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Titolo:
Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression
Autore:
Achermann, JC; Ito, M; Silverman, BL; Habiby, RL; Pang, S; Rosler, A; Jameson, JL;
Indirizzi:
Northwestern Univ, Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA Northwestern Univ Chicago IL USA 60611 b & Mol Med, Chicago, IL 60611 USA Univ Illinois, Coll Med, Dept Pediat, Chicago, IL 60612 USA Univ IllinoisChicago IL USA 60612 ed, Dept Pediat, Chicago, IL 60612 USA Hadassah Univ Hosp, Dept Endocrinol & Metab, IL-91120 Jerusalem, Israel Hadassah Univ Hosp Jerusalem Israel IL-91120 IL-91120 Jerusalem, Israel
Titolo Testata:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
fascicolo: 7, volume: 86, anno: 2001,
pagine: 3171 - 3175
SICI:
0021-972X(200107)86:7<3171:MMCWTC>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
ADRENAL HYPOPLASIA CONGENITA; STEROIDOGENIC FACTOR-I; HYPOGONADOTROPIC HYPOGONADISM; SEX DETERMINATION; HORMONE-RECEPTOR; GONADAL AXIS; DNA-BINDING; GENE; EXPRESSION; ACTIVATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Jameson, JL Northwestern Univ, Sch Med, Div Endocrinol Metab & Mol Med, Tarry 15-709,303 E Chicago Ave, Chicago, IL 60611 USA Northwestern Univ Tarry15-709,303 E Chicago Ave Chicago IL USA 60611
Citazione:
J.C. Achermann et al., "Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression", J CLIN END, 86(7), 2001, pp. 3171-3175

Abstract

DAX-1 is an orphan nuclear receptor that plays a key role in the development and function of the adrenal gland and hypothalamic-pituitary gonadal axis. Mutations in the gene encoding DAX-1 result in X-linked adrenal hypoplasia congenita (AHC). Affected boys typically present with primary adrenal failure in infancy or childhood and hypogonadotropic hypogonadism at the timeof puberty. The majority of DAX1 mutations described to date are nonsense or frameshift mutations that result in premature truncation of the DAX-1 protein and loss of DAX-1 repressor function. Relatively few missense mutations in DAX1 have been reported. Here, we describe missense mutations in three additional families with X-linked AHC. When combined with previous reports, the DAX1 missense mutations appear to cluster within restricted regions of the putative ligand-binding domain of DAX-1 and affect amino acids that are evolutionarily conserved, suggesting that these regions correspond to critical functional domains. Transcription assays, using a variety of artificial and native target genes, were performed to assess the effects of thesemutations on the function of DAX-1. All DAX-1 missense mutant constructs showed marked loss of repressor function, with the exception of I439S, a mutation previously shown to be associated with delayed-onset adrenal failure and incomplete hypogonadotropic hypogonadism. These data indicate that mostDAX1 missense mutations associated with classic AHC exhibit marked loss offunction. The locations of these mutations thereby identify important functional domains in the carboxyl-terminus of the protein.

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Documento generato il 29/11/20 alle ore 06:52:49