Molecular basis for alpha-thalassemia associated with the structural mutant hemoglobin Suan-Dok (alpha 2 109leu----arg)
Hemoglobin (Hb) Suan-Dok (alpha 109Arg) is a rare alpha-globin structural mutation that is linked to an alpha-thalassemia (alpha-thal) determinant. When inherited in trans to an alpha-thal-1 mutation (-), it results in Hb H disease associated with low levels (9%) of the Suan-Dok Hb. The nature of the thalassemic defect associated with the alpha SD mutation has been investigated by structural and functional studies. Sequence analysis of the cloned Suan-Dok allele showed a missense mutation (T----G) at codon 109 in an otherwise normal alpha 2-globin gene. When the alpha 2SD-globin gene was introduced into mouse erythroleukemia cells, the steady state alpha-globin messenger RNA (mRNA) level was equivalent to the alpha A-globin gene control. Although in vitro translation of a synthetic alpha 2SD-globin mRNA generated levels of alpha globin equivalent to alpha 2A-globin mRNA at early time points, the ratio of alpha SD to alpha A globin decreased markedly at later time points. These data suggest that the thalassemic defect associated with the Suan-Dok mutation results from a significant instability of the alpha SD globin.
Weiss
I
I
Howard Hughes Medical Institute, Department of Human Genetics, University of Pennsylvania School of Medicine, Philadelphia.
Cash
F E
FE
Coleman
M B
MB
Pressley
A
A
Adams
J G
JG
Sanguansermsri
T
T
Liebhaber
S A
SA
Steinberg
M H
MH
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D004247:DNA / Q000032:analysis / Q000235:genetics; D004588:Electrophoresis, Cellulose Acetate; D005914:Globins / Q000235:genetics / Q000378:metabolism; D006455:Hemoglobins, Abnormal / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D010957:Plasmids; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013789:Thalassemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D014162:Transfection
D006455:Hemoglobins, Abnormal; D012333:RNA, Messenger; C065341:hemoglobin Suan-Dok; D005914:Globins; D004247:DNA