International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F39 The stargazer Gene Product is One Member of a Family of Gamma Subunits of Voltage Dependent Calcium Channels

Verity A. Letts, Connie L. Mahaffey and Wayne N. Frankel. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609

The gamma2 gene, Cacng2, was first identified as the defective gene in the stargazer mouse. This mouse has epileptic seizures in addition to an ataxic gait and a distinctive head tossing activity. The Cacng2 gene encodes a protein of 323 amino acids with four transmembrane domains, a feature in common with the secondary protein structure of the gamma subunit, Cacng1, found in skeletal muscle. However unlike Cacng1, the Cacng2 gene is expressed exclusively in brain, predominantly in the cerebellum, hippocampus and olfactory lobes.

Although Cacng1 and Cacng2 retain only 25% identity at the amino acid level, the Cacng2 sequence has striking similarity to two other brain-specific genes that we have recently cloned; 75% identity with the Cacng3 product and 60% identity with the Cacng4 protein. We have mapped the Cacng3 gene to mouse Chromosome 7 and the Cacng4 gene to mouse Chromosome 11; thus they are both distinct to Cacng2 on mouse Chromosome 15 but are obviously closely-related members of the same family.

As with the brain gamma subunits, it has been found that the other calcium channel subunits, namely alpha1, beta and alpha2-delta, also have multiple isoforms. Thus calcium channels can be assembled with a variety of combinations of these proteins, providing they are present in the same cellular location. However, clearly certain isoforms do play a critical role in normal brain development as mutations in the alpha1A (tottering), beta4 (lethargic) and gamma2 (stargazer) genes all result in mice with ataxic gaits and absence epilepsy.

To understand more about the function of the related gamma subunit members, we have produced mice with targeted disruptions in these genes and we will present our studies of these mice. In addition we will present analysis of the expression of these genes within the brain, and how their expression compares with Cacng2 and other subunit genes of the voltage dependent calcium channels.

 


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