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nature genetics volume 19 august 1998 313

exceedingly time-sensitive; the applicationof conventional biochemistry and cell biol-ogy approaches, combined with theaccrual of additional RP2 mutations, meanthat despite its extremely low expression,the true function of RP2 is unlikely toremain in the dark. ■■

Stargazing nets new calciumchannel subunit

Ram S. Puranam1 & James O. McNamara1,2

1Department of Veterans Affairs Medical Center and Department of Medicine, Division of Neurology, (puranam@neuro.duke.edu) and 2Department ofPharmacology and Cancer Biology, (jmc@neuro.duke.edu), Duke University Medical Center, 401 Bryan Research Building, Research Drive,

Durham, North Carolina 27710, USA.

Epilepsy, a brain disorder manifested byrecurrent seizures, afflicts approximately1% of humans. A seizure is a fleetingchange in behaviour caused by disor-dered, rhythmic, and synchronous firingof populations of neurons in the centralnervous system (CNS). The behaviouralfeatures of different types of seizures aredetermined by the distinct populations ofCNS neurons that fire abnormally.Together, the epilepsies are an extraordi-narily diverse collection of disorders, as istestified by the more than 40 distinctforms of human epileptic syndromes1.Genetic susceptibility contributes to atleast one third of human epilepsies, butthe identity of the susceptibility genes islargely unknown.

On page 340 of this issue2, Verity Lettand colleagues identify the gene mutationthat underlies a spontaneously arisingform of genetic epilepsy in a mousemutant called ‘stargazer’, a name inspiredby its distinctive head movement, presum-ably due to a defect in vestibular function3.The gene encodes a γ subunit of a voltage-sensitive calcium channel (VSCC) and isthe first γ subunit known to be expressedin the nervous system. The stargazermouse is one of several spontaneouslyarising mutants that exhibit spike-waveepilepsy; the spike-wave electroencephalo-gram of stargazer closely resembles thatobserved in humans with absence (orpetit-mal) epilepsy. VSCCs constitute afamily of diverse proteins that mediateCa2+ entry through the plasma mem-brane4, thereby controlling release of neu-rotransmitters, intracellular signalingpathways and gene expression5. They arecomposed of an α1 subunit that serves asthe membrane pore and voltage sensor.

Auxiliary subunits α2, δ and β modulatethe kinetics of activation, inactivation,current density and drug binding4. Inaddition, the presence of the γ subunit inskeletal muscle regulates both the peakcurrents and rates of activation at morenegative potentials6.

The evidence that the Ca2+ channel γsubunit is indeed the mutant proteinunderlying the stargazer phenotype iscompelling. The authors used standardmethods to narrow down a chromosomalregion previously demonstrated to‘house’ the critical gene7, and, uponobserving a suspect pattern by Southernblot analysis of ‘stargazer’ DNA (whencompared with wildtype), suspected thatinsertion of an early transposon might beto blame. Sequence analysis confirmedthis suspicion, and defined the ‘inter-rupted’ gene, subsequently called Cacng2.Its expression was found to be restrictedto the brain, and its coexpression in a cellline stably expressing neuronal α1AVSCCs (alongside α2δ, and β1d) dis-closed a negative shift of the voltagedependence of inactivation. This wouldlead to a significant reduction in channelavailability at typical neuronal restingpotential. Removal of this effect, as ispredicted to be the case in the stargazer

mouse, would facilitate Ca2+ entry intothe cell—an effect probably mediated bythe interaction of Cacng2 with the othersubunits of the VSCC. This observationincreases the likelihood that the novelgene is indeed a γ subunit, because themuscle γ subunit exerts a similar effect onsome VSCCs.

The discovery that a mutant ion chan-nel underlies a paroxysmal disorder inwhich the affected individual is normalmost of the time is not surprising. Similardisorders, such as cardiac arrhythmias,have been linked to mutations of genesencoding voltage-sensitive sodium andpotassium channels. Episodic ataxias havebeen linked to genes encoding mutationsof voltage-sensitive potassium and cal-cium channels. Completing the triangleare episodic paralyses due intrinsic mus-cle disorder, which have been linked tomutations in genes encoding voltage-sen-sitive sodium and calcium channels8.Other epilepsies have been linked tomutant ion channels9–12, and on page 366of this issue, Robyn Wallace and col-leagues13 demonstrate that febrile seizureand generalized epilepsy is caused bymutation in SCN1B, which encodes asodium channel subunit. In addition, twoother mutant mouse strains, lethargic andtottering, have mutations in genes en-coding the α1A and β subunits, respec-tively, of the voltage-regulated calciumchannels14,15. It is remarkable, therefore,that despite the recurring theme of peri-odic disturbances linked to aberrant ionchannels and the fact that these distur-bances share precipitating factors (forexample, stress), it remains to be deter-mined how and why a defective ion chan-nel results in periodic disturbance.

