Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk

Gaddiel Galarza-Muñoz; Farren B S Briggs; Irina Evsyukova; Geraldine Schott-Lerner; Edward M Kennedy; Tinashe Nyanhete; Liuyang Wang; Laura Bergamaschi; Steven G Widen; Georgia D Tomaras; Dennis C Ko; Shelton S Bradrick; Lisa F Barcellos; Simon G Gregory; Mariano A Garcia-Blanco

doi:10.1016/j.cell.2017.03.007

Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk

Cell. 2017 Mar 23;169(1):72-84.e13. doi: 10.1016/j.cell.2017.03.007.

Authors

Affiliations

¹ Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Center for RNA Biology, Duke University, Durham, NC 27710, USA; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
² Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
³ Center for RNA Biology, Duke University, Durham, NC 27710, USA.
⁴ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁵ Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
⁶ Department of Immunology, Duke University Durham, NC 27710, USA; Department of Surgery, Duke University Durham, NC 27710, USA.
⁷ Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
⁸ Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Durham, NC 27710, USA; Department of Surgery, Duke University Durham, NC 27710, USA.
⁹ Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA.
¹⁰ Division of Epidemiology, School of Public Health, University of California Berkeley, Berkeley, CA 94720, USA.
¹¹ Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA; Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: simon.gregory@duke.edu.
¹² Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Center for RNA Biology, Duke University, Durham, NC 27710, USA; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: maragarc@utmb.edu.

Abstract

Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5' UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.

Keywords: DDX39B; IL7R; alternative splicing; autoimmune disorders; epistasis; genetic association; multiple sclerosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DEAD-box RNA Helicases / genetics
DEAD-box RNA Helicases / metabolism*
Epistasis, Genetic*
Exons
HeLa Cells
Humans
Interleukin-7 Receptor alpha Subunit / genetics*
Multiple Sclerosis / genetics
Protein Biosynthesis
RNA Splicing*
RNA, Small Interfering / metabolism
T-Lymphocytes / immunology

Substances

IL7R protein, human
Interleukin-7 Receptor alpha Subunit
RNA, Small Interfering
DDX39B protein, human
DEAD-box RNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding