Co-inheritance of Hb Pak Num Po, a Novel α1 Gene Mutation, and α⁰Thalassemia Associated with Transfusion-Dependent Hb H Disease

Abstract

Hb H disease is generally associated with moderate to severe anemia but rarely requires regular blood transfusion. We recently studied two apparently unrelated patients with transfusion-dependent Hb H disease. Hemoglobin studies demonstrated Hb H and Hb Bart's without other detectable abnormal globin species. Extensive molecular analyses of the α globin genes and their regulatory sequence (HS-40) revealed that both patients are compound heterozygotes for α0thalassemia (- -SEA) and a novel point mutation, a thymidine insertion after codon 131 of the α1 gene. The resulting frameshift gives rise to a highly unstable α globin chain, which we refer to as "Hb Pak Num Po," containing an additional 34 amino acids. This unusual α1 globin variant clearly causes α thalassemia, but the unexpectedly severe phenotype suggests that this mutation may have additional effects on red cell physiology. A PCR-based (ARMS) assay was developed for rapid detection of this novel mutation, and this might be useful to study the prevalence of this novel mutation which poses potentially significant clinical consequences in populations of Southeast Asia. Detecting carriers of this mutation using the molecular diagnostic procedures described will provide the means to screen and prevent a potentially severe form of α thalassemia in Thailand. © 2004 Wiley-Liss, Inc.