This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reutens, A. T. Articles by Jameson, J. L. Search for Related Content PubMed PubMed Citation Articles by Reutens, A. T. Articles by Jameson, J. L. Pubmed/NCBI databases OMIM Genetics Home Reference

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.

This article has been cited by other articles:

				C. J. Kim, L. Lin, N. Huang, C. A. Quigley, T. W. AvRuskin, J. C. Achermann, and W. L. Miller Severe Combined Adrenal and Gonadal Deficiency Caused by Novel Mutations in the Cholesterol Side Chain Cleavage Enzyme, P450scc J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 696 - 702. [Abstract] [Full Text] [PDF]

				N. Weintrob, J. Drouin, S. Vallette-Kasic, E. Taub, D. Marom, Y. Lebenthal, G. Klinger, E. Bron-Harlev, and M. Shohat Low Estriol Levels in the Maternal Triple-Marker Screen as a Predictor of Isolated Adrenocorticotropic Hormone Deficiency Caused by a New Mutation in the TPIT Gene Pediatrics, February 1, 2006; 117(2): e322 - e327. [Abstract] [Full Text] [PDF]

				E. De Menis, F. Roncaroli, V. Calvari, V. Chiarini, P. Pauletto, G. Camerino, and N. Cremonini Corticotroph adenoma of the pituitary in a patient with X-linked adrenal hypoplasia congenita due to a novel mutation of the DAX-1 gene Eur. J. Endocrinol., August 1, 2005; 153(2): 211 - 215. [Abstract] [Full Text] [PDF]

				I. Bergada, G. del Rey, P. Lapunzina, C. Bergada, M. Fellous, and S. Copelli Familial Occurrence of the IMAGe Association: Additional Clinical Variants and a Proposed Mode of Inheritance J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3186 - 3190. [Abstract] [Full Text] [PDF]

				S. Y. Park, J. J. Meeks, G. Raverot, L. E. Pfaff, J. Weiss, G. D. Hammer, and J. L. Jameson Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development Development, May 15, 2005; 132(10): 2415 - 2423. [Abstract] [Full Text] [PDF]

				I. Marshall, F. Ugrasbul, F. Manginello, M. P. Wajnrajch, C. H. L. Shackleton, M. I. New, and M. V. Vogiatzi Congenital Hypopituitarism as a Cause of Undetectable Estriol Levels in the Maternal Triple-Marker Screen J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4144 - 4148. [Abstract] [Full Text] [PDF]

				P. Brown, G. A. Scobie, J. Townsend, R. A. L. Bayne, J. R. Seckl, P. T. K. Saunders, and R. A. Anderson Identification of a Novel Missense Mutation That Is as Damaging to DAX-1 Repressor Function as a Nonsense Mutation J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1341 - 1349. [Abstract] [Full Text] [PDF]

				J. J. Meeks, S. E. Crawford, T. A. Russell, K.-i. Morohashi, J. Weiss, and J. L. Jameson Dax1 regulates testis cord organization during gonadal differentiation Development, March 1, 2003; 130(5): 1029 - 1036. [Abstract] [Full Text] [PDF]

				R. Salvi, F. Gomez, M. Fiaux, D. Schorderet, J. L. Jameson, J. C. Achermann, R. C. Gaillard, and F. P. Pralong Progressive Onset of Adrenal Insufficiency and Hypogonadism of Pituitary Origin Caused by a Complex Genetic Rearrangement within DAX-1 J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4094 - 4100. [Abstract] [Full Text] [PDF]

				S. B. Seminara and W. F. Crowley Jr. Genetic Approaches to Unraveling Reproductive Disorders: Examples of Bedside to Bench Research in the Genomic Era Endocr. Rev., June 1, 2002; 23(3): 382 - 392. [Abstract] [Full Text] [PDF]

				S. N. Kalantaridou and G. P. Chrousos Monogenic Disorders of Puberty J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2481 - 2494. [Full Text] [PDF]

				E. Holter, N. Kotaja, S. Makela, L. Strauss, S. Kietz, O. A. Janne, J.-A. Gustafsson, J. J. Palvimo, and E. Treuter Inhibition of Androgen Receptor (AR) Function by the Reproductive Orphan Nuclear Receptor DAX-1 Mol. Endocrinol., March 1, 2002; 16(3): 515 - 528. [Abstract] [Full Text] [PDF]

				G. Mantovani, G. Ozisik, J. C. Achermann, R. Romoli, G. Borretta, L. Persani, A. Spada, J. L. Jameson, and P. Beck-Peccoz Hypogonadotropic Hypogonadism as a Presenting Feature of Late-Onset X-Linked Adrenal Hypoplasia Congenita J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 44 - 48. [Abstract] [Full Text] [PDF]

				S. Domenice, A. C. Latronico, V. N. Brito, I. J. P. Arnhold, F. Kok, and B. B. Mendonca Adrenocorticotropin-Dependent Precocious Puberty of Testicular Origin in a Boy with X-Linked Adrenal Hypoplasia Congenita Due to a Novel Mutation in the DAX1 Gene J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4068 - 4071. [Abstract] [Full Text] [PDF]

				S. Ten, M. New, and N. Maclaren Addison's Disease 2001 J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 2909 - 2922. [Abstract] [Full Text] [PDF]

				J. C. Achermann, M. Ito, B. L. Silverman, R. L. Habiby, S. Pang, A. Rosler, and J. L. Jameson Missense Mutations Cluster within the Carboxyl-Terminal Region of DAX-1 and Impair Transcriptional Repression J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3171 - 3175. [Abstract] [Full Text] [PDF]

				J. J. Tremblay and R. S. Viger Nuclear Receptor Dax-1 Represses the Transcriptional Cooperation Between GATA-4 and SF-1 in Sertoli Cells Biol Reprod, April 1, 2001; 64(4): 1191 - 1199. [Abstract] [Full Text]

				Y.-K. Lee, H. Dell, D. H. Dowhan, M. Hadzopoulou-Cladaras, and D. D. Moore The Orphan Nuclear Receptor SHP Inhibits Hepatocyte Nuclear Factor 4 and Retinoid X Receptor Transactivation: Two Mechanisms for Repression Mol. Cell. Biol., January 1, 2000; 20(1): 187 - 195. [Abstract] [Full Text]

				Mutational Analysis of DAX1 in Patients with Hypogonadotropic Hypogonadism or Pubertal Delay J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4497 - 4500. [Abstract] [Full Text]

				X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4501 - 4509. [Abstract] [Full Text]