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Clinical and Functional Effects of Mutations in the DAX-1 Gene in Patients with Adrenal Hypoplasia Congenita¹

Division of Endocrinology, Metabolism, and Molecular Medicine (A.T.R., J.C.A., Ma.I., Mi.I., W.-X.G., R.L.H., J.L.J.), Northwestern University Medical School, Chicago, Illinois 60611; London Centre for Paediatric Endocrinology and Metabolism (J.C.A., P.C.H.), University College London, London, United Kingdom W1N 8AA; Department of Pediatrics (P.A.D.), University of Iowa College of Medicine, Iowa City, Iowa, 52242; and Department of Pediatrics (S.P.), University of Illinois College of Medicine, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: J. Larry Jameson, M.D., Ph.D., Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, 303 East Chicago Avenue, Tarry Building 15-709, Chicago, IL 60611. E-mail: ljameson{at}nwu.edu

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.

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