Ozisik, G;
Mantovani, G;
Achermann, JC;
Persani, L;
Spada, A;
Weiss, J;
Beck-Peccoz, P;
(2003)
An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita.
The Journal of Clinical Endocrinology & Metabolism
, 88
(1)
417 - 423.
10.1210/jc.2002-021034.
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Abstract
Mutations in DAX1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome gene 1; NROB1] 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 ARC 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.
| Type: | Article |
|---|---|
| Title: | An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1210/jc.2002-021034 |
| Publisher version: | http://dx.doi.org/10.1210/jc.2002-021034 |
| Language: | English |
| Additional information: | © 2003 by The Endocrine Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | MESSENGER-RNA DECAY, HYPOGONADOTROPIC HYPOGONADISM, ANDROGEN RECEPTOR, GENE, PROTEIN, TRUNCATION, EXPRESSION, PHENOTYPE, ISOFORMS, INSIGHTS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/95059 |
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