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

John C. Achermann, Masafumi Ito, Bernard L. Silverman, Reema L. Habiby, Songya Pang, Ariel Rosler, J. Larry Jameson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


DAX-1 is an orphan nuclear receptor that plays a key role in the development and function of the adrenal gland and hypothalamicpituitary 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 frame-shift 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 1439S, 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.

Original languageEnglish (US)
Pages (from-to)3171-3175
Number of pages5
JournalJournal of clinical endocrinology and metabolism
Issue number7
StatePublished - 2001

ASJC Scopus subject areas

  • Biochemistry, medical
  • Endocrinology
  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism


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