Dystonia associated with mutation of the neuronal sodium channel Scn8a and identification of the modifier locus Scnm1 on mouse chromosome 3
Abstract
The mouse mutant medJ contains a splice site mutation in the neuronal sodium channel Scn8a that results in a very low level of expression. On a C57BL/6J genetic background, medJ homozygotes exhibit progressive paralysis and juvenile lethality. The C3H genetic background has an ameliorating effect, producing viable adults with a novel dystonic phenotype. The dystonic mice exhibit movement-induced, sustained abnormal postures of the trunk and limbs. A dominant modifier locus responsible for the difference between strains was mapped to a 4.5 +/- 1.3 cM interval on mouse chromosome 3. Our findings establish a role for ion channels in dystonia and demonstrate the impact of genetic background on its severity and progression. This new model suggests that SCN8A on chromosome 12q13 and SCNM1 on chromosome 1p21-1q21 may contribute to human inherited dystonia.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the C3H background, medJ mice live a normal lifespan with dystonia and ataxia, with 10% of Scn8a transcripts correctly spliced.
“In the C3H background, medJ mice live a normal lifespan with dystonia and ataxia, with 10% of Scn8a transcripts correctly spliced.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [152]
The severity of the medJ phenotype is affected by genetic background and correlates with the amount of correctly spliced transcript.
“The severity of the medJ phenotype was found to be affected by genetic background and to correlate with the amount of correctly spliced transcript152.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [152]
The phenotypic severity of the Scn8amedJ hypomorphic allele is determined by a single gene modifier, Scnm1.
“The phenotypic severity of the Scn8amedJ hypomorphic allele is determined by a single gene modifier, sodium channel modifier 1 (Scnm1).”
From The neurogenetics of alternative splicing (2016) · cites this paper as [152]
Targeted deletion of Scnm1 in the C3H strain confirmed that SCNM1 affects both the splicing of the Scn8amedJ transcript and the mouse phenotype.
“targeted deletion of Scnm1 in the C3H strain confirmed that SCNM1 affects both the splicing of the Scn8amedJ transcript and the mouse phenotype152,153.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [152]
Cites
Ionic channels of excitable membranes
(1985) · General Pharmacology The Vascular System · doi:10.1016/0306-3623(85)90172-7 · Cited by 7,133 · see citing works
The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein
Ozelius, L. J., Hewett, J. W., Page, C. E., Bressman, S., Kramer, P. L., Shalish, C., de Leon, D., Brin, M. F., Raymond, D., Corey, D. P., et al. (1997) · Nature Genetics · doi:10.1038/ng0997-40 · Cited by 999 · see citing works
Simon, M. A., Bowtell, D. D. L., Dodson, G. S., Laverty, T., & Rubin, G. M. (1991) · Cell · doi:10.1016/0092-8674(91)90065-7 · Cited by 860 · see citing works
The pathophysiology of primary dystonia
Berardelli, A. (1998) · Brain · doi:10.1093/brain/121.7.1195 · Cited by 832 · see citing works
Ichinose, H., Ohye, T., Takahashi, E.-I., Seki, N., Hori, T.-A., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., et al. (1994) · Nature Genetics · doi:10.1038/ng1194-236 · Cited by 770 · see citing works
Epidemiology of focal and generalized dystonia in Rochester, Minnesota
Nutt, J. G., Muenter, M. D., Aronson, A., Kurland, L. T., & Melton, L. J. (1988) · Movement Disorders · doi:10.1002/mds.870030302 · Cited by 479 · see citing works
Mutant Mice and Neuroscience: Recommendations Concerning Genetic Background
Silva, A. J., Simpson, E. M., Takahashi, J. S., Lipp, H.-P., Nakanishi, S., Wehner, J. M., Giese, K. P., Tully, T., Abel, T., Chapman, P. F., et al. (1997) · Neuron · doi:10.1016/s0896-6273(00)80958-7 · Cited by 479 · see citing works
Correction of Deafness in shaker-2 Mice by an Unconventional Myosin in a BAC Transgene
Probst, F. J., Fridell, R. A., Raphael, Y., et al. (1998) · Science · doi:10.1126/science.280.5368.1444 · Cited by 418 · see citing works
Raman, I. M., Sprunger, L. K., Meisler, M. H., & Bean, B. P. (1997) · Neuron · doi:10.1016/s0896-6273(00)80969-1 · Cited by 390 · see citing works
Self-citationRozmahe, R., Wilschanski, M. A., Matin, A., Plyte, S., Oliver, M. G., Auerbach, W., Moore, A. M., Forstner, J., Durie, P. R., Nadeau, J. H., et al. (1996) · Nature Genetics · doi:10.1038/ng0396-280 · Cited by 385 · see citing works
