Mutation of the Ca2+ Channel β Subunit Gene Cchb4 Is Associated with Ataxia and Seizures in the Lethargic (lh) Mouse

Burgess, Daniel L.; Jones, Julie Miller; Meisler, Miriam H.; Noebels, Jeffrey L.

doi:10.1016/s0092-8674(00)81877-2

Cited by 392 publications

(243 citation statements)

References 48 publications

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“…A significant reduction in calcium current density was recorded from Purkinje cells of tottering mice (28). A splice site mutation in the β4 subunit gene Cacnb4 that produces a truncated, nonfunctional protein was identified in the mouse mutant lethargic (12). lethargic mice exhibit absence seizures, lethargy, and ataxia, and go through a crisis during the third week of life.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

“…Underrepresentation of one allele could be caused by a mutation in regulatory sequences or reduced mRNA stability due to a transcribed variant. The mouse calcium channel mutations lethargic (12) and spike wave epilepsy (22) both reduce mRNA stability in addition to changing the protein sequence.…”

Section: Future Prospects Additional Monogenic Epilepsy Genes In Humanmentioning

confidence: 99%

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Identification of Epilepsy Genes in Human and Mouse

et al. 2001

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The development of molecular markers and genomic resources has facilitated the isolation of genes responsible for rare monogenic epilepsies in human and mouse. Many of the identified genes encode ion channels or other components of neuronal signaling. The electrophysiological properties of mutant alleles indicate that neuronal hyperexcitability is one cellular mechanism underlying seizures. Genetic heterogeneity and allelic variability are hallmarks of human epilepsy. For example, mutations in three different sodium channel genes can produce the same syndrome, GEFS+, while individuals with the same allele can experience different types of seizures. Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations. Large-scale patient screening is in progress to determine whether less severe alleles of the genes responsible for monogenic epilepsy may contribute to the common types of epilepsy in the human population. The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies.

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Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Section: Future Prospects Additional Monogenic Epilepsy Genes In Humanmentioning

confidence: 99%

Identification of Epilepsy Genes in Human and Mouse

et al. 2001

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“…Interestingly, it was recently shown that a mutation in the calcium channel 4 subunit gene is associated with ataxia and seizures in the lethargic mouse (1h). 102 Homozygotes of the 1h mouse are characterised by ataxia, lethargic behaviour, motor seizures and seizures resembling absence seizures of human petit mal epilepsy. 102…”

Section: P/q Type Calcium Channel α 1a Subunit Gene In Mice With Epilmentioning

confidence: 99%

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Terwindt

Ophoff²,

Haan

et al. 1998

Eur J Hum Genet

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Clinical and genetic heterogeneity as well as influence of environmental factors have hampered identification of the genetic factors which are involved in episodic diseases such as migraine, episodic ataxia and epilepsy. The study of rare, but clearly genetically determined subtypes, may help to unravel the pathogenesis of the more common forms. Recently, different types of mutation in the brain-specific P/Q type calcium channel α 1A subunit gene (CACNA1A) on chromosome 19p13 were shown to be involved in three human disorders: familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2), and chronic spinocerebellar ataxia type 6 (SCA6). In addition, evidence is accumulating that the same gene is also involved in the common forms of migraine with and without aura. In the tottering and leaner mouse, which are characterised by epilepsy and ataxia, similar mutations were identified in the mouse homologue of the calcium channel α 1A subunit gene. These findings add to the growing list of episodic (and now also chronic) neurological disorders, which are caused by inherited abnormalities of voltage-dependent ion channels. The findings in migraine illustrate that rare, but monogenic variants of a disorder, may be successfully used to identify candidate genes for the more common, but genetically more complex, forms.

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“…Knockout of ␤ 3 reduces the activities of neuronal L-type and N-type channels (20). The lethargic mouse, an effective ␤ 4 null mutant, is characterized by seizure activity and ataxia; however, the density of presynaptic calcium channels is not affected possibly because of compensation from other ␤ subunit subtypes (19,44). Indeed, the combinatorial complexity of multiple ␤ and ␣ 1 subunits has prevented detailed insights into the precise function of ␤ subunits in synaptic terminals in vivo (21).…”

Section: Lymnaea Neurons Express a Ca V ␤ Subunit-a Full-lengthmentioning

confidence: 99%

Uncoupling of Calcium Channel α1 and β Subunits in Developing Neurons

Spafford

Minnen

Larsen

et al. 2004

Journal of Biological Chemistry

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Calcium channel ␤ subunits are key modulators of calcium channel function and membrane targeting of the pore-forming ␣ 1 subunit. Here we show that an invertebrate (Lymnaea stagnalis) homolog of P/Q-and Ntype calcium channels (LCa v 2), although colocalized with ␤ subunits in synapses of mature neurons, is physically uncoupled from the ␤ subunits in the leading edge of growth cones of outgrowing neurons. Moreover, LCa v 2 channels that mediate transmitter release in mature synapses also participate in neuronal outgrowth in growth cones. The differential association of ␤ subunits with synaptic calcium channels and those expressed in emergent neuronal growth suggests that ␤ subunits may play a role in the transformation of Ca v 2 calcium channel function in immature neurons and mature synapses.

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Mutation of the Ca2+ Channel β Subunit Gene Cchb4 Is Associated with Ataxia and Seizures in the Lethargic (lh) Mouse

Cited by 392 publications

References 48 publications

Identification of Epilepsy Genes in Human and Mouse

Identification of Epilepsy Genes in Human and Mouse

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Uncoupling of Calcium Channel α1 and β Subunits in Developing Neurons

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