COMPOUND HETEROZYGOSITY FOR 2 ALPHA-GLOBIN GENE DEFECTS, HB-TAYBE (ALPHA-1, 38 OR 39 MINUS THR) AND A POLY A MUTATION (ALPHA-2, AATAA(A)UNDER-BAR-]AATAA(G)UNDER-BAR), RESULTS IN A SEVERE HEMOLYTIC-ANEMIA

We have identified two alpha-globin gene variations in an Arabian male with severe hemolytic disease through sequencing of amplified DNA of his alpha 2- and alpha 1-globin genes. One of the abnormalities involv es a CAC (ACC or CCA) deletion between codons 36 and 41 of the alpha 1 -globin gene. This leads to the synthesis of an abnormal a chain with one instead of two threonine residues at positions 38-39 and to the fo rmation of the unstable Hb Taybe. The second variation is a mutation l ocated in the poly A site of the alpha 2-globin gene (AATAA ($) under bar A-->AATAA ($) under bar G) which is common among Arabian people. F amily studies have shown that the two variations are located on opposi te chromosomes. The hemolytic disease in this man, resembling Hb H dis ease, is likely the result of a severe downregulation of both alpha-gl obin genes on the chromosome with the alpha 2 poly A mutation, and the instability of the alpha-Taybe chain being the product of an alpha 1- globin gene; this leaves only one alpha 2-globin gene normally active. (C) 1994 Wiley-Liss, Inc.