An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita

Gokhan Ozisik, Giovanna Mantovani, John C. Achermann, Luca Persani, Anna Spada, Jeffrey Weiss, Paolo Beck-Peccoz, J. Larry Jameson*

*Corresponding author for this work

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

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 non-functional 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.

Original languageEnglish (US)
Pages (from-to)417-423
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume88
Issue number1
DOIs
StatePublished - Jan 1 2003

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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