title: A silent exonic SNP in kdm3a affects nucleic acids structure but does not regulate experimental autoimmune encephalomyelitis.
abstract: 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.
authors: Department of Clinical Neuroscience, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Alan
authors: A
authors: Gillett
authors: Petra
authors: P
authors: Bergman
authors: Roham
authors: R
authors: Parsa
authors: Andreas
authors: A
authors: Bremges
authors: Robert
authors: R
authors: Giegerich
authors: Maja
authors: M
authors: Jagodic
mesh_terms: D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D018076:DNA, Complementary / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D005091:Exons / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D056484:Jumonji Domain-Containing Histone Demethylases / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012313:RNA / Q000737:chemistry*; D051381:Rats
chemical_list: D018076:DNA, Complementary; D012313:RNA; D004247:DNA; D056484:Jumonji Domain-Containing Histone Demethylases; C511045:Kdm3a protein, mouse