An Unusual Hemoglobin Anomaly and Its Relation to α-Thalassemia and Hemoglobin-H Disease

Ефремов, Г. Д.; Wrightstone, Ruth N.; Huisman, T. H. J.; Schroeder, W. A.; Hyman, Chester; Ortega, Jorge A.; Williams, Kenneth O.

doi:10.1172/jci106651

Cited by 16 publications

(4 citation statements)

References 24 publications

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“…While this sequence work was in progress, Efremov et (1971) reported some preliminary sequence studies on an a-chain variant which was obviously the same as Hb CS. They sequenced two peptides, one of which had an identical sequence to Y, and the other of 8 residues which had an identical sequence to that proposed here for the first eight residues of Wl or the complete sequence of peptide Z.…”

Section: (A) the Structure Of The Elongated Variantsmentioning

confidence: 99%

The α-chain-termination mutants and their relation to the α-thalassaemias

Weatherall

Clegg

1975

Phil. Trans. R. Soc. Lond. B

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The structure, synthesis, genetic transmission, clinical associations and distribution of the elongated alpha-chain haemoglobin variants has been described. The data indicate that the most likely molecular basis for these common abnormal haemoglobins is a single base substitution in the alpha-chain termination codon. Because these variants are produced inefficiently they give rise to the clinical picture of alpha-thalassaemia. When these findings are taken together with recent work regarding the molecular basis for other forms of alpha-thalassaemia it is possible to build up a fairly complete picture of the molecular pathology of the alpha-thalassaemias.

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Section: (A) the Structure Of The Elongated Variantsmentioning

confidence: 99%

The α-chain-termination mutants and their relation to the α-thalassaemias

Weatherall

Clegg

1975

Phil. Trans. R. Soc. Lond. B

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“…The extra glutamyl residue in the inserted segment Glu-Phe-Thr is responsible for the observed electrophoretic and chromatographic properties. Although chains elongated at the carboxyl terminus have been described (14)(15)(16)(17), Hb-Grady is the first example of elongation by insertion of residues somewhere between the termini. Seven variants are known in which one to five residues are deleted (18)(19)(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin Grady: The First Example of a Variant with Elongated Chains Due to an Insertion of Residues

Huisman

Wilson

Gravely

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

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A black 25-year-old woman and her father have a fast-moving a chain variant in an amount of 8% (the father) and 18% (the daughter). Structural data indicate that this chain has been elongated by the addition of three amino-acid residues to give the sequence: -Pro-(114)-Ala(115)-Glu(116)-Phe(117)-Thr(118)-Glu-Phe-ThrPro(119)-Ala(120)-. The underlying genetic alteration responsible for hemoglobin Grady appears, therefore, to be a tandem duplication of nine base pairs which may have arisen by a process of mismatched intragenic crossing over. Functional and physicochemical properties of the variant are not greatly altered, and hematological data are normal.Comparative phylogenetic studies of sequences of many proteins suggest that intragenic duplications have played an important role in the evolution of structural genes and proteins. The evidence for such duplications has been reviewed elsewhere (1). We report here the first case of tandem repetition of a short sequence of amino-acid residues occurring in the a chain of a human hemoglobin (Hb). The variant, termed Hb-Grady, was observed in a 25-year-old black woman and her father. It has an increased electrophoretic mobility at alkaline pH, and subsequent structural analyses showed that its a chains were elongated with three amino-acid residues because the sequence Glu-Phe-Thr in positions 116-118 was repeated. Since this variant has been detected thus far in only two members of one family, it may be assumed that the tandem intragenic duplication is of recent origin. The nature of the duplication is such as to suggest that it may have arisen by unequal crossing-over. EXPERIMENTALSource of Blood. Samples from the propositus and from five relatives were collected in EDTA and analyzed in Atlanta or shipped by air to Augusta, Ga.Identification Procedures. Solutions of Hb were prepared by mixing one volume of washed erythrocytes with one volume of distilled water and 0.5 volume of carbontetrachloride. Debris was removed by centrifugation. Initial identification of the Hb types was made by cellulose acetate electrophoresis in Tris-EDTA-borate buffer (pH 8.4) (2), and by starch gel electrophoresis with the Tris-EDTA-borate discontinuous buffer system, pH 9.0 (3). Alkali-resistant Hb was measured by the method of Betke et al. (4). Chromatographic analyses made use of columns of DEAE-Sephadex (5, 6) or DEAEcellulose (7).Isolation of Hb Variant and Abnormal Chain. The variant was isolated bv chromatography on DEAE-Sephadex (5, 6). Hb-Grady was contaminated with the normally occurring minor Hb-A1, but was used without further purification because the abnormal a chain of Hb-Grady was readily separated from the the normal a chain of Hb-A1 on 1.7 X 15-cm columns of carboxymethylcellulose (8).Digestion of the a Chain. The chain was digested with trypsin for 4 hr at room temperature in a pH stat at pH 9.0 with addition of enzyme at zero and at 1 hr in an enzyme: protein ratio of 1: 100. The pH was lowered to 6.5, and the insoluble core was isolated by centrifugation. The pH...

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“…The most clinically significant Stop . Gln), caused by an antitermination mutation at the a2 stop codon Efremov et al 1971;Milner et al 1971;Clegg and Weatherall 1974). This elongates the protein by 31 amino acids, generating an unstable protein that is relatively underrepresented in hemolysates, but can be detected by physical methods (see sections on Basic Principles, Laboratory Testing for Hb Variants, and Physical methods of Hb separation).…”

Section: Globin Chain Elongation Mutantsmentioning

confidence: 99%

Hemoglobin Variants: Biochemical Properties and Clinical Correlates

Thom

Dickson

Gell

et al. 2013

Cold Spring Harbor Perspectives in Medicine

222

182

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Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples.

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An Unusual Hemoglobin Anomaly and Its Relation to α-Thalassemia and Hemoglobin-H Disease

Cited by 16 publications

References 24 publications

The α-chain-termination mutants and their relation to the α-thalassaemias

The α-chain-termination mutants and their relation to the α-thalassaemias

Hemoglobin Grady: The First Example of a Variant with Elongated Chains Due to an Insertion of Residues

Hemoglobin Variants: Biochemical Properties and Clinical Correlates

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