SCNM1, a Putative RNA Splicing Factor That Modifies Disease Severity in Mice

• Published in: Science (American Association for the Advancement of Science) 2003-08, Vol.301 (5635), p.967-969
• Main Authors: Buchner, David A., Trudeau, Michelle, Meisler, Miriam H.
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Sequence; Anatomy; Animals; Biological and medical sciences; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Chromosome Mapping; Codon, Nonsense; Codon, Terminator; Disease; Donors; Exons; Genes; Genetic aspects; Genetic disorders; Genetic mutation; Genetic Predisposition to Disease; Genetics; Heredity; Humans; Inbred strains; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Neurologic Mutants; Mice, Transgenic; Molecular Sequence Data; Movement Disorders - genetics; Movement Disorders - metabolism; Mutation; NAV1.6 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Nervous system (semeiology, syndromes); Nervous system as a whole; Nervous system diseases; Nervous System Diseases - genetics; Nervous System Diseases - metabolism; Neurological disorders; Neurology; Phenotype; Phylogeny; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA Splicing; RNA Splicing Factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Sodium channels; Sodium Channels - genetics; Sodium Channels - metabolism; Splicing; Transcripts (Written Records); Transgenic animals; Zinc Fingers
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1086187

The severity of many inherited disorders is influenced by genetic background. We describe a modifier interaction in C57BL/6J mice that converts a chronic movement disorder into a lethal neurological disease. The primary mutation ($med^J$) changes a splice donor site of the sodium channel gene Scn8a (Nav1.6). The modifier mutation is characteristic of strain C57BL/6J and introduces a nonsense codon into sodium channel modifier 1 (SCNM1), a zinc finger protein and a putative splice factor. An internally deleted SCNM1 protein is also predicted as a result of exon skipping associated with disruption of a consensus exonic splicing enhancer. The effect of the modifier mutation is to reduce the abundance of correctly spliced sodium channel transcripts below the threshold for survival. Our finding that genetic variation in a putative RNA splicing factor influences disease susceptibility in mice raises the possibility that a similar mechanism modifies the severity of human inherited disorders.