title: A mild form of SLC29A3 disorder: a frameshift deletion leads to the paradoxical translation of an otherwise noncoding mRNA splice variant.
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.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United States of America. alexandre.bolze@gmail.com
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bolze
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Audrey V
authors.initials: AV
authors.lastname: Grant
authors.forename: Bhavi
authors.initials: B
authors.lastname: Patel
authors.forename: Ruchi
authors.initials: R
authors.lastname: Yadav
authors.forename: Minji
authors.initials: M
authors.lastname: Byun
authors.forename: Daniel
authors.initials: D
authors.lastname: Caillez
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Emile
authors.forename: Marçal
authors.initials: M
authors.lastname: Pastor-Anglada
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Rajgopal
authors.initials: R
authors.lastname: Govindarajan
authors.forename: Loic
authors.initials: L
authors.lastname: de Pontual
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000328:Adult; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D015614:Histiocytosis / Q000235:genetics*; D006801:Humans; D008297:Male; D009668:Nose Diseases / Q000235:genetics*; D033703:Nucleoside Transport Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D014176:Protein Biosynthesis / Q000235:genetics; D059368:RNA Isoforms / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics*; D017384:Sequence Deletion; D012720:Severity of Illness Index; D035781:Siblings; D055815:Young Adult
chemical_list: D033703:Nucleoside Transport Proteins; D059368:RNA Isoforms; D022821:RNA Splice Sites; D022661:RNA, Untranslated; C501424:SLC29A3 protein, human