Abstract
Tottering and leaner, two mutations of the mouse tottering locus, have been studied extensively as models for human epilepsy. Here we describe the isolation, mapping, and expression analysis of Cacnl1a4, a gene encoding the alpha subunit of a proposed P-type calcium channel, and also report the physical mapping and expression patterns of the orthologous human gene. DNA sequencing and gene expression data demonstrate that Cacnl1a4 mutations are the primary cause of seizures and ataxia in tottering and leaner mutant mice, and suggest that tottering locus mutations and human diseases, episodic ataxia 2 and familial hemiplegic migraine, represent mutations in mouse and human versions of the same channel-encoding gene.
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Ashworth LK, Batzer MA, Brandriff B, Branscomb E, deJong P, Garcia E, Games J, Gordon L, Lamerdin JE, Lennon G, Mohrenweiser H, Olsen A, Slezak T, Carrano AV (1995). A metric physical map of human chromosome 19. Nature Genet 11, 422–427
Browne DL, Gancher ST, Nutt JG, Brunt ER, Smith EA, Kramer P, Litt M (1994). Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nature Genet 8, 136–140
Catterall WA (1995). Structure and function of voltage-gated ion channels. Annu Rev Biochem 64, 493–531
Ceci JD (1994). Mouse chromosome 8. Mamm Genome 5 (Suppl), S124-S138
Diriong S, Lory P, Williams ME, Ellis SB, Harpold MM, Taviaux S (1995). Chromosomal localization of the human genes for αIA, α1B, and α1E voltage-dependent Ca2+ channel subunits. Genomics 30, 605–609
Doyle J, Hellevuo K, Stubbs L (1996a). The gene encoding adenylyl cyclase VII is located in central mouse chromosome 8. Mamm Genome 7, 320–321
Doyle J, Hoffman S, Ucla C, Reith W, Mach B, Stubbs L (1996b). Locations of human and mouse genes encoding the RFX1 and RFX2 transcription factor proteins. Genomics 35, 227–230
Gancher ST, Nutt JG (1986). Autosomal dominant episodic ataxia: a heterogeneous syndrome. Movement Disorders 1, 239–253
Green MC, Sidman RL (1962). Tottering-a neuromuscular mutation in the mouse. J Hered 53, 233–237
Griggs RC, Nutt JG (1995). Episodic ataxias as channelopathies. Ann Neurol 37, 285–287
Heckroth JA, Abbott LC (1996). Purkinje cell loss from alternating sagittal zones in the cerebellum of leaner mutant mice. Brain Res 658, 93–104
Hellevuo K, Yoshimura M, Mons N, Hoffman PL, Cooper DM, Tabakoff B (1995). The characterization of a novel human adenylyl cyclase which is present in brain and other tissues. J Biol Chem 270, 11581–11589
Herrup K, and Wilcynski SL (1995). Cerebellar cell degeneration in the leaner mutant mouse. Neuroscience 7, 2185–2196
Hua X, Enerbaeck S, Hudson J, Youkhana K, Gimble JM (1991). Cloning and characterization of the promoter of the murine lipoprotein lipase-encoding gene: structural and functional analysis. Gene 107, 247–258
Joutel A, Bousser MG, Biousse V, Labauge P, Chabriat H, Nibbio A, Maciazek J, Meyer B, Bach MA, Weissenbach J, Lanthrop GM, Tournier-Lasserve E (1993). A gene for familial hemiplegic migraine maps to chromosome 19. Nature Genet 5, 40–45
Kostopoulos GK (1992). The tottering mouse: a critical review of its usefulness in the study of the neuronal mechanisms underlying epilepsy. J Neural Transm 35, 21–36
Kramer PL, Smith E, Carrero-Valenzuela R, Root D, Browne D, Lovrien E, Gancher S, Nutt J, Litt M (1994). A gene for nystagmus-associated episodic ataxia maps to chromosome 19p. (abstract) Am J Hum Genet 55 (Suppl.), A191
Kramer PL, Yue Q, Gancher ST, Nutt JG, Baloh R, Smith E, Browne D, Bussey K, Lovrien E, Nelson S, Litt M (1995). A locus for the nystagmus-associated form of episodic ataxia maps to an 11 cM region on chromosome 19p. Am J Hum Genet 57, 185–189
Kuroiwa Y, Kaneko-Ishino T, Kagitani F, Khoda T, Li L-L, Tada M, Suzuki R, Yokoyama M, Shiroishi T, Wakana S, Barton SC, Ishino F, Surani MA (1996). Peg3 imprinted gene on proximal chromosome 7 encodes a zinc finger protein. Nature Genet 12, 186–190
