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An Alternate Translation Initiation Site Circumvents an Amino-Terminal DAX1 Nonsense Mutation Leading to a Mild Form of X-Linked Adrenal Hypoplasia Congenita

Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University, The Feinberg School of Medicine (G.O., J.W., J.L.J.), Chicago, Illinois 60611-3008; Institute of Endocrine Sciences, Ospedale Maggiore Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) and Istituto Auxologico Italiano IRCCS (G.M., L.P., A.S., P.B.-P.), 20122 Milan, Italy; and Center for Human Growth and Maturation, Department of Medicine and Institute of Child Health, University College London (J.C.A.), London, United Kingdom WC1N 1EH

Address all correspondence and requests for reprints to: J. Larry Jameson, M.D., Ph.D., Department of Medicine, Northwestern University, The Feinberg School of Medicine, Galter Pavilion, Suite 3-150, 251 East Huron Street, Chicago, Illinois 60611-2908. E-mail: ljameson{at}northwestern.edu.

Mutations in DAX1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome gene 1; NR0B1] cause X-linked AHC, a disease characterized by primary adrenal failure in infancy or childhood and reproductive abnormalities later in life. Most of these patients have nonsense or frameshift mutations that cause premature truncation of the DAX1 protein, thereby eliminating its transcriptional silencing activity. We evaluated a patient with an unusual form of AHC manifest as late-onset adrenal insufficiency and gonadal failure. DNA sequence analysis revealed a novel amino-terminal DAX1 nonsense mutation (Q37X), predicted to cause a severe truncation of the protein. Using a combination of in vitro translation assays and studies of DAX1 expression and function in transfected cells, we demonstrate that, in contrast to more distal mutations leading to a nonfunctional protein, this mutation is associated with a milder phenotype due to the expression of a partially functional, amino-truncated DAX1 protein generated from an alternate in-frame translation start site (methionine, codon 83). The production of this amino-truncated isoform appears to rescue the classical AHC phenotype, thereby delaying the onset of clinically significant adrenal dysfunction until early adulthood. Thus, this case demonstrates a relatively rare phenomenon by which the clinical severity of an inherited human disease is reduced after alternate translation from a site downstream of a premature stop codon.

This work was performed as part of the National Cooperative Program for Infertility Research and was supported by NIH Grants U54-HD-29164 and PO1-HD-21921 and by MURST-Rome (9906153187), Fondi Ricerca Corrente-Istituto Di Ricovero e Cura a Carattere Scientifico, and Research Funds of Istituto Auxologico Italiano IRCCS (Project 05C801).

G.O. and G.M. contributed equally to this work.

Abbreviations: AF2, Activation function-2; AHC, adrenal hypoplasia congenita; LBD, ligand-binding domain; SF1, steroidogenic factor-1; WT, wild type.

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