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Three ENU-induced neurological mutations in the pore loop of sodium channel Scn8a (Na(v)1.6) and a genetically linked retinal mutation, rd13.
Mamm Genome. 2004 May; 15(5):344-51.MG

Abstract

The goal of The Jackson Laboratory Neuroscience Mutagenesis Facility is to generate mouse models of human neurological disease. We describe three new models obtained from a three-generation screen for recessive mutations. Homozygous mutant mice from lines nmf2 and nmf5 exhibit hind limb paralysis and juvenile lethality. Homozygous nmf58 mice exhibit a less severe movement disorder that includes sustained dystonic postures. The mutations were mapped to the distal region of mouse Chromosome (Chr) 15. Failure to complement a mutant allele of a positional candidate gene, Scn8a, demonstrated that the mutations are new alleles of Scn8a. Missense mutations of evolutionarily conserved residues of the sodium channel were identified in the three lines, with the predicted amino acid substitutions N1370T, I1392F, and L1404H. These residues are located within the pore loop of domain 3 of sodium channel Na(v)1.6. The lethal phenotypes suggest that the new alleles encode proteins with partial or complete loss of function. Several human disorders are caused by mutation in the pore loop of domain 3 of paralogous sodium channel genes. Line nmf5 contains a second, independent mutation in the rd13 locus that causes a reduction in cell number in the outer nuclear layer of the retina. rd13 was mapped to the distal 4 Mb of Chr 15. No coding or splice site mutations were detected in Pde1b, a candidate gene for rd13. The generation of three independent Scn8a mutations among 1100 tested G3 families demonstrates that the Scn8a locus is highly susceptible to ENU mutagenesis. The new alleles of Scn8a will be valuable for analysis of sodium channel physiology and disease.

Authors+Show Affiliations

Department of Human Genetics, University of Michigan, Ann Arbor 48109-0618, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15170223

Citation

Buchner, David A., et al. "Three ENU-induced Neurological Mutations in the Pore Loop of Sodium Channel Scn8a (Na(v)1.6) and a Genetically Linked Retinal Mutation, Rd13." Mammalian Genome : Official Journal of the International Mammalian Genome Society, vol. 15, no. 5, 2004, pp. 344-51.
Buchner DA, Seburn KL, Frankel WN, et al. Three ENU-induced neurological mutations in the pore loop of sodium channel Scn8a (Na(v)1.6) and a genetically linked retinal mutation, rd13. Mamm Genome. 2004;15(5):344-51.
Buchner, D. A., Seburn, K. L., Frankel, W. N., & Meisler, M. H. (2004). Three ENU-induced neurological mutations in the pore loop of sodium channel Scn8a (Na(v)1.6) and a genetically linked retinal mutation, rd13. Mammalian Genome : Official Journal of the International Mammalian Genome Society, 15(5), 344-51.
Buchner DA, et al. Three ENU-induced Neurological Mutations in the Pore Loop of Sodium Channel Scn8a (Na(v)1.6) and a Genetically Linked Retinal Mutation, Rd13. Mamm Genome. 2004;15(5):344-51. PubMed PMID: 15170223.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Three ENU-induced neurological mutations in the pore loop of sodium channel Scn8a (Na(v)1.6) and a genetically linked retinal mutation, rd13. AU - Buchner,David A, AU - Seburn,Kevin L, AU - Frankel,Wayne N, AU - Meisler,Miriam H, PY - 2003/09/22/received PY - 2003/12/02/accepted PY - 2004/6/1/pubmed PY - 2004/11/9/medline PY - 2004/6/1/entrez SP - 344 EP - 51 JF - Mammalian genome : official journal of the International Mammalian Genome Society JO - Mamm. Genome VL - 15 IS - 5 N2 - The goal of The Jackson Laboratory Neuroscience Mutagenesis Facility is to generate mouse models of human neurological disease. We describe three new models obtained from a three-generation screen for recessive mutations. Homozygous mutant mice from lines nmf2 and nmf5 exhibit hind limb paralysis and juvenile lethality. Homozygous nmf58 mice exhibit a less severe movement disorder that includes sustained dystonic postures. The mutations were mapped to the distal region of mouse Chromosome (Chr) 15. Failure to complement a mutant allele of a positional candidate gene, Scn8a, demonstrated that the mutations are new alleles of Scn8a. Missense mutations of evolutionarily conserved residues of the sodium channel were identified in the three lines, with the predicted amino acid substitutions N1370T, I1392F, and L1404H. These residues are located within the pore loop of domain 3 of sodium channel Na(v)1.6. The lethal phenotypes suggest that the new alleles encode proteins with partial or complete loss of function. Several human disorders are caused by mutation in the pore loop of domain 3 of paralogous sodium channel genes. Line nmf5 contains a second, independent mutation in the rd13 locus that causes a reduction in cell number in the outer nuclear layer of the retina. rd13 was mapped to the distal 4 Mb of Chr 15. No coding or splice site mutations were detected in Pde1b, a candidate gene for rd13. The generation of three independent Scn8a mutations among 1100 tested G3 families demonstrates that the Scn8a locus is highly susceptible to ENU mutagenesis. The new alleles of Scn8a will be valuable for analysis of sodium channel physiology and disease. SN - 0938-8990 UR - https://www.unboundmedicine.com/medline/citation/15170223/Three_ENU_induced_neurological_mutations_in_the_pore_loop_of_sodium_channel_Scn8a__Na_v_1_6__and_a_genetically_linked_retinal_mutation_rd13_ L2 - https://dx.doi.org/10.1007/s00335-004-2332-1 DB - PRIME DP - Unbound Medicine ER -