Coding and Noncoding Variation of the Human Calcium-Channel β4-Subunit Gene CACNB4 in Patients with Idiopathic Generalized Epilepsy and Episodic Ataxia

Description

Inactivation of the subunit of the calcium channel in the mouse neurological mutant b4 lethargic results in a complexneurological disorder that includes absence epilepsy and ataxia. To determine the role of the calcium-channel b4-subunit gene CACNB4 on chromosome 2q22-23 in related human disorders, we screened for mutations in smallpedigrees with familial epilepsy and ataxia. The premature-termination mutation R482X was identified in a patientwith juvenile myoclonic epilepsy. The R482X protein lacks the 38 C-terminal amino acids containing part of aninteraction domain for the subunit. The missense mutation C104F was identified both in a German family with a1generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. These codingmutations were not detected in 255 unaffected control individuals (510 chromosomes), and they may be consideredcandidate disease mutations. The results of functional tests of the truncated protein R482X in Xenopus laevisoocytes demonstrated a small decrease in the fast time constant for inactivation of the cotransfected subunit. a1Further studies will be required to evaluate the in vivo consequences of these mutations. We also describe eightnoncoding single-nucleotide substitutions, two of which are present at polymorphic frequency, and a previouslyunrecognized first intron of CACNB4 that interrupts exon 1 at codon 21

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