<italic>Scnm1</italic> modifies the severity of a neurological disease by an effect on sodium channel splicing.
Buchner, David Alan
2003
Abstract
The severity of many Mendelian disorders is influenced by genetic background. This study focused on a mouse model of neuromuscular disease (med<super>J </super>) caused by a splice site mutation in the sodium channel gene <italic> Scn8a</italic> (Na<sub>v</sub>1.6). med<super>J</super> mice express both wildtype transcripts (10%) and exon-skipped mutant transcripts encoding a nonfunctional protein (90%). On most inbred backgrounds, med<super>J</super> homozygotes display movement disorders that include ataxia, tremor, and dystonia. On a C57BL/6J background, med<super>J</super> homozygotes exhibit paralysis and juvenile lethality. The greater susceptibility of strain C57BL/6J is caused by a two-fold reduction in splicing efficiency of the <italic>Scn8a</italic> pre-mRNA. Analysis of 2,304 offspring from an intercross between strains C57BL/6J-med<super> J</super>/+ and C3H localized the modifier gene, <italic>Scnm1</italic>, to a 1 Mb interval on chromosome 3 and identified a 1.3 kb recombination hotspot with a ratio of genetic to physical distance of 85 cM/Mb. Strain 129X1 was also found to carry the resistant allele of <italic>Scnm1</italic>. Comparative sequence analysis of 34 genes from the nonrecombinant region revealed a premature termination codon on one gene that was restricted to strain C57BL/6J. This mutation in the predicted gene MGC3180 truncates 43 of 229 amino acids and destroys a consensus exonic splicing enhancer resulting in skipping of exon 6. Among 36 inbred strains, the nonsense mutation was present only in 5 closely related C57 and C58 strains, excluding C57BLKS. A BAC transgene containing the full-length MGC3180 gene, and a cDNA transgene, rescued the lethal phenotype and corrected the splicing defect of C57BL/6J-med<super>J</super>/med<super> J</super> mice demonstrating that MGC3180 is the <italic>Scnm1</italic> modifier gene. SCNM1 contains a U1C-like zinc finger domain often found in splicing factors, suggesting that SCNM1 directly affects splicing of <italic>Scn8a </italic> pre-mRNA. Consistent with this hypothesis, a GFP-SCNM1 fusion protein was localized to the nucleus of transfected cells. To detect human variation in SCNM1, we screened 179 genomic DNA samples. Nine individuals (4%) were heterozygous for coding variants, including two nonconservative substitutions in evolutionarily conserved residues. In addition to isolating the <italic>Scnm1</italic> gene, I identified four new ENU-induced missense mutations in <italic>Scn8a</italic> that are responsible for lethal neurological disorders. The mutations are located in the D3 pore loop and N-terminus of the channel and are likely to be loss of function alleles.Subjects
Effect Modifies Neurological Disease Scnm1 Severity Sodium Channel Splicing
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