SCNM1, a putative RNA splicing factor that modifies disease severity in mice.
The severity of many inherited disorders is influenced by genetic background. We describe a modifier interaction in C57BL/6Jmice that converts a chronic movement disorder into a lethal neurological disease. The primary mutation (medJ) changes a splice donor site of the sodium channel gene Scn8a (Nav1.6). The modifier mutation is characteristic of strain C57BL/6Jand 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.
Buchner
David A
DA
Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, MI 48109-0618, USA.
Trudeau
Michelle
M
Meisler
Miriam H
MH
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D018389:Codon, Nonsense; D018388:Codon, Terminator; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D009422:Nervous System Diseases / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D010802:Phylogeny; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers
D002352:Carrier Proteins; D018389:Codon, Nonsense; D018388:Codon, Terminator; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; C100681:SCN8A protein, human; C486783:SCNM1 protein, human; C491046:Scn8a protein, mouse; C476996:Scnm1 protein, mouse; D015222:Sodium Channels