Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/43148
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-Francois
Pastor Anglada, Marçal
Abel, Laurent
Puel, Anne
Govindarajan, Rajgopal
Pontual, L. 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
Related resource: http://dx.doi.org/10.1371/journal.pone.0029708
URI: http://hdl.handle.net/2445/43148
ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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