Ordway, J. M., Tallaksen‐Greene, S. J., Gutekunst, C., Bernstein, E. M., Cearley, J. A., Wiener, H. W., Dure, L. S., Lindsey, R., Hersch, S. M., Jope, R. S., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)80464-x · Cited by 370 · see citing works
Felts, P. A., Yokoyama, S., Dib‐Hajj, S. D., Black, J. A., & Waxman, S. G. (1997) · Molecular Brain Research · doi:10.1016/s0169-328x(96)00241-0 · Cited by 333 · see citing works
Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis
Cormier, R. T., Hong, K. H., Halberg, R. B., Hawkins, T. L., Richardson, P., Mulherkar, R., Dove, W. F., & Lander, E. S. (1997) · Nature Genetics · doi:10.1038/ng0997-88 · Cited by 324 · see citing works
Mutation of a new sodium channel gene, Scn8a, in the mouse mutant ‘motor endplate disease’
Burgess, D. L., Kohrman, D. C., Galt, J., Plummer, N. W., Jones, J. M., Spear, B. T., & Meisler, M. H. (1995) · Nature Genetics · doi:10.1038/ng0895-461 · Cited by 307 · see citing works
Movement disorders : neurologic principles and practice
Watts, R. L., & Koller, W. C. (1997) · McGraw-Hill, Health Professions Division eBooks · Cited by 256 · see citing works
Synthetic enhancement in gene interaction: a genetic tool come of age
Guarente, L. P. (1993) · Trends in Genetics · doi:10.1016/0168-9525(93)90042-g · Cited by 238 · see citing works
A novel, abundant sodium channel expressed in neurons and glia
Schaller, K., Krzemien, D., Yarowsky, P., Krueger, B., & Caldwell, J. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-05-03231.1995 · Cited by 231 · see citing works
A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome
L�decke, B., Dworniczak, B., & Bartholom�, K. (1995) · Human Genetics · doi:10.1007/bf00225091 · Cited by 208 · see citing works
Evolution and Diversity of Mammalian Sodium Channel Genes
Plummer, N. W., & Meisler, M. H. (1999) · Genomics · doi:10.1006/geno.1998.5735 · Cited by 202 · see citing works
Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa.
Dryja, T. P., Hahn, L. B., Kajiwara, K., & Berson, E. L. (1997) · PubMed · Cited by 191 · see citing works
Hamilton, B. A., Smith, D. J., Mueller, K. L., Kerrebrock, A. W., Bronson, R. T., van Berkel, V. H., Daly, M. J., Kruglyak, L., Reeve, M. P., Nemhauser, J. L., et al. (1997) · Neuron · doi:10.1016/s0896-6273(00)80312-8 · Cited by 183 · see citing works
Mapping of a major genetic modifier of embryonic lethality in TGFβ1 knockout mice
Bonyadi, M., Rusholme, S. A. B., Cousins, F. M., Su, H. C., Biron, C. A., Farrall, M., & Akhurst, R. J. (1997) · Nature Genetics · doi:10.1038/ng0297-207 · Cited by 166 · see citing works
Cooperation of Pax2 and Pax5 in midbrain and cerebellum development
Urbánek, P., Fetka, I., Meisler, M. H., & Busslinger, M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.11.5703 · Cited by 162 · see citing works
Mutation Detection in the and Alleles of the Sodium Channel
Kohrman, D. C., Harris, J. B., & Meisler, M. H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.29.17576 · Cited by 140 · see citing works
Kohrman, D. C., Smith, M. R., Goldin, A. L., Harris, J. B., & Meisler, M. H. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-19-05993.1996 · Cited by 132 · see citing works
Pathophysiology of idiopathic dystonia: findings from genetic animal models
Richter, A., & Löscher, W. (1998) · Progress in Neurobiology · doi:10.1016/s0301-0082(97)00089-0 · Cited by 126 · see citing works
Neumann, P. E., Frankel, W. N., Letts, V. A., Coffin, J. M., Copp, A. J., & Bernfield, M. R. (1994) · Nature Genetics · doi:10.1038/ng0494-357 · Cited by 119 · see citing works
Duchen, L. W., & Stefani, E. (1971) · The Journal of Physiology · doi:10.1113/jphysiol.1971.sp009340 · Cited by 94 · see citing works
Plummer, N. W., Galt, J., Jones, J. M., Burgess, D. L., Sprunger, L. K., Kohrman, D. C., & Meisler, M. H. (1998) · Genomics · doi:10.1006/geno.1998.5550 · Cited by 91 · see citing works
Self-citationHelwig, U., Imai, K., Schmahl, W., Thomas, B., Varnum, D. S., Nadeau, J. H., & Balling, R. (1995) · Nature Genetics · doi:10.1038/ng0995-60 · Cited by 74 · see citing works
Klein, C., Brin, M. F., de Leon, D., et al. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.7.1133 · Cited by 62 · see citing works
Neuron Death in the Substantia Nigra of Weaver Mouse Occurs Late in Development and Is Not Apoptotic
Oo, T. F., Blazeski, R., Harrison, S. M. W., Henchcliffe, C., Mason, C. A., Roffler-Tarlov, S. K., & Burke, R. E. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-19-06134.1996 · Cited by 61 · see citing works
Garcia, K. D., Sprunger, L. K., Meisler, M. H., & Beam, K. G. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-14-05234.1998 · Cited by 58 · see citing works
