Mammalian Genome 4, 711-715 (1993). "~renome 9 Springer-Verlag New York Inc. 1993 Localization of Shaw-related K § channel genes on mouse and human chromosomes M. Haas, 1 D.C. Ward, 1 J. Lee, 2 A.D. Roses, 3 V. Clarke, 4 P. D'Eustachio, 4 D. Lau, s E. Vega-Saenz de Miera, s B. Rudy5 1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA ZDepartment of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710, USA 3Division of Neurology, Duke University Medical Center, Durham, North Carolina 27710, USA 4Department of Biochemistry, New York University Medical Center, 550 First Avenue, New York, New York 10016, USA 5Department of Physiology and Biophysics, New York University Medical Center, 550 First Avenue, New York, New York 10016, USA Received: 5 May 1993 / Accepted: 19 July 1993 Abstract. Four related genes, Shaker, Shab, Shaw, and Shal, encode voltage-gated K § channels in Dro- sophila. Multigene subfamilies corresponding to each of these Drosophila genes have been identified in ro- dents and primates; this suggests that the four genes are older than the common ancestor of present-day insects and mammals and that the expansion of each into a family occurred before the divergence of rodents and primates. In order to define these evolutionary relationships more precisely and to facilitate the search for mam- malian candidate K + channel gene mutations, we have mapped members of the Shaw-homologous gene fam- ily in humans and mice. Fluorescence in situ hybrid- ization analysis of human metaphase chromosomes mapped KCNC2 (KShlIIA, KV3.2) and KCNC3 (KShlIID, KV3.3) to Chromosome (Chr) 19q13.3- q13.4. Inheritance patterns of DNA restriction frag- ment length variants in recombinant inbred strains of mice placed the homologous mouse genes on distal Chr 10 near Ms15-8 and Mdm-1. The mouse Kcncl (KShlIIB, NGK2-KV4, KV3.1) gene mapped to Chr 7 near Tam-1. These results are consistent with the hypothesis that the generation of the mammalian KCNC gene family included both duplication events to generate family members in tandem arrays (KCNC2, KCNC3) and dispersion of family members to unlinked chromo- somal sites (KCNC1). The KNCN2 and KCNC3 genes define a new synteny group between humans and mice. Correspondence to: B. Rudy Introduction Voltage-gated potassium channels are ubiquitous membrane proteins of eukaryotic cells and are impli- cated in functions ranging from modulation of the fir- ing properties of neurons to regulation of T lympho- cyte mitogenesis (Cahalan et al. 1991; Hille 1992; Lli- nas 1988; Rudy 1988). In Drosophila, four related genes, Shaker, Shab, Shaw, and Shal, encode K § channels with distinctive kinetics and voltage sensitiv- ities (Wei et al. 1990). In rodents and humans, families of genes have been identified that correspond to each of the four Drosophila K § channel genes (Rudy et al. 1991a; Jan and Jan 1990; Perney and Kaczmarek 1991). Determining the chromosomal locations of these mammalian channel genes is of considerable interest for two reasons. First, the existence of these four sep- arate genes encoding K + channels appears to pre-date the divergence of ancestors of present-day insects and mammals, and the mammalian gene families in turn appear to have arisen before the divergence of the an- cestors of present-day rodents and primates. These genes should thus be exceptionally useful for the anal- ysis of synteny and paralogy relationships (Nadeau 1991; O'Brien et al. 1993). Second, there are extensive catalogs of genetically well-characterized mutations of humans and mice that cause visible neurological de- fects but whose molecular causes remain unknown. These include both classical single-locus visible de- fects (Green 1989; McKusick et al. 1992) and complex traits such as susceptibility to epileptic seizures (Rise et al. 1991). K + channels are a promising source of candidate genes for such defects. We and others have recently isolated human and rodent genes encoding Shaw-related (KCNC) channels