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Titolo:
Heterozygous mutation in the cholesterol side chain cleavage enzyme (P450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency
Autore:
Tajima, T; Fujieda, K; Kouda, N; Nakae, J; Miller, WL;
Indirizzi:
Hokkaido Univ, Sch Med N15, Dept Pediat, Sapporo, Hokkaido 0608638, Japan Hokkaido Univ Sapporo Hokkaido Japan 0608638 oro, Hokkaido 0608638, Japan Saitama Childrens Med Ctr, Div Endocrinol & Metab, Iwatsuki, Saitama 3398551, Japan Saitama Childrens Med Ctr Iwatsuki Saitama Japan 3398551 a 3398551, Japan Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA Univ Calif San Francisco San Francisco CA USA 94143 ancisco, CA 94143 USA
Titolo Testata:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
fascicolo: 8, volume: 86, anno: 2001,
pagine: 3820 - 3825
SICI:
0021-972X(200108)86:8<3820:HMITCS>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACUTE REGULATORY PROTEIN; 3-BETA-HYDROXYSTEROID DEHYDROGENASE-DEFICIENCY; ADDISONS-DISEASE; COS-1 CELLS; STAR GENE; HYPERPLASIA; EXPRESSION; STEROIDOGENESIS; MITOCHONDRIAL; KNOCKOUT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Fujieda, K Asahikawa Med Coll, Dept Pediat, 2-1-1-1 Midorigaoka, Asahikawa, Hokkaido 0788510, Japan Asahikawa Med Coll 2-1-1-1 Midorigaoka Asahikawa Hokkaido Japan 0788510
Citazione:
T. Tajima et al., "Heterozygous mutation in the cholesterol side chain cleavage enzyme (P450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency", J CLIN END, 86(8), 2001, pp. 3820-3825

Abstract

Cytochrome P450scc, the mitochondrial cholesterol side chain cleavage enzyme, is the only enzyme that catalyzes the conversion of cholesterol to pregnenolone and, thus, is required for the biosynthesis of all steroid hormones. Congenital lipoid adrenal hyperplasia is a severe disorder of steroidogenesis in which cholesterol accumulates within steroidogenic cells and the synthesis of all adrenal and gonadal steroids is impaired, hormonally suggesting a disorder in P450scc. However, congenital lipoid adrenal hyperplasia is caused by mutations in the steroidogenic acute regulatory protein StAR; it has been thought that P450scc mutations are incompatible with human termgestation, because P450scc is needed for placental biosynthesis of progesterone, which is required to maintain pregnancy. In studying patients with congenital lipoid adrenal hyperplasia, we identified an individual with normal StAR and SF-1 genes and a heterozygous mutation in P450scc. The mutationwas found in multiple cell types, but neither parent carried the mutation,suggesting it arose de novo during meiosis, before fertilization. The patient was atypical for congenital lipoid adrenal hyperplasia, having survivedfor 4 yr without hormonal replacement before experiencing life-threateningadrenal insufficiency. The P450scc mutation, an in-frame insertion of Gly and Asp between Asp271 and Val272, was inserted into a catalytically activefusion protein of the P450scc system (H2N-P450sceAdrenodoxin Reductase-Adrenodoxin-COOH), completely inactivating enzymatic activity. Cotransfection of wild-type and mutant vectors showed that the mutation did not exert a dominant negative effect. Because P450scc is normally a slow and inefficient enzyme, we propose that P450scc haploinsufficiency results in subnormal responses to ACTH, so that recurrent ACTH stimulation leads to a slow accumulation of adrenal cholesterol, eventually causing cellular damage. Thus, although homozygous absence of P450scc should be incompatible with term gestation, haploinsufficiency of P450scc causes a late-onset form of congenital lipoid adrenal hyperplasia that can be explained by the same two-hit model that has been validated for congenital lipoid adrenal hyperplasia caused by StAR deficiency.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/10/20 alle ore 05:55:38