A novel basis for delta beta-thalassemia in a Chinese family

Abstract We have studied a Chinese family in which beta-thalassemia and delta beta-thalassemia were found in simple and compound heterozygous states. The delta beta-thalassemia heterozygote (the mother) had 22.3% hemoglobin F, of which 40% was G gamma and 60% A gamma; globin chain studies showed an alpha/beta + gamma ratio of 1.36. The compound heterozygote for delta beta-thalassemia and beta-thalassemia (the child) had the clinical picture of thalassemia intermedia and an alpha/beta + gamma ratio of 4.44. Gene mapping studies were performed using DNA from the affected child. Seventy kilobases of DNA in the beta- globin gene cluster starting upstream from the epsilon-globin gene and ending downstream from the beta-globin gene were mapped, and no detectable deletions or rearrangements were detected. In addition, heterozygosity was detected at multiple polymorphic restriction sites in and 3′ to the beta-globin gene, which excludes the possibility of a deletion of the entire beta-globin gene cluster. This is the first example of a nondeletion delta beta-thalassemia associated with increased expression of both G gamma and A gamma genes.

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A novel basis for delta beta-thalassemia in a Chinese family

Blood ◽

10.1182/blood.v68.5.1108.bloodjournal6851108 ◽

1986 ◽

Vol 68 (5) ◽

pp. 1108-1113

Author(s):

GF Atweh ◽

DE Zhu ◽

BG Forget

Keyword(s):

Gene Cluster ◽

Globin Gene ◽

Beta Thalassemia ◽

Chinese Family ◽

Compound Heterozygous ◽

Beta Globin ◽

Hemoglobin F ◽

Beta Globin Gene ◽

Globin Gene Cluster ◽

Alpha Beta

We have studied a Chinese family in which beta-thalassemia and delta beta-thalassemia were found in simple and compound heterozygous states. The delta beta-thalassemia heterozygote (the mother) had 22.3% hemoglobin F, of which 40% was G gamma and 60% A gamma; globin chain studies showed an alpha/beta + gamma ratio of 1.36. The compound heterozygote for delta beta-thalassemia and beta-thalassemia (the child) had the clinical picture of thalassemia intermedia and an alpha/beta + gamma ratio of 4.44. Gene mapping studies were performed using DNA from the affected child. Seventy kilobases of DNA in the beta- globin gene cluster starting upstream from the epsilon-globin gene and ending downstream from the beta-globin gene were mapped, and no detectable deletions or rearrangements were detected. In addition, heterozygosity was detected at multiple polymorphic restriction sites in and 3′ to the beta-globin gene, which excludes the possibility of a deletion of the entire beta-globin gene cluster. This is the first example of a nondeletion delta beta-thalassemia associated with increased expression of both G gamma and A gamma genes.

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The entire beta-globin gene cluster is deleted in a form of gamma delta beta-thalassemia

Blood ◽

10.1182/blood.v61.6.1269.bloodjournal6161269 ◽

1983 ◽

Vol 61 (6) ◽

pp. 1269-1274

Author(s):

ER Fearon ◽

HH Jr Kazazian ◽

PG Waber ◽

JI Lee ◽

SE Antonarakis ◽

...

Keyword(s):

Gene Cluster ◽

Mexican American ◽

Globin Gene ◽

Dna Polymorphisms ◽

Beta Thalassemia ◽

Beta Globin ◽

Gamma Delta ◽

Beta Globin Gene ◽

Globin Gene Cluster ◽

Endonuclease Mapping

We have used restriction endonuclease mapping to study a deletion involving the beta-globin gene cluster in a Mexican-American family with gamma delta beta-thalassemia. Analysis of DNA polymorphisms demonstrated deletion of the beta-globin gene from the affected chromosome. Using a DNA fragment that maps greater than 40 kilobases (kb) 5′ to the epsilon-gene as a probe, reduced amounts of normal fragments were found in the DNA of affected family members. Similar analysis using radiolabeled DNA fragments located 3′ to the beta-globin cluster has shown that the deletion extends more than 17 kb 3′ to the beta-gene, but terminates before the 3′ endpoint of the Ghanian HPFH deletion. Hence, this gamma delta beta-thalassemia deletion eliminates over 105 kb of DNA and is the first report of a deletion of the entire beta-globin gene cluster.

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Interaction of two different disorders in the beta-globin gene cluster associated with an increased hemoglobin F production: a novel deletion type of (G) gamma + ((A) gamma delta beta)(0)-thalassemia and a delta(0)-hereditary persistence of fetal hemoglobin determinant

Blood ◽

10.1182/blood.v77.4.861.bloodjournal774861 ◽

1991 ◽

Vol 77 (4) ◽

pp. 861-867

Author(s):

M Losekoot ◽

R Fodde ◽

EJ Gerritsen ◽

I van de Kuit ◽

A Schreuder ◽

...

Keyword(s):

Gene Cluster ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Beta Globin ◽

Gamma Delta ◽

Hemoglobin F ◽

Beta Globin Gene ◽

Globin Gene Cluster ◽

Hereditary Persistence

We report two different disorders of the beta-globin gene cluster segregating in a Belgian family: a novel deletion that results in (G) gamma + ((A) gamma delta beta)(0)-thalassemia (thal) and a heterocellular hereditary persistence of foetal hemoglobin of the Swiss type linked to a delta(0)-thal gene (delta (0)-HPFH). Heterozygosity for the heterocellular HPFH brings about a moderate (3.4% to 8.24%) increase of hemoglobin (Hb) F having a G gamma/A gamