IDENTIFICATION OF MUTATIONS IN 2 MAJOR MESSENGER-RNA ISOFORMS OF THE CHEDIAK-HIGASHI-SYNDROME GENE IN HUMAN AND MOUSE

Chediak-Higashi syndrome is an autosomal recessive, immune deficiency disorder of human (CHS) and mouse (beige, bg) that is characterized by abnormal intracellular protein transport to, and from, the lysosome, Recent reports have described the identification of homologous genes t hat are mutated in human CHS and bg mice, Here we report the sequences of two major mRNA isoforms of the CHS gene in human and mouse. These isoforms differ both in size and in sequence at the 3' end of their co ding domains, with the smaller isoform (similar to 5.8 kb) arising fro m incomplete splicing and reading through an intron. These mRNAs also differ in tissue distribution of transcription and in predicted biolog ical properties, Novel mutations were identified within the region of the coding domain common to both isoforms in three CHS patients: C-->T transitions that generated stop codons (R50X and Q1029X) were found i n two patients, and a novel frameshift mutation (deletion of nucleotid es 3073 and 3074 of the coding domain) was found in a third, Northern blots of lymphoblastoid mRNA from CHS patients revealed loss of the la rgest transcript (similar to 13.5 kb) in two of seven CHS patients, wh ile the small mRNA was undiminished in abundance, These results sugges t that the small isoform alone cannot complement Chediak-Higashi syndr ome.