1. Dryja, T.P. & Li T. Hum. Mol. Genet. 4, 1739−1743(1995).

2. McWilliam, P. et al. Genomics 5, 619−622 (1989).3. Dryja, T.P. et al. Nature 343, 364−366 (1990).4. Meindl, A. et al. Nature Genet. 13, 35−42 (1996).5. Roepman, R. et al. Hum. Mol. Genet. 5, 1035−1041

(1996).6. Buraczynska, M. et al. Am. J. Hum. Genet. 61, 1287−

1292 (1997).7. Jay, M. Br. J. Ophthalmol. 66, 405−416 (1982).8. The European Chromosome 16 Tuberous Sclerosis

Consortium. Cell 75, 1305−1315 (1993).9. Nishimura, D.Y. et al. Nature Genet. 19, 140−147

(1998).10. Kazazian, H.H. Jr. & Moran, J.V. Nature Genet. 19,

19−24 (1998).11. Allikmets, R. et al. Nature Genet. 15, 236−246

(1997).12. Tian, G. et al. Cell 26, 287−296 (1996).13. Sung, C.H., Schneider, B.G., Agarwal, N.,

Papermaster, D.S. & Nathans, J. Proc. Natl Acad. Sci.USA 88, 8840−8844 (1991).

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314 nature genetics volume 19 august 1998

Casing out Cacng2The discovery of Cacng2 raises a diversityof intriguing questions for calcium channelaficionados. What Ca2+ channel subunitsinteract with it? Is the α1 A subunit uniqueamong α1 subunits in its presumed inter-action with the novel gene? An intriguingalternative to the α1 A subunit is therecently discovered α1 G subunit whichhas similar properties to T channels16. Tchannel activation results in the generationof calcium action potentials that con-tribute to the disordered cortical thalamicoscillations and spike wave seizures; anti-convulsants used to treat absence seizuresinhibit T channel activation. In what partof the neuron is the γsubunit expressed? Itssubcellular site (for example, dendriticspines or presynaptic terminals) will pro-vide additional clues with respect to poten-tial role(s) in the regulation of cell firingand transmitter release. The demonstratedrole of Ca2+ entry through VSCCs in thecontrol of gene expression suggests thatthe local demesne of intracellular Ca2+

includes proteins involved in signal trans-duction which culminates in transcrip-tional control. Interestingly, the neuronalγsubunit contains an additional 100 aminoacids in the C terminus in comparison tothe γ subunit of skeletal muscle. Given thepresumptive intracellular locale of theC terminus, might these 100 amino acidsmediate some protein-protein interactionspivotal in signalling? Answers to thesequestions will be obtained by usinghighly selective antibodies to map ex-pression patterns, a green fluorescent pro-tein–γ subunit fusion protein to determinesubcellular locale and the yeast two-hybrid system, using portions of theneuronal γ subunit as bait to detect inter-acting proteins.

Two aspects of the stargazer phenotypeare equally intriguing and yet strikinglydisparate in their time course and func-tional neuroanatomy. Seizures occurepisodically, begin and end abruptly, andlast seconds. By contrast, the ataxia is per-sistent. With respect to neuroanatomy, theseizures involve abnormal firing of neu-ronal populations in cerebral cortex andthalamus whereas the ataxia is presumablydue to defective function intrinsic to neu-rons of the cerebellum and/or its connec-tions. The absence of overt depletion ofcerebellar neuronal populations suggeststhat the ataxia may be due to defectivefunction of otherwise normal circuitry.These disparate features raise the interest-ing possibility that distinct consequencesof mutant Ca2+ channels underlie theseizures and the ataxia. With respect to theseizures, it is easy to imagine that defectiverelease of neurotransmitters mediated bychannels in presynaptic terminals over aperiod of milliseconds to seconds mightdisrupt the delicate balance of neuronalexcitability and be expressed as a spikewave seizure. This raises the question ofwhether the mutant channel differentiallymodifies release of inhibitory comparedwith excitatory transmitter in effectingincreased excitability. It also begs the ques-tions: what actually precipitates the onsetof the seizure, what terminates the seizure,and why does the animal not have contin-ual seizure? With respect to the ataxia, per-sistence of the defect suggests that somelong-lasting consequence of defective Ca2+

