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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 alpha globin genes and their regulatory sequence (HS-40) revealed that both patients are compound heterozygotes for alpha0 thalassemia (--(SEA)) and a novel point mutation, a thymidine insertion after codon 131 of the alpha1 gene. The resulting frameshift gives rise to a highly unstable alpha globin chain, which we refer to as "Hb Pak Num Po," containing an additional 34 amino acids. This unusual alpha1 globin variant clearly causes alpha 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 alpha thalassemia in Thailand.

Original publication

DOI

10.1002/ajh.10479

Type

Journal article

Journal

Am J Hematol

Publication Date

03/2004

Volume

75

Pages

157 - 163

Keywords

Amino Acid Sequence, Base Sequence, Blood Transfusion, Child, Child, Preschool, Codon, DNA Mutational Analysis, Female, Globins, Haplotypes, Hemoglobins, Abnormal, Heterozygote, Humans, Hydrops Fetalis, Male, Molecular Sequence Data, Point Mutation, Thymidine, alpha-Thalassemia