NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency

Novoselova, Tatiana ORCID logoORCID: https://orcid.org/0000-0002-2394-4667, Rath, Shoshana R., Carpenter, Karen, Pachter, Nicholas, Dickinson, Jan E., Price, Glynis, Chan, Li F., Choong, Catherine S. and Metherell, Louise A. (2015) NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency. The Journal of Clinical Endocrinology and Metabolism, 100 (2) . E350-E354. ISSN 0021-972X [Article] (doi:10.1210/jc.2014-3641)

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Intronic DNA frequently encodes potential exonic sequences called pseudoexons. In recent years, mutations resulting in aberrant pseudoexon inclusion have been increasingly recognized to cause disease.
To find the genetic cause of familial glucocorticoid deficiency (FGD) in two siblings.
The proband and his affected sibling, from nonconsanguineous parents of East Asian and South African origin, were diagnosed with FGD at the ages of 21 and 8 months, respectively.
Whole exome sequencing was performed on genomic DNA (gDNA) of the siblings. Variants in genes known to cause FGD were assessed for causality. Further analysis of gDNA and cDNA was performed by PCR/RT-PCR followed by automated Sanger sequencing.
Whole exome sequencing identified a single, novel heterozygous variant (p.Arg71*) in nicotinamide nucleotide transhydrogenase (NNT) in both affected individuals. Follow-up cDNA analysis in the proband identified a 69-bp pseudoexon inclusion event, and Sanger sequencing of his gDNA identified a 4-bp duplication responsible for its activation. The variants segregated with the disease: p.Arg71* was inherited from the mother, the pseudoexon change was inherited from the father, and an unaffected sibling had inherited only the p.Arg71* variant.
FGD in these siblings is caused by compound heterozygous mutations in NNT; one causing pseudoexon inclusion in combination with another leading to Arg71*. Discovery of this pseudoexon activation mutation highlights the importance of identifying sequence changes in introns by cDNA analysis. The clinical implications of these findings include: facilitation of antenatal genetic diagnosis, early institution of potentially lifesaving therapy, and the possibility of preventative or curative intervention

Item Type: Article
Research Areas: A. > School of Science and Technology > Natural Sciences
Item ID: 28131
Notes on copyright: This article has been published under the terms of the Creative Commons Attribution License (CC-BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).
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Depositing User: Tatiana Novoselova
Date Deposited: 11 Nov 2019 18:03
Last Modified: 20 Aug 2020 22:11
URI: https://eprints.mdx.ac.uk/id/eprint/28131

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