A silent exonic SNP in kdm3a affects nucleic acids structure but does not regulate experimental autoimmune encephalomyelitis

• Published in: PloS one Vol. 8; no. 12; p. e81912
• Main Authors: Gillett, Alan, Bergman, Petra, Parsa, Roham, Bremges, Andreas, Giegerich, Robert, Jagodic, Maja
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.12.2013; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Arthritis; Base Sequence; Care and treatment; Chromosome 4; Disease; DNA - chemistry; DNA, Complementary - genetics; Efficiency; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Enzymes; Exons - genetics; Experimental allergic encephalomyelitis; Female; Gene expression; Gene Knockdown Techniques; Gene mapping; Gene Silencing; Genetic aspects; Genetic diversity; Genetic variance; Genomes; Immune system; Immunologi inom det medicinska området; Jumonji Domain-Containing Histone Demethylases - deficiency; Jumonji Domain-Containing Histone Demethylases - genetics; Laboratory animals; Lysine; Macrophages; Medicin och hälsovetenskap; Medicine; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Mice; Neurosciences; Nucleic acids; Pathogenesis; Phenotype; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Protein folding; Proteins; Quantitative trait loci; Rats; Ribonucleic acid; RNA; RNA - chemistry; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Tumor necrosis factor; Tumor necrosis factor-TNF; Sweden
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0081912

Defining genetic variants that predispose for diseases is an important initiative that can improve biological understanding and focus therapeutic development. Genetic mapping in humans and animal models has defined genomic regions controlling a variety of phenotypes known as quantitative trait loci (QTL). Causative disease determinants, including single nucleotide polymorphisms (SNPs), lie within these regions and can often be identified through effects on gene expression. We previously identified a QTL on rat chromosome 4 regulating macrophage phenotypes and immune-mediated diseases including experimental autoimmune encephalomyelitis (EAE). Gene analysis and a literature search identified lysine-specific demethylase 3A (Kdm3a) as a potential regulator of these phenotypes. Genomic sequencing determined only two synonymous SNPs in Kdm3a. The silent synonymous SNP in exon 15 of Kdm3a caused problems with quantitative PCR detection in the susceptible strain through reduced amplification efficiency due to altered secondary cDNA structure. Shape Probability Shift analysis predicted that the SNP often affects RNA folding; thus, it may impact protein translation. Despite these differences in rats, genetic knockout of Kdm3a in mice resulted in no dramatic effect on immune system development and activation or EAE susceptibility and severity. These results provide support for tools that analyze causative SNPs that impact nucleic acid structures.