Faculty Collaboration Database

Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita. J Clin Endocrinol Metab 1999 Feb;84(2):504-11

Date

02/18/1999

Pubmed ID

10022408

DOI

10.1210/jcem.84.2.5468

Scopus ID

2-s2.0-0032977119 (requires institutional sign-in at Scopus site)   161 Citations

Abstract

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.

Author List

Reutens AT, Achermann JC, Ito M, Ito M, Gu WX, Habiby RL, Donohoue PA, Pang S, Hindmarsh PC, Jameson JL

MESH terms used to index this publication - Major topics in bold

Adrenal Insufficiency
Adult
Child
Child, Preschool
Codon
DAX-1 Orphan Nuclear Receptor
DNA Mutational Analysis
DNA-Binding Proteins
Female
Frameshift Mutation
Genetic Linkage
Humans
Hypogonadism
Infant
Infant, Newborn
Male
Mutation
Pedigree
Receptors, Retinoic Acid
Repressor Proteins
Steroidogenic Factor 1
Transcription Factors
X Chromosome