Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.

TY - JOUR

T1 - Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.

AU - Jouvenceau, A

AU - Eunson, L H

AU - Spauschus, Alexander

AU - Ramesh, V

AU - Zuberi, S M

AU - Kullmann, D M

AU - Hanna, M G

PY - 2001

Y1 - 2001

N2 - BACKGROUND: The genetic basis of most common forms of human paroxysmal disorders of the central nervous system, such as epilepsy, remains unidentified. Several animal models of absence epilepsy, commonly accompanied by ataxia, are caused by mutations in the brain P/Q-type voltage-gated calcium (Ca(2+)) channel. We aimed to determine whether the P/Q-type Ca(2+) channel is associated with both epilepsy and episodic ataxia type 2 in human beings. METHODS: We identified an 11-year-old boy with a complex phenotype comprising primary generalised epilepsy, episodic and progressive ataxia, and mild learning difficulties. We sequenced the entire coding region of the gene encoding the voltage-gated P/Q-type Ca(2+) channel (CACNA1A) on chromosome 19. We then introduced the newly identified heterozygous mutation into the full-length rabbit cDNA and did detailed electrophysiological expression studies of mutant and wild type Ca(2+) channels. FINDINGS: We identified a previously undescribed heterozygous point mutation (C5733T) in CACNA1A. This mutation introduces a premature stop codon (R1820stop) resulting in complete loss of the C terminal region of the pore-forming subunit of this Ca(2+) channel. Expression studies provided direct evidence that this mutation impairs Ca(2+) channel function. Mutant/wild-type co-expression studies indicated a dominant negative effect. INTERPRETATION: Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca(2+) channel. The phenotype in this patient has striking parallels with the mouse absence epilepsy models.

AB - BACKGROUND: The genetic basis of most common forms of human paroxysmal disorders of the central nervous system, such as epilepsy, remains unidentified. Several animal models of absence epilepsy, commonly accompanied by ataxia, are caused by mutations in the brain P/Q-type voltage-gated calcium (Ca(2+)) channel. We aimed to determine whether the P/Q-type Ca(2+) channel is associated with both epilepsy and episodic ataxia type 2 in human beings. METHODS: We identified an 11-year-old boy with a complex phenotype comprising primary generalised epilepsy, episodic and progressive ataxia, and mild learning difficulties. We sequenced the entire coding region of the gene encoding the voltage-gated P/Q-type Ca(2+) channel (CACNA1A) on chromosome 19. We then introduced the newly identified heterozygous mutation into the full-length rabbit cDNA and did detailed electrophysiological expression studies of mutant and wild type Ca(2+) channels. FINDINGS: We identified a previously undescribed heterozygous point mutation (C5733T) in CACNA1A. This mutation introduces a premature stop codon (R1820stop) resulting in complete loss of the C terminal region of the pore-forming subunit of this Ca(2+) channel. Expression studies provided direct evidence that this mutation impairs Ca(2+) channel function. Mutant/wild-type co-expression studies indicated a dominant negative effect. INTERPRETATION: Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca(2+) channel. The phenotype in this patient has striking parallels with the mouse absence epilepsy models.

M3 - SCORING: Zeitschriftenaufsatz

VL - 358

SP - 801

EP - 807

JO - LANCET

JF - LANCET

SN - 0140-6736

IS - 9284

M1 - 9284

ER -