An Alternate Translation Initiation Site Circumvents an Amino-Terminal DAX1 Nonsense Mutation Leading to a Mild Form of X-Linked Adrenal Hypoplasia Congenita
| Autor: | Giovanna Mantovani, Jeffrey Weiss, Paolo Beck-Peccoz, J. Larry Jameson, John C. Achermann, Gokhan Ozisik, Luca Persani, Anna Spada |
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| Rok vydání: | 2003 |
| Předmět: |
Male
medicine.medical_specialty Transcription Genetic Genetic Linkage Receptors Retinoic Acid messenger-RNA decay hypogonadotropic hypogonadism androgen receptor gene protein truncation expression phenotype isoforms insights Endocrinology Diabetes and Metabolism Clinical Biochemistry Nonsense mutation Biology Biochemistry Settore MED/13 - Endocrinologia Frameshift mutation Endocrinology X-linked adrenal hypoplasia congenita Internal medicine medicine Adrenal insufficiency Humans Amino Acid Sequence X chromosome X-linked recessive inheritance Genetics Chromosomes Human X Adrenal Hyperplasia Congenital Base Sequence DAX-1 Orphan Nuclear Receptor Biochemistry (medical) medicine.disease Hypoplasia DNA-Binding Proteins Repressor Proteins Phenotype Codon Nonsense DAX1 Transcription Factors |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 88:417-423 |
| ISSN: | 1945-7197 0021-972X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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