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Titolo:
Genetic analysis of the cytochrome P-450c17 alpha (CYP17) and aldosterone synthase (CYP11B2) in Japanese patients with 17 alpha-hydroxylase deficiency
Autore:
Takeda, Y; Yoneda, T; Demura, M; Furukawa, K; Koshida, H; Miyamori, I; Mabuchi, H;
Indirizzi:
Kanazawa Univ, Sch Med, Dept Internal Med 2, Kanazawa, Ishikawa 920, JapanKanazawa Univ Kanazawa Ishikawa Japan 920 , Kanazawa, Ishikawa 920, Japan Kanazawa Univ, Sch Med, Dept Hlth Sci, Kanazawa, Ishikawa 920, Japan Kanazawa Univ Kanazawa Ishikawa Japan 920 , Kanazawa, Ishikawa 920, Japan Fukui Med Sch, Dept Internal Med 3, Fukui 91011, Japan Fukui Med Sch Fukui Japan 91011 Dept Internal Med 3, Fukui 91011, Japan Koseiren Takaoka Hosp, Takaoka, Toyama, Japan Koseiren Takaoka Hosp Takaoka Toyama Japan Hosp, Takaoka, Toyama, Japan
Titolo Testata:
CLINICAL ENDOCRINOLOGY
fascicolo: 6, volume: 54, anno: 2001,
pagine: 751 - 758
SICI:
0300-0664(200106)54:6<751:GAOTCP>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
ISOLATED 17,20-LYASE DEFICIENCY; P450SCC 20,22-DESMOLASE; II DEFICIENCY; P450C17; MUTATION; CORTICOSTERONE; EXPRESSION; HYPERALDOSTERONISM; BIOSYNTHESIS; DISORDERS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Takeda, Y Kanazawa Univ, Sch Med, Dept Internal Med 2, 13-1 Takara Machi, Kanazawa, Ishikawa 920, Japan Kanazawa Univ 13-1 Takara Machi Kanazawa Ishikawa Japan 920 apan
Citazione:
Y. Takeda et al., "Genetic analysis of the cytochrome P-450c17 alpha (CYP17) and aldosterone synthase (CYP11B2) in Japanese patients with 17 alpha-hydroxylase deficiency", CLIN ENDOCR, 54(6), 2001, pp. 751-758

Abstract

OBJECTIVE To determine the clinical and molecular genetic characterizationof two Japanese patients with 17 alpha -hydroxylase deficiency, we analysed the 17 alpha -hydroxylase/17,20-lyase gene (CYP17). Next, to clarify the mechanism of hypoaldosteronism in 17 alpha -hydroxylase deficiency, we analysed the expression of aldosterone synthase (CYP11B2) messenger RNA and sequenced CYP11B2 in these patients. PATIENTS Patient 1 (46 XY), phenotypically female, sought medical attention for hypertension, amenorrhea and infantile genitalia. Patient 2 (46 XX), phenotypically female, presented for hypertension and amenorrhea, Hormonal data in both patients showed decreased levels of sex steroids, cortisol, aldosterone and plasma renin activity and extreme elevation of deoxycortisol. DESIGN Direct sequencing of CYP17 and CYP11B2 was performed using genomic DNA from the patients. An expression studies of mutated forms of CYP17 was performed using COS-1 cells. The expression of CYP11B2 messenger RNA in mononuclear leucocytes (MNLs) of these patients and normal subjects was measured using the competitive polymerase chain reaction method. The effect of renin secretion stimulation on the levels of CYP11B2 messenger RNA in MNLs ofnormal subjects was also studied. RESULTS We detected two novel genetic defects in 17 alpha -hydroxylase. Sequence analysis revealed one base pair deletion (T) at codon 243 in exon 4 in patient 1. CYP17 in patient 2 contained a point mutation (C to T) at position 415 in exon 8. Transfected cells of mutant from patient 1 had no 17 alpha -hydroxylase or 17,20-lyase activity. The R415C mutant protein showed very weak activity of 17 alpha -hydroxylase or 17,20-lyase activity. In therenin secretion stimulating test, the increase in CYP11B2 messenger RNA levels in MNLs was parallel with that of plasma aldosterone concentration. The expression of CYP11B2 mRNA in NMLs of these patients was lower compared to controls. No mutations in CYP11B2, including the 5' flanking region, werefound. CONCLUSIONS These results indicate that the novel mutations of the CYP17 gene found in these patients inactivate cytochrome P450c17 function, and that hypoaldosteronism in these patients may be partly explained by a decreased activity of aldosterone synthase, which is regulated at the transcriptional level.

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Documento generato il 04/12/20 alle ore 16:28:47