High-resolution mapping of the sodium channel modifier Scnm1 on mouse chromosome 3 and identification of a 1.3-kb recombination hot spot

• Published in: Genomics (San Diego, Calif.) Calif.), 2003-10, Vol.82 (4), p.452-459
• Main Authors: Buchner, David A, Trudeau, Michelle, George, Alfred L, Sprunger, Leslie K, Meisler, Miriam H
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological and medical sciences; Carrier Proteins - genetics; Cell membranes. Ionic channels. Membrane pores; Cell structures and functions; Chromosome Mapping - methods; Crosses, Genetic; Fundamental and applied biological sciences. Psychology; Genes. Genome; Genetic Markers; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes; Humans; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Modifier gene; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Nav1.6; Neuromuscular disease; Neuromuscular Diseases - genetics; Pre-mRNA splicing; RNA Splicing Factors; Scn8a; Sequence Analysis, DNA; SNP; Sodium Channels - genetics
• ISSN: 0888-7543; 1089-8646
• DOI: 10.1016/S0888-7543(03)00152-6

Variation between inbred strains of mice can be used to identify modifier genes affecting the susceptibility to inherited disease. The med J allele of the sodium channel Scn8a contains a splice site mutation that results in sodium channel deficiency. The severity of the neurological disorder is determined by the modifier locus Scnm1. The wild-type allele of the modifier results in correct splicing of 10% of Scn8a medJ pre-mRNA and a dystonic phenotype. The susceptible allele of the modifier in strain C57BL/6J results in 5% correctly spliced transcripts and a lethal phenotype. A mapping cross with C3H using 26 new markers and 2304 affected F2 animals localized the modifier gene to a 950-kb interval on mouse chromosome 3. Fine mapping of recombination breakpoints revealed a recombination hot spot of 1.3 kb. The ratio of genetic to physical distance in the hot spot is 85 cM/Mb, two orders of magnitude higher than the mouse genome average of 0.5 cM/Mb. The role of the modifier in other disorders in human and mouse can be tested with linked markers described here.