PubMed 7676316

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Cav1.1 , Kir2.3 , Slo1

Title: Altered calcium currents in human hypokalemic periodic paralysis myotubes expressing mutant L-type calcium channels.

Authors: F Lehmann-Horn, I Sipos, K Jurkat-Rott, R Heine, H Brinkmeier, B Fontaine, L Kovács, W Melzer

Journal, date & volume: Soc. Gen. Physiol. Ser., 1995 , 50, 101-13

PubMed link:

In a genome-wide search, linkage of hypokalemic periodic paralysis (HypoPP), a muscle disease with autosomal dominant inheritance, to chromosome 1q31-32 and cosegregation with the gene encoding the L-type calcium channel/DHP receptor alpha 1 subunit has been reported (Fontaine et al., 1994). Here we show the extended haplotypes of a large HypoPP family who made the detection of the gene product possible. Sequencing of cDNA synthesized from RNA isolated from muscle specimens of two affected family members revealed a G-to-A transition of nucleotide 3716. This base exchange predicts a substitution of histidine for arginine 1239 located in segment IVS4 of the channel protein. By restriction fragment analysis, the mutation was detected in the genomic DNA of all affected family members. Myotubes cultured from the muscle specimens also revealed the mutation suggesting the expression of mutant L-type calcium channel/DHP receptors. Whole-cell recordings of 20 such myotubes showed a strong reduction of the DHP sensitive, slowly activating and inactivating L-type current density to 30% of the current in normal controls. A rapidly activating and inactivating current component (third-type), which is distinct from the also occurring T-type current, was increased. We conclude that HypoPP is a disease of the skeletal muscle DHP receptor. The point mutation in repeat IV of the protein may have a similar effect as drugs which downregulate the channel activity by binding to this domain.