Self-citationINHERITED MUSCLE AND NERVE DISEASES IN MICE: A TABULATION WITH COMMENTARY *
Sidman, R. L., Cowen, J. S., & Eicher, E. M. (1979) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1979.tb56567.x · Cited by 51 · see citing works
Insertional mutation of the motor endplate disease (med) locus on mouse chromosome 15
Kohrman, D. C., Plummer, N. W., Schuster, T. G., Jones, J. M., Jang, W., Burgess, D. L., Galt, J., Spear, B. T., & Meisler, M. H. (1995) · Genomics · doi:10.1016/0888-7543(95)80198-u · Cited by 49 · see citing works
Degenerative cerebellar ataxia and focal dystonia
Fletcher, N. A., Stell, R., Harding, A. E., et al. (1988) · Movement Disorders · doi:10.1002/mds.870030410 · Cited by 36 · see citing works
Ion Channel Mutations in Mouse Models of Inherited Neurological Disease
Meisler, M. H., Sprunger, L. K., Plummer, N. W., Escayg, A., & Jones, J. M. (1997) · Annals of Medicine · doi:10.3109/07853899709007484 · Cited by 34 · see citing works
Self-citationNeuromuscular transmission in the murine mutants “motor end-plate disease” and “jolting”
Harris, J. B., & Pollard, S. (1986) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(86)90172-3 · Cited by 28 · see citing works
Lees, A. J., Cools, A. R., van den Bercken, J. H. L., et al. (1990) · Movement Disorders · doi:10.1002/mds.870050218 · Cited by 21 · see citing works
Larkin, L. M., Faulkner, J. A., Hinkle, R. T., Hassett, C. A., Supiano, M. A., & Halter, J. B. (1997) · Journal of Applied Physiology · doi:10.1152/jappl.1997.83.1.67 · Cited by 9 · see citing works
Ezine, S., Papiernik, M., Rieger, F., et al. (1983) · PubMed · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sodium channel Na <sub>v</sub> 1.6 is localized at nodes of Ranvier, dendrites, and synapses
Caldwell, J. H., Schaller, K. L., Lasher, R. S., Peles, E., & Levinson, S. R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.090034797 · Cited by 649 · see citing works
The neurogenetics of alternative splicing
Vuong, C. K., Black, D. L., & Zheng, S. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.27 · Cited by 340 · see citing works
Barclay, J., Balaguero, N., Mione, M., Ackerman, S. L., Letts, V. A., Brodbeck, J., Canti, C., Meir, A., Page, K. M., Kusumi, K., et al. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-16-06095.2001 · Cited by 326 · see citing works
Levin, S. I., Khaliq, Z. M., Aman, T. K., Grieco, T. M., Kearney, J. A., Raman, I. M., & Meisler, M. H. (2006) · Journal of Neurophysiology · doi:10.1152/jn.01193.2005 · Cited by 138 · see citing works
SCNM1, a Putative RNA Splicing Factor That Modifies Disease Severity in Mice
Buchner, D. A., Trudeau, M., & Meisler, M. H. (2003) · Science · doi:10.1126/science.1086187 · Cited by 137 · see citing works
Kearney, J. A. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.22.2765 · Cited by 104 · see citing works
Sodium Channels and Neurological Disease: Insights from Scn8a Mutations in the Mouse
Meisler, M. H., Kearney, J., Escayg, A., Macdonald, B. T., & Sprunger, L. K. (2001) · The Neuroscientist · doi:10.1177/107385840100700208 · Cited by 68 · see citing works
Self-citation
- Authors
- Sprunger, L.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Sprunger, L.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-03-01
- Volume
- 8
- Issue
- 3
- Pages
- 471-479
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2125784996
- Cited by
- 72
- References
- 41
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 1 · 2016: 5 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 1
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- University of Michigan
- National Institutes of Health (5k08hl002972-06)
- National Heart, Lung, and Blood Institute (K08 HL02972)
- National Institute of General Medical Sciences (R01GM024872, GM 24872)
- National Institute of Neurological Disorders and Stroke (NS 34509, R01NS034509)
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- dystonia, SCN8A, neuronal sodium channels, modifier locus, splice site mutation, genetic background effects, progressive paralysis, mouse chromosome 3, ion channels, inherited dystonia
- MeSH terms
- Animals, Central Nervous System, Chromosome Mapping, Crosses, Genetic, Disease Models, Animal, Dystonia, Homozygote, Humans, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Nerve Tissue Proteins, Phenotype, RNA Splicing, Species Specificity, Sodium Channels, Muscle, Skeletal, Mice, NAV1.6 Voltage-Gated Sodium Channel
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
