IDENTIFICATION OF THE HOMOLOGOUS BEIGE AND CHEDIAK-HIGASHI-SYNDROME GENES

VESICULAR transport to and from the lysosome and late endosome is defe ctive in patients with Chediak-Higashi syndrome (CHS) and in mutant be ige (bg) mice(1-4). CHS and bg cells have giant, perinuclear vesicles with characteriscs of late endosomes and lysosomes that arise from dys regulated homotypic fusion(3-5). CHS and bg lysosomes also exhibit com partmental missorting of proteins, such as elastase, glucuronidase and cathepsin G(2,3,6,7) Lyst, a candidate gene for bg, was identified by direct complementary DNA selection from a yeast artificial chromosome (YAC) clone containing a 650-kilobase segment of the bg-critical regi on on mouse chromosome 13. Lyst is disrupted by a 5-kilobase deletion in bg(11J) mice, and Lyst messenger RNA is markedly reduced in bg(2J) homozygotes. The homologous human gene, LYST, is highly conserved with mouse Lyst, and contains a frame-shift mutation at nucleotides 117-11 8 of the coding domain in a CHS patient. Thus bg mice and human CHS pa tients have homologous disorders associated with Lyst mutations. Lyst encodes a protein with a carboxy-terminal prenylation motif and multip le potential phosphorylation sites. Lyst protein is predicted to form extended helical domains, and has a region of sequence similar to stat hmin, a coiled coil phosphoprotein thought to act as a relay integrati ng cellular signal response coupling(8-10).