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

PLoS One

Marçal Pastor-Anglada¹  Jean-Laurent Casanova²  Jean-Francois Emile³  Rajgopal Govindarajan⁴  Audrey V. Grant⁴  Anne Puel⁴  Daniel Caillez⁵  Laurent Abel⁶  Alexandre Bolze⁶  Avinash Abhyankar⁶  Minji Byun⁶  Ruchi Yadav⁷  Loic de Pontual⁷  Bhavi Patel⁷ 

[1] Department of Biochemistry and Molecular Biology, Institute of Biomedicine (IBUB), University of Barcelona and National Institute for the Study of Liver and Gastrointestinal Diseases (CIBER EHD), Barcelona, Spain;Department of Pediatrics, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France;EA4340, University Versailles SQY and Ambroise Paré Hospital, APHP, Boulogne, France;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Medicale, INSERM U980, University Paris Descartes, Paris, France;Laboratory of Pathology, Groupe Hospitalier du Havre, Jacques Monod Hospital, Montivilliers, France;St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United States of America;Wilson Pharmacy, Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America

关键词: Frameshift mutation;    Histiocytes;    Biopsy;    Messenger RNA;    Histology;    Lesions;    Diabetes mellitus;    Fibrosis;   

DOI  :  10.1371/journal.pone.0029708

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY