEF from preparations generating flow under conditions of low F/ high SV (treated with Ach 10(-7) M) were significantly greater than under conditions of high F/ low SV (untreated). The MEF of preparations appears to be related to inotropic state. The negative inotropy and increased mechanical efficiency produced by Ach appears to be the opposite of the so-called 'oxygen-wasting' effect produced by the positive inotropic agents, the catecholamines. This effect of Ach may be related to the dependence of teleost myocardium on extracellular Ca(2+) for excitation-contraction coupling during the cardiac cycle.
Comp Biochem Physiol A Mol Integr Physiol 2001 Jan
PMID:Mechanical efficiency of isolated in situ perfused hearts of the eel Anguilla australis. 1113 49

In an effort to characterize the basis of abnormalities in body weight regulation (i.e. wasting) in Huntington's disease (HD), we examined adipocytes in a transgenic model of HD, the R6/2 mouse. These mice typically show severe wasting beginning at approximately 12 weeks of age and die between 12 and 15 weeks. Despite an overall growth retardation compared with wild-type littermates, we observed an enhanced accumulation of body fat at 8-9 weeks of age in R6/2 mice fed laboratory chow or a synthetic high fat, high sugar diet. The obesity was not accompanied by symptoms associated with diabetes, as there were no abnormalities in serum glucose, serum insulin or the ability of insulin to stimulate glucose metabolism in epididymal adipose tissue. As expected, the obesity in the high fat, high sugar-fed R6/2 mice was accompanied by increased serum leptin. The ability of insulin to stimulate leptin release from isolated epididymal adipose tissue was also enhanced in R6/2 mice. In contrast, the ability of isoproterenol to inhibit leptin release was reduced in adipose tissue from R6/2 mice, as was the lipolytic effect of isoproterenol. These data suggest that the obesity observed at 8-9 weeks in R6/2 mice may stem from a defect in fat breakdown by adipocytes.
Hum Mol Genet 2001 Jan 15
PMID:Abnormalities in the functioning of adipocytes from R6/2 mice that are transgenic for the Huntington's disease mutation. 1115 62

Growth hormone (GH) treatment causes salt and water retention, and this effect has been suggested to be mediated by activation of epithelial sodium channel (ENaC). Multi-system pseudohypoaldosteronism (PHA) is a salt wasting disease resulting from mutations in ENaC subunit genes. We examined effects of GH therapy for 12-21 months on the renin-angiotensin-aldosterone system (RAAS) in 12 children with idiopathic short stature (ISS) and a PHA patient with defective ENaC function and concomitant GH deficiency. On GH therapy (0.7 U/kg/week), plasma renin activity (PRA), serum aldosterone and insulin-like growth factor-I (IGF-I) levels were periodically determined every 1-3 months in all children. The PHA patient was studied for 6 yr during which time serum, urine, and sweat electrolytes and secretion rate were also examined before, on and off GH therapy. In the PHA patient, mean plasma aldosterone concentration, 7.7 nmol/l (278 ng/dl) before therapy (n=9) rose to 73 nmol/l (2650 ng/dl) 10 months after GH. PRA and IGF-I increased similarly, reaching a plateau between 8 and 12 months. Off GH, there was a decrease to pretreatment levels in 30 months. Aldosterone and PRA strongly correlated with IGF-I (r=0.66 and 0.67). GH therapy also improved the growth rate, and increased both sweat secretion rate and Na(+)/K(+) ratio. In children with ISS, aldosterone and IGF-I peaked 6-12 months after GH. Off GH their levels normalized in 3 months. These findings indicate that long-term GH activates the RAAS in both children with ISS and a PHA patient, and that this effect does not depend on a fully functional ENaC.
J Steroid Biochem Mol Biol 2001 Apr
PMID:Growth hormone activates renin-aldosterone system in children with idiopathic short stature and in a pseudohypoaldosteronism patient with a mutation in epithelial sodium channel alpha subunit. 1135 74

Thyroid hormones have some actions that might be useful therapeutically, but others that are deleterious. Potential therapeutically useful actions include those to induce weight loss and lower plasma cholesterol levels. Potential deleterious actions are those on the heart to induce tachycardia and arrhythmia, on bone to decrease mineral density, and on muscle to induce wasting. There have been successes in selectively modulating the actions of other classes of hormones through various means, including the use of pharmaceuticals that have enhanced affinities for certain receptor isoforms. Thus, there is reason to pursue selective modulation of thyroid hormone receptor (TR) function, and several agents have been shown to have some beta-selective, hepatic selective and/or cardiac sparring activities, although development of these was largely not based on detailed understanding of mechanisms for the specificity. The possibility of selectively targeting the TRbeta was suggested by the findings that there are alpha- and beta-TR forms and that the TRalpha-forms may preferentially regulate the heart rate, whereas many other actions of these hormones are mediated by the TRbeta. We determined X-ray crystal structures of the TRalpha and TRbeta ligand-binding domains (LBDs) complexed with the thyroid hormone analog 3,5,3'-triiodithyroacetic acid (Triac). The data suggested that a single amino acid difference in the ligand-binding cavities of the two receptors could affect hydrogen bonding in the receptor region, where the ligand's 1-position substituent fits and might be exploited to generate beta-selective ligands. The compound GC-1, with oxoacetate in the 1-position instead of acetate as in Triac, exhibited TRbeta-selective binding and actions in cultured cells. An X-ray crystal structure of the GC-1-TRbeta LBD complex suggests that the oxoacetate does participate in a network of hydrogen bonding in the TR LBD polar pocket. GC-1 displayed actions in tadpoles that were TRbeta-selective. When administered to mice, GC-1 was as effective in lowering plasma cholesterol levels as T(3), and was more effective than T(3) in lowering plasma triglyceride levels. At these doses, GC-1 did not increase the heart rate. GC-1 was also less active than T(3) in modulating activities of several other cardiac parameters, and especially a cardiac pacemaker channel such as HCN-2, which may participate in regulation of the heart rate. GC-1 showed intermediate activity in suppressing plasma thyroid stimulating hormone (TSH) levels. The tissue/plasma ratio for GC-1 in heart was also less than for the liver. These data suggest that compounds can be generated that are TR-selective and that compounds with this property and/or that exhibit selective uptake, might have clinical utility as selective TR modulators.
J Steroid Biochem Mol Biol
PMID:Selective modulation of thyroid hormone receptor action. 1138 61


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