channel function compromises cerebellarneuronal function. One such consequencewould be alterations in gene expression.The authors note that mRNA encoding theneurotrophin Bdnf (which has powefuleffects on synaptic transmission) is strik-

ingly reduced in the cerebellum ofstargazer mice. As Ca2+ entry throughVSCCs plays a crucial role in controllingthe transcription of Bdnf, it is easy to imag-ine that defective expression of Bdnf wouldresult; the authors’ suggestion that alteredexpression of Bdnf might contribute to theataxia is certainly plausible.

The identification of the stargazer genehas clinical implications. Absence epilepsyin humans is a complex genetic disease; itoccurs with a greater frequency in relativesof affected individuals yet does not exhibita simple mendelian pattern—it seems thatmultiple genes are simultaneously involved(that is, the disorder is polygenic) and thata diversity of ‘susceptibility’ genes collabo-rate in determining risk. The γ subunit ofthe VSCCs warrants careful study by allinvestigators seeking these genes. Withrespect to clinical practice, patients withabsence epilepsy respond differently tocurrently available anti-convulsants; eluci-dating how the stargazer genotype resultsin the phenotype of absence seizurespromises new vistas of anti-absence phar-macology and may benefit large numbersof affected individuals. ■■

1. Commission on Classifiication and Terminology othe International League against Epilepsy. Epilepsia30, 389–399 (1989).

2. Letts, V.A. et al. Nature Genet. 19, 340–347 (1998).3. Noebels, J.L. et al. Epilepsy Res. 7, 129–135 (1990).4. Varadi, G. et al. Trends Pharmacol. Sci. 16, 43–49

(1995).5. Bito, H. et al. Curr. Opin. Neurobiol. 7, 419–429

(1997).6. Wei, X.Y. et al. J. Biol. Chem. 266, 21943–21947

(1991).7. Letts,V.A. et al. Genomics 43, 62–68 (1997).8. Ptacek, L.J. Curr. Opin. Neurol. 11, 217–226 (1998).9. Phillips, H.A. et al. Nature Genet. 10, 117–118 (1995).

10. Singh, N.A. et al. Nature Genet. 18, 25–29 (1998).11. Biervert, C. et al. Science 279, 403–406 (1998).12. Charlier, C. et al. Nature Genet. 18, 53–55 (1998).13. Wallace, R. et al. Nature Genet. 19, 366–370 (1998).14. Fletcher, C.F. et al. Cell 87, 607–617 (1996). 15. Burgess, D.L. et al. Cell 88, 385–392 (1997).16. Perez-Reyes, E. et al. Nature 391, 896–900 (1998).

Alzheimer disease—when and why?Donald L. Price1, Sangram S. Sisodia2 & David R. Borchelt3

1,3Departments of Pathology, 1Neurology and 1Neuroscience and the 1,3Division of Neuropathology, The Johns Hopkins University School of Medicine,Baltimore, Maryland, USA. 2Department of Pharmacological & Physiological Sciences, University of Chicago, Chicago, Illinois, USA.

e-mail: dlprice@welchlink.welch.jhu.edu

With changing global demography, age-associated impairments in cognition andmemory processes are becoming increas-ingly prevalent. The most frequent cause ofdementia in the elderly is Alzheimer dis-ease (AD), an illness resulting from selec-tive damage of specific neuronal circuits inthe neocortex, hippocampus, and basalforebrain cholinergic system1 (Fig. 1).

Within these circuits, many neuronsdevelop neurofibrillary tangles and dys-trophic neurites, which reflect the localaccumulation of abnormal intracytoplas-mic filaments, composed principally ofhyperphosphorylated isoforms of the tauprotein2. Affected regions also show senileplaques (Fig. 2), comprised of neurites dis-played around extracellular deposits of

small, 4-kD β-amyloid peptides, the latteracting as a nidus for the recruitment ofastrocytes and microglia and for the depo-sition of other proteins.

It is now well-established that someforms of AD, mainly early-onset cases,show autosomal dominant inheritancepatterns due to the presence of mutatedgenes3, including those encoding amyloid

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