A Mild Form of SLC29A3 Disorder: A Frameshift Deletion Leads to the Paradoxical Translation of an Otherwise Noncoding mRNA Splice Variant

• Published in: PloS one Vol. 7; no. 1; p. e29708
• Main Authors: Bolze, Alexandre, Abhyankar, Avinash, Grant, Audrey V., Patel, Bhavi, Yadav, Ruchi, Byun, Minji, Caillez, Daniel, Emile, Jean-Francois, Pastor-Anglada, Marçal, Abel, Laurent, Puel, Anne, Govindarajan, Rajgopal, de Pontual, Loic, Casanova, Jean-Laurent
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.01.2012; Public Library of Science (PLoS)
• Subjects: Adult; Age; Alternative splicing; Amino acids; Analysis; B cells; Bioinformatics; Biology; Cancer; Diabetes mellitus; Diabetes mellitus (insulin dependent); Drosophila; Female; Fenotip; Frameshift Mutation - genetics; Gene deletion; Gene expression; Gene mutation; Gene sequencing; Genetic aspects; Genetics; Genomes; Genomics; Genètica; Hereditary diseases; Histiocytosis; Histiocytosis - genetics; Humans; Hypertrichosis; Identification; Infectious diseases; Insects; Insulin; Laboratories; Linkage analysis; Male; Medical imaging; Medical prognosis; Medical research; Medicine; Messenger RNA; Mimicry; mRNA turnover; Mutation; Nonsense-mediated mRNA decay; Nose Diseases - genetics; Nucleoside Transport Proteins - genetics; Nucleoside transporter; Patients; Pedigree; Pharmaceuticals; Pharmacy; Phenotype; Phenotypes; Protein Biosynthesis - genetics; Rhinoscleroma; RNA; RNA Isoforms - genetics; RNA Splice Sites - genetics; RNA, Untranslated - genetics; Rodents; Sequence Deletion; Severity of Illness Index; Siblings; Survival analysis; Translation; Translation (Genetics); Young Adult; New York; Georgia; France; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0029708

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.