[17,20-Desmolase deficiency].
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Aldehyde-Lyases↗
Biomedical subjects
T Yanase
Publications and source records attributed to T Yanase.
[The role of endothelin in adrenal medulla: identification of endothelin and its receptor in two cases of pheochromocytoma].
To clarify the role of a novel vasoactive peptide endothelin in endocrine hypertension, we examined endothelin (ET)-like immunoreactivity and the ET binding sites in the tissues of two pheochromocytoma. Case 1 was a 25-year-old woman who manifested multiple endocrine neoplasia (MEN) II b with left adrenal pheochromocytoma, and case 2 was a 48-year-old woman with familial bilateral pheochromocytoma. In both cases, fairly high amount of ET-like immunoreactivity was detected in the resected tumors. By competitive binding analysis, high affinity binding sites for 125I-ET-1 were also detected in the same resected tissues. Concomitant existence of ET and its receptor suggests that ET may play an important role in these tumors in modulating the secretion of catecholamines from the tumors by an autocrine/paracrine fashion.
Adrenal Gland Neoplasms↗
Molecular basis of apparent isolated 17,20-lyase deficiency: compound heterozygous mutations in the C-terminal region (Arg(496)----Cys, Gln(461)----Stop) actually cause combined 17 alpha-hydroxylase/17,20-lyase deficiency.
The molecular defect in a reported case of isolated 17,20-lyase deficiency in a 46XY individual has been elucidated. The patient was found to be a compound heterozygote, carrying two different mutant alleles in the CYP17 gene. One allele contains a point mutation of arginine (CGC) to cysteine (TGC) at amino acid 496 in exon 8. The second allele contains a stop codon (TAG) in place of glutamine (CAG) at position 461 in exon 8 which is located 19 amino acids to the carboxy-terminal side of the P-450(17) alpha heme binding cysteine. COS-1 cells transfected with cDNAs containing one or the other of these mutations showed dramatically reduced 17 alpha-hydroxylase and 17,20-lyase activities relative to cells transfected with the wild type P-450(17) alpha cDNA. While the in vitro data in COS 1 cells can explain the patient's physical phenotype, with female external genitalia, it was somewhat discordant with the clinical expression of isolated 17,20-lyase deficiency with relative preservation of 17 alpha-hydroxylase activity in vivo. In addition to the expression studies of these two examples of mutants in the C-terminal region of cytochrome P-450(17) alpha, a third mutant cDNA construct containing a 4-base duplication at codon 480 previously found in patients with combined 17 alpha-hydroxylase/17,20-lyase deficiency was also expressed in COS-1 cells. This expressed protein was completely inactive with respect to both activities, supporting the biochemical findings in serum and in vitro biochemical data obtained using a testis from the patient. The results from these patients clearly indicate the importance of the C-terminal region of human P-450(17) alpha in its enzymatic activities.
Adolescent↗
Molecular cloning, sequence analysis and expression of a cDNA encoding human type-1 angiotensin II receptor.
We isolated a cDNA encoding type-1 angiotensin II receptor from a human liver cDNA library. The cDNA had an open reading frame encoding a protein of 359 amino acid residues with a relative Mr of 41,060. The deduced amino acid sequence of the human angiotensin II (Ang II) receptor was 95.3% and 94.2% identical to those of bovine and rat type-1 Ang II receptors, respectively, and had a significant similarity with the G protein-coupled receptor. The rank order of the binding to the receptor expressed in COS-7 cells was Ang II greater than Ang III greater than Ang I. The expression of the Ang II receptor mRNA was detected in human liver, lung, adrenal and adrenocortical adenomas but not in adrenomedullary tumor, pheochromocytoma, by Northern blot analysis.
Amino Acid Sequence↗
Canadian Mennonites and individuals residing in the Friesland region of The Netherlands share the same molecular basis of 17 alpha-hydroxylase deficiency.
A common mutation within the CYP17 gene that causes 17 alpha-hydroxylase deficiency, a form of congenital adrenal hyperplasia, has been found by direct sequencing of polymerase chain reaction (PCR) fragments of genomic DNA from six families residing in the Friesland region of the Netherlands. The mutation is a 4-base duplication within exon 8 of the CYP17 gene, which alters the reading frame encoding the C-terminal 26 amino acids of cytochrome P45017 alpha. This mutation has previously been found in two Canadian patients who are members of ostensibly unrelated Mennonite families. The Mennonite Churches derive their name from Menno Simons, an early leader of the sect in Friesland. Presumably this 4-base duplication appeared within the Friesian population prior to emigration of the Mennonites from the Netherlands.
Adrenal Hyperplasia, Congenital↗
Compound heterozygous mutations (Arg 239----stop, Pro 342----Thr) in the CYP17 (P45017 alpha) gene lead to ambiguous external genitalia in a male patient with partial combined 17 alpha-hydroxylase/17,20-lyase deficiency.
17 alpha-Hydroxylase deficiency is characterized by defects in either or both the 17 alpha-hydroxylase/17,20-lyase activities. We have, for the first time, elucidated the molecular basis of the deficiency in a male pseudohermaphrodite with ambiguous external genitalia resulting from partial combined deficiency of both activities. The patient is found to be a compound heterozygote, carrying two different inherited mutant alleles in the cytochrome P45017 alpha (CYP17) gene. One allele, from his mother, contains a stop codon (TGA) in place of arginine (CGA) at amino acid position 239 in exon 4. Because this occurs at the N-terminal side of the heme binding sequence, the putative resultant truncated protein is nonfunctional. The second allele, from his father, contains a missense mutation encoding the substitution of proline (CCA) by threonine (ACA) at position 342 in exon 6. Reconstruction of this mutation by site-directed mutagenesis into human P45017 alpha cDNA followed by expression in COS 1 cells leads to the same amount of immunodetectable P45017 alpha protein as found with expression of the normal P45017 alpha cDNA, although both the 17 alpha-hydroxylase and 17,20-lyase activities are found to be reduced to 40-45% of those of the normal enzyme. The presence of ambiguous external genitalia in this 46 XY individual indicates that greater than 20% of the total normal 17,20-lyase activity is required for complete virilization in the male.
Adrenal Hyperplasia, Congenital↗
A single amino acid substitution (Met786----Val) in the steroid-binding domain of human androgen receptor leads to complete androgen insensitivity syndrome.
Androgen receptors (ARs) in two Japanese siblings with complete androgen insensitivity syndrome were characterized, and their molecular bases were investigated. Androgen binding was undetectable in cultured pubic skin fibroblasts from the patients by whole cell assay. Sequence analysis of exons B-H, which encode the DNA- and steroid-binding domains, of the AR gene from these patients using polymerase chain reaction revealed a single nucleotide substitution in exon F, resulting in an amino acid change at 786 from methionine (ATG) to valine (GTG) within the steroid-binding domain of AR. Reconstruction of this mutation by site-directed mutagenesis into human AR cDNA followed by expression in COS-1 cells led to production of the same amount and the same molecular mass of immunodetectable AR protein as those found with expression of the normal human AR cDNA. However, in contrast to wild-type AR expressed in COS-1 cells, the mutant AR showed markedly low affinity of androgen binding by whole cell assay. These results suggest that androgen resistance in these patients is due to the point mutation in the steroid-binding domain of the AR.
Adult↗
Disordered expression of adrenal steroidogenic P450 mRNAs in incidentally discovered nonfunctioning adrenal adenoma.