Levitt P and Noebels JL (1981). Mutant mouse tottering: selective increase of locus ceruleus axons in a defined single-locus mutation. Proc Natl Acad Sci USA 78, 4630–4634
Malouf NM, McMahon DK, Hainsworth CN, Kay BK (1992). A two-motif isoform of the major calcium channel subunit in skeletal muscle. Neuron 8, 899–906
Manly KF (1993). A Macintosh program for the storage and analysis of experimental genetic mapping data. Mamm Genome 4, 303–313
Margolis RL, Breschel TS, Shi-Hua L, Kidwai AS, Antonarakis SE, McInnis MG, Ross CA (1995). Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain. Somatic Cell Mol Genet 21, 279–284
Meier H, MacPike D (1971). Three syndromes produced by two mutant genes in the mouse. J Hered 62, 297–302
Mori Y, Friedrich T, Man-Suk K, Mikami A, Nakai J, Ruth P, Bosse E, Hofmann F, Flockerzi V, Furuichi T, Mikoshiba K, Imoto K, Tanabe T, Numa S (1991). Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature 350, 398–402
Noebels JL, Sidman RL (1979). Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science 204, 1334–1336
Ovnic M, Swank RT, Fletcher C, Zhen L, Novak EK, Baumann H, Heintz N, Ganschow RE (1991). Characterization and functional expression of a cDNA encoding egasyn (esterase-22): the endoplasmic reticulum-targeting protein of β-glucuronidase. Genomics 11, 956–967
Patil N, Cox DR, Bhat D, Faham M, Myers RM, Peterson AS (1995). A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation. Nature Genet 11, 126–129
Ptacek LJ, George AL, Jr, Griggs RC, Tawil R, Kallen RG, Barchi RL, Robertson M, Leppert MF (1991). Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell 67, 1021–1027
Sidman RL, Green MC, Appel SH, eds. (1965). Catalog of the Neurological Mutants of the Mouse (Cambridge, Mass.: Harvard University Press) p 32
Stanfield BB (1989). Excessive intra- and supragranular mossy fibers in the dentate gyrus of tottering (tg/tg) mice. Brain Res 480, 294–299
Starr TV, Prystay W, Snutch TP (1991). Primary structure of a calcium channel that is highly expressed in the rat cerebellum. Proc Natl Acad Sci USA 88, 5621–5625
Stubbs L, Poustka A, Baron A, Lehrach H, Lonai P, Duboule D (1990). The murine genes Hox-5.1 and Hox-4.1 belong to the same HOX complex on chromosome 2. Genomics 7, 422–427
Stubbs L, Carver EA, Shannon ME, Kim J, Geisler J, Generoso EE, Stanford BG, Dunn WC, Mohrenweiser H, Zimmermann W, Watt SM, Ashworth LK (1996). Detailed comparative map of human Chromosome 19q and related regions of the mouse genome. Genomics 35, 499–508
Teh BT, Silburn P, Lindblad K, Betz R, Boyle R, Schalling M, Larsson C (1995). Familial periodic cerebellar ataxia without myokymia maps to a 19-cM region on 19pl3. Am J Hum Genet 56, 1443–1449
Tsuji S, Meier H (1971). Evidence for allelism of leaner and tottering in the mouse. Genet Res 17, 83–88
Vahedi K (1995). A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. Ann Neurol 37, 289–293
Veres G, Gibbs RA, Scherer SE, Caskey CT (1987). The molecular basis of the sparse fur mouse mutation. Science 237, 415–417
von Brederlow B, Hahn AF, Koopman WJ, Ebers GC, Bulman DE (1995). Mapping the gene for acetozolamide responsive hereditary paroxysmal cerebellar ataxia to chromosome 19p. Hum Mol Genet 4, 279–284
Yoon CH (1969). Disturbances in the developmental pathways leading to a neurological disorder of genetic origin, “leaner,” in mice. Dev Biol 20, 158–181
Zasorin NL, Baloh RW, Myers LB (1983). Acetazolamide-responsive episodic ataxia syndrome. Neurology 33, 1212–1214
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Doyle, J., Ren, X., Lennon, G. et al. Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration, and ataxia in tottering and leaner mutant mice. Mammalian Genome 8, 113–120 (1997). https://doi.org/10.1007/s003359900369
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DOI: https://doi.org/10.1007/s003359900369