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Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression

Achermann, JC; Ito, M; Silverman, BL; Habiby, RL; Pang, S; Rosler, A; Jameson, JL; (2001) Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression. The Journal of Clinical Endocrinology & Metabolism , 86 (7) 3171 - 3175. 10.1210/jc.86.7.3171. Green open access

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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 time of 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 these mutations 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 most DAX1 missense mutations associated with classic AHC exhibit marked loss of function. The locations of these mutations thereby identify important functional domains in the carboxyl-terminus of the protein.

Type: Article
Title: Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression
Open access status: An open access version is available from UCL Discovery
DOI: 10.1210/jc.86.7.3171
Publisher version: http://dx.doi.org/10.1210/jc.86.7.3171
Language: English
Additional information: © 2001 by The Endocrine Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: ADRENAL HYPOPLASIA CONGENITA, STEROIDOGENIC FACTOR-I, HYPOGONADOTROPIC HYPOGONADISM, SEX DETERMINATION, HORMONE-RECEPTOR, GONADAL AXIS, DNA-BINDING, GENE, EXPRESSION, ACTIVATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/145330
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