Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disease with autosomal dominant inheritance triggered by exposure to commonly used inhalational anaesthetics or depolarising muscle relaxants. A MHS locus has been identified on human chromosome 19q12-q13.2 and the gene for the skeletal muscle calcium release channel of sarcoplasmic reticulum (ryanodine receptor) (RYR1) is considered a candidate for the molecular defect. However, MH has been shown to be genetically heterogeneous, and in the ensuing search for other MHS genes, a locus on chromosome 17q has been proposed, and the gene for the adult muscle sodium channel (SCN4A) was suggested as a candidate. We performed linkage studies using polymorphic microsatellite markers for subunits of the skeletal muscle dihydropyridine (DHP) receptor, CACNL1A3 mapped to chromosome 1q, as well as C-ACNLB1 and CACNLG, the latter two localised on chromosome 17q11.2-q24 in proximity to the proposed MHS2 and the SCN4A loci, and we also included markers for the loci D17S250, D17S579, NM23 (NME1), GH1, and SCN4A from that region. Our results exclude the alpha 1, beta 1 and gamma subunit of the DHP receptor as well as the SCN4A locus from that region. Our results exclude the alpha 1, beta 1, and gamma subunit of the DHP receptor as well as the SCN4A locus as candidates for the molecular defect in MHS for these pedigrees where also the RYR1 on chromosome 19q13.1 has been excluded. A multipoint analysis excludes the disease from the entire 84 cM interval containing the proposed MHS locus on chromosome 17q.(ABSTRACT TRUNCATED AT 250 WORDS)