Hb Osler [beta 145(HC2)Tyr-->Asp] results from posttranslational modification.
We studied two members of an African American family with erythrocytosis. An abnormal hemoglobin variant with an electrophoretic pattern on cellulose acetate similar to Hb J was identified. The oxygen dissociation curve using whole blood was biphasic, dramatically left-shifted, and hyperbolic. Sequence analysis of DNA from the proband showed heterozygosity for a T-->A change at the first position of codon 145 in the beta-globin gene which results in the substitution of an asparagine residue for normal tyrosine. The second cycle of C-terminal amino acid sequence analysis of a mixture of alpha- and beta-globin chains showed tyrosine, aspartic acid, and small amounts of asparagine. Collectively, these results indicate the existence of a mutation at codon 145 of the beta-globin gene which encodes for asparagine instead of tyrosine, and that asparagine then undergoes a partial posttranslational deamidation to aspartic acid. This amino acid substitution corresponds to Hb Osler, which is a high oxygen affinity hemoglobin variant, initially described to be caused by a substitution of Tyr-->Asp at beta 145. Posttranslational amino acid modification may constitute an important component in the pathophysiology of hemoglobinopathies.
Kattamis
A C
AC
Division of Hematology, Children's Hospital of Philadelphia, PA, USA.
Kelly
K M
KM
Ohene-Frempong
K
K
Reilly
M P
MP
Keller
M
M
Cubeddu
R
R
Adachi
K
K
Surrey
S
S
Fortina
P
P
D000328:Adult; D044383:Black People / Q000235:genetics*; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006801:Humans; D008297:Male; D011086:Polycythemia / Q000097:blood / Q000235:genetics; D011499:Protein Processing, Post-Translational; D017422:Sequence Analysis, DNA; D001741:Black or African American
D006455:Hemoglobins, Abnormal; C036601:hemoglobin Osler