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

E30 Seizure Susceptibility from a Locus on Chromosome 1: Gene Candidates for Szs1

R. J. Buono, T. N. Ferraro, M. R. Sperling, M. J. O'Connor, S. G. Ryan, G. T. Golden, G. G. Smith, and W. H. Berrettini. University of Pennsylvania, Philadelphia, PA, VAMC, Coatsville, PA; Thomas Jefferson University, Philadelphia, PA; Childrens Hospital of Philadelphia

Quantitative trait locus (QTL) mapping in DBA/2J (D2) and C57BL/6J (B6) mice has identified Szs1, a site on chromosome 1 harboring a gene(s) of large effect on susceptibility to both generalized and partial seizures. We have begun to investigate candidates for Szs1 to identify the gene (s) responsible for the inherent seizure sensitivity of the D2 strain. Evidence continues to accumulate suggesting that genes related to ion homeostasis are logical candidates for involvement in susceptibility to complex forms of human and murine seizure disorder. Seventy-five mouse genes have been mapped to the QTL region of interest. Among the various of candidates under investigation are ATP1A2 and ATP1B1, alpha and beta subunits respectively of the Na-K ATPase and KIR.4.1 an inward-rectifying potassium ion channel. The syntenic region of human chromosome 1 has provided additional candidates for study including the potassium ion channel genes KIR 3.3, TREK1, TWIK-1, HLK and KCNN3, and acetylcholine receptor subunit genes CHRNB2 and CHRM3 as well as the gene encoding glutamine synthetase (GS). We have isolated candidate gene cDNAs and compared the D2 and B6 sequences searching for polymorphisms which represent Szs1. Results show no exonic nucleotide variations that cause amino acid changes between B6 and D2 mice for KIR3.3, ATP1A2, ATP1B1 or TREK1. Other candidates are in various stages of analysis. Studies on KIR 4.1 have identified a single conservative amino acid change between B6 and D2 mice (B6/D2 T261S, [C785G]), the functional significance of which remains to be tested. TWIK1 and HLK3 have been mapped to murine chromosomes 8 and 3 respectively and are therefore excluded as Szs1 candidates.

Additionally, mutation scanning of the human homologs of these candidates is being conducted on samples from patients with both generalized and partial epilepsy. Three novel polymorphisms have been identified in the human ATP1A2 gene, but preliminary data suggest a lack of association between these variations and human partial (temporal lobe) or generalized epilepsy (CAE, JME). Our goal is to systematically investigate candidates until we translate the Szs1 QTL into a known gene mutation for study in mice as well as humans with epilepsy.


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