Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita

Anne T. Reutens, John C. Achermann, Masafumi Ito, Mika Ito, Wen Xia Gu, Reema L. Habiby, Patricia A. Donohoue, Songya Pang, Peter C. Hindmarsh, J. Larry Jameson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

142 Scopus citations


Adrenal hypoplasia congenita (AHC) is an X-linked disorder caused by mutations in a gene referred to as DAX-1. AHC is characterized by adrenal insufficiency and failure to undergo puberty because of hypogonadotropic hypogonadism. The DAX-1 protein is structurally related to orphan nuclear receptors, although it lacks the characteristic zinc finger DNA-binding domain that is highly conserved in other members of this family. In this report, we describe the clinical features and genetic alterations in six families with AHC. These patients reveal the variable clinical presentation of adrenal insufficiency in AHC and underscore the importance of considering this diagnosis. Nonsense mutations that introduce a stop codon were found in three cases (W171X, W171X, Y399X). Frameshift mutations (405delT, 501delA, and 702delC), each of which resulted in a premature stop codon at amino acid 263, were found in the other three families. Three of these mutations (Y399X, 405delT, 702delC) are novel. Using transient gene expression assays to assess DAX-1 function, these mutations were shown to eliminate the ability of DAX-1 to repress the transcription of genes that are stimulated by a related nuclear receptor, steroidogenic factor-1. These studies reveal the variable clinical presentation of DAX-1 mutations and emphasize the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked AHC.

Original languageEnglish (US)
Pages (from-to)504-511
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Issue number2
StatePublished - 1999

ASJC Scopus subject areas

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


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