In order to elucidate the steroidogenesis of clinically nonfunctioning adrenocortical adenoma, we studied the aldosterone, cortisol (F) and dehydroepiandrosterone (DHEA) content and the expression of mRNA of cytochrome P450 for side chain cleavage (P450scc), 17 alpha-hydroxylase (P450c17). 21-hydroxylase (P450c21) and 11 beta-hydroxylase (P450c11) in four clinically nonfunctioning adrenocortical adenomas discovered incidentally in asymptomatic patients (Cases 1, 2, 3 and 4). The results were compared with those in normal adrenal glands. In the adenomas from cases 1 and 2, the abundance of steroidogenic P450s mRNA were similar to those in normal adrenal glands, except P450c11 mRNA expression in the adenoma from case 1 which was slightly higher than normal. The steroid content was normal level, except for higher F in the adenoma from case 1 and lower aldosterone in case 2 adenoma than normal. The adenoma from case 3 contained much less P450scc, P450c17 and P450c21 mRNA, while the amount of P450c11 mRNA was slightly greater than in normal adrenals. The adenoma showed normal aldosterone, high F and low DHEA content compared with normal adrenal glands. In the adenoma from case 4, the accumulation of all four P450 mRNAs decreased, whereas aldosterone, F and DHEA content in the adenoma was similar to that of normal adrenal glands. These data indicated that nonfunctioning adrenocortical adenoma showed similar or decreased expression of steroidogenic P450 mRNAs that the normal adrenal gland. This decreased expression of steroidogenic P450 mRNAs may be at least partly concerned with the absence of clinical symptoms in patients with nonfunctioning adenoma.
Adenoma↗
Human recombinant activin-A modulates the steroidogenesis of cultured bovine adrenocortical cells.
The effect of human recombinant activin-A on adrenal steroidogenesis was studied in cultured bovine adrenocortical cells. Activin-A significantly reduced cortisol output from ACTH (10nmol/l)-stimulated adrenocortical cells incubated for 24 hours in a dose-dependent manner (10, 100 and 500ng activin-A/ml suppressed cortisol secretion by 19, 33 and 40%), although no significant effect was observed in the case of 3 h incubation. Dehydroepiandrosterone (DHEA) secretion from ACTH-stimulated adrenocortical cells incubated for 24 h was also decreased by the addition of activin-A in a dose-dependent manner. (10, 100 and 500ng activin-A/ml suppressed DHEA secretion by 22, 56 and 58%). These inhibitory effects of activin-A (100ng/ml) on cortisol and DHEA secretion were partially blocked by the addition of follistatin/FSH-Suppressing Protein (200ng/ml). In contrast, activin-A treatment resulted in no significant decrease in aldosterone secretion. There were no significant effects of activin-A on basal secretions of cortisol, DHEA or aldosterone from adrenocortical cells. These results suggest that activin-A has a direct inhibitory effect on ACTH-stimulated bovine adrenocortical steroidogenesis.
Activins↗
[Ward supervisors. My design of home health services for the elderly].
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Aged↗
[Congenital adrenal hyperplasia].
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Adrenal Hyperplasia, Congenital↗
The modification and expression of 21-hydroxylase gene in normal human adrenal gland and adrenal cancer.
Genomic DNA and total RNA from three adrenal cancer tissues were analyzed by hybridization with human 21-hydroxylase gene. Southern blot analysis with restriction enzyme Eco RI revealed major fragments at 18, 13 and 9 kilobase (kb) in normal adrenal glands. In two of three adrenal cancers, however, the band at 18 kb was either absent or decreased and the 9 kb fragment showed an increase in its intensity. Normal liver, kidney and leucocytes has only 18 and 13 kb while lacking the 9 kb fragment. Using Taq I, Bam HI or Bgl II, we found no difference in restriction fragment patterns between adrenal cancer and normal tissues. Cleavage with Hpa II after digestion with Bgl II showed that significantly more DNA was digested into low-molecular weight fragments in adrenal cancer and the normal adrenal gland than those in other normal tissues. By Northern blot analysis, there was difference of signal intensity of hybridizing mRNA between the adrenal cancers and normal adrenal glands. These results suggest that the Eco RI site in the flanking region of the 21-hydroxylase gene may be modified in adrenal cancer tissue, and that inadequate 21-hydroxylase is present in some forms of adrenal cancers.
Adrenal Cortex Hormones↗
17 alpha-hydroxylase/17,20-lyase deficiency: from clinical investigation to molecular definition.
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Adrenal Hyperplasia, Congenital↗
[Effect of endotoxin on plasma angiotensin-converting enzyme in dogs].
We calculated angiotensin converting enzyme (ACE) index (ACE/CO) to exclude the influence of pulmonary perfusion and investigated the relationship among ACE, ACE index, hemodynamic changes in 6 endotoxin dogs. Systemic arterial pressure and cardiac output (CO) decreased significantly after 3 mg.kg-1 of endotoxin administration, but neither pulmonary arterial pressure nor pulmonary arterial wedge pressure changed. Lung wet/dry ratio was higher. Although endotoxin administration caused the pulmonary capillary endothelial damage in this experiment, plasma ACE showed a nonsignificant increase. The main reason may be related to the reduction of surface area of pulmonary capillary endothelial cells caused by the decrease in cardiac output. The increased ACE index lasted for 15 to 90 min and began to return to baseline at 120 min after endotoxin administration. We conclude that ACE index is more useful than plasma ACE as an early marker of the pulmonary capillary endothelial damage induced by endotoxin.
Animals↗
[An operated case of gestational ovarian choriocarcinoma formed a huge abdominal tumor].
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Choriocarcinoma↗
Pressure-supported ventilation for posterior fossa operation.
To maintain enough gas exchange while using spontaneous respiration as a monitor of the normal brainstem function, we tried pressure-supported ventilation (PSV) with a Servo 900C ventilator (Siemens Elema AB, Sweden) on 12 otherwise healthy patients during posterior fossa operation. Ventilation mode was switched from controlled to PSV after the dura was open uneventfully in all cases but one. With a trigger level of -1 to -2 cm H2O, spontaneous respiration was triggered to start the inspiration. With supporting inspiratory pressure of 4-20 cm H2O, PaCO2 was kept at 31.7-45.9 mm Hg. The ventilatory level could be monitored breath by breath by ventilatory frequency, tidal volume, minute volume, and end-tidal CO2 concentration shown on the ventilator system. Apnea was observed in two cases during surgical manipulation around the brainstem. It was indicated immediately by the ventilator's alarm for decreased expiratory minute volume, and no sign of brainstem dysfunction was observed postoperatively. PSV was useful in maintaining adequate ventilation whereas spontaneous respiration was used as an indicator of normal brainstem function. The alarm system of the ventilator was sensitive enough to detect the surgical invasion of the brainstem at a very early stage.
Journal Article↗
Expression of c-fos and c-myc proto-oncogenes in human adrenal pheochromocytomas.
We examined c-fos and c-myc expressions in pheochromocytoma tissues from six patients. All samples contained c-fos and c-myc transcripts, whereas mRNA from bovine adrenal medulla, as a control, did not contain these transcripts at detectable levels. Southern blot analysis revealed no amplification and no rearrangement of c-fos and c-myc genes. We also examined the gene expression of insulin-like growth factor-II (IGF-II), a mitogen for rat pheochromocytoma cells exerted by autocrine or paracrine fashion. All samples from the pheochromocytomas contained IGF-II transcripts as well as c-fos and c-myc transcripts. The constitutive expressions of c-fos and c-myc genes may be interpreted to mean that pheochromocytoma is in a state of growth stimulation in vivo by growth factors, including IGF-II.
Adrenal Gland Neoplasms↗
Combined 17 alpha-hydroxylase/17,20-lyase deficiency due to a 7-basepair duplication in the N-terminal region of the cytochrome P45017 alpha (CYP17) gene.
17 alpha-Hydroxylase deficiency is characterized by defects in either or both of the 17 alpha-hydroxylase/17,20-lyase activities. We have elucidated the molecular basis of the combined deficiency of these activities in a Japanese female who is genotypically male and the child of a consanguineous marriage. The complete exonic sequence of the patient's CYP17 (P45017 alpha) gene revealed a seven-basepair duplication (GCGCACA) in exon 2 which leads to a frame shift and, subsequently, a premature stop codon. Because this stop codon occurs N-terminal to the heme-binding sequence, the presence of this mutation leads to the absence of a functional P45017 alpha-protein in adrenal cortex and testis. This, in turn, leads to an absence of sex steroids and excessive secretion of steroids with mineralocorticoid activity and, consequently, female external genitalia and hypertension in this 46XY patient.
Adolescent↗