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Title: | A mild form of SLC29A3 disorder: a frameshift deletion leads to the paradoxical translation of an otherwise noncoding mRNA splice variant |
Author: | Bolze, Alexandre Abhyankar, Avinas Grant, Audrey V. Patel, Bhavi Yadav, Ruchi Byun, Minji Caillez, Daniel Emile, Jean-François Pastor Anglada, Marçal Abel, Laurent Puel, Anne Govindarajan, Rajgopal Pontual, Loic de Casanova, Jean-Laurent |
Keywords: | Genètica Fenotip RNA Genetics Phenotype RNA |
Issue Date: | Jan-2012 |
Publisher: | Public Library of Science (PLoS) |
Abstract: | We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the"rescue" role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic. |
Note: | Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pone.0029708 |
It is part of: | PLoS One, 2012, vol. 7, num. 1, p. e29708 |
URI: | http://hdl.handle.net/2445/43148 |
Related resource: | http://dx.doi.org/10.1371/journal.pone.0029708 |
ISSN: | 1932-6203 |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) |
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