An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita.
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.
Ozisik
Gokhan
G
Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University, The Feinberg School of Medicine, Chicago, Illinois 60611-3008, USA.
Mantovani
Giovanna
G
Achermann
John C
JC
Persani
Luca
L
Spada
Anna
A
Weiss
Jeffrey
J
Beck-Peccoz
Paolo
P
Jameson
J Larry
JL
D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics*; D018389:Codon, Nonsense / Q000502:physiology*; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology*
D018389:Codon, Nonsense; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors