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.