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

E36 Szs1, A Fundamental Seizure-Related Locus on Mouse Chromosome 1

T. N. Ferraro, G. T. Golden, G. G. Smith, P. St. Jean, N. J. Schork, R. J. Buono, and W. H. Berrettini. University of Pennsylvania, Philadelphia, PA; VAMC Coatesville PA; Case Western Reserve University, Cleveland, OH

DBA (D2) mice are sensitive to a wide variety of experimentally-induced seizures whereas C57 (B6) mice are relatively resistant. The large difference in seizure sensitivity between D2 and B6 mice is a multifactorial trait amenable to dissection by quantitative trait locus (QTL) mapping. Three parallel QTL studies utilizing D2 x B6 F2 mice were conducted to map loci for seizure response to kainic acid (KA, 25 mg/kg, sc, n = 257) and pentylenetetrazol (PTZ, 80 mg/kg, sc, n = 511) and for maximal electroshock seizure threshold (MEST, n=297). Testing involved determination of seizure expression and latency using one injection of KA or PTZ or measurement of MEST using a stardard ramp-up paradigm. Mapping involved a full genome scan (10-20 cM resolution) and a battery of statistical tests including contingency analysis, multivariate logistic regression and multipoint linkage. Results document a complex genetic determinism for seizure sensitivity in D2 and B6 mice with several loci in common between the QTL studies and other paradigm-specific loci. The locus of greatest effect in all three studies, termed Szs1, is on distal chr.1 and explains about 25% of the total phenotypic variance between D2 and B6 mice. The bounds of this locus overlap closely in the 3 studies with the interval between D1Mit30 and D1Mit17 giving LOD scores of 5.5, 12 and 10 for KA, PTZ and MEST, respectively. These scores each correspond to P < 10-4, a suggested threshold for declaring significant linkage in QTL studies. Refinement of the interval containing Szs1 using congenic strains derived from D2 and B6 mice has localized MEST and PTZ sensitivity to an 8-16 cM region between D1Mit145 and D1Mit17. We conclude that this region contains a gene(s) with a fundamental role in neuronal excitability, variations of which are related to lower seizure threshold and higher seizure sensitivity.

 


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