Coding and noncoding variation of the human calcium-channel beta(4)-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodicataxia

Inactivation of the beta(4) subunit of the calcium channel in the mouse neu rological mutant lethargic results in a complex neurological disorder that includes absence epilepsy and ataxia. To determine the role of the calcium- channel beta(4)-subunit gene CACNB4 on chromosome 2q22-23 in related human disorders, we screened for mutations in small pedigrees with familial epile psy and ataxia. The premature-termination mutation R482X was identified in a patient with juvenile myoclonic epilepsy. The R482X protein lacks the 38 C-terminal amino acids containing part of an interaction domain for the alp ha(1) subunit, The missense mutation C104F was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a Frenc h Canadian family with episodic ataxia. These coding mutations were not det ected in 255 unaffected control individuals (510 chromosomes), and they may be considered candidate disease mutations, The results of functional tests of the truncated protein R482X in Xenopus laevis oocytes demonstrated a sm all decrease in the fast time constant for inactivation of the cotransfecte d alpha(1), subunit, Further studies will be required to evaluate the in vi vo consequences of these mutations. We also describe eight noncoding single -nucleotide substitutions, two of which are present at polymorphic frequenc y, and a previously unrecognized first intron of CACNB4 that interrupts exo n 1 at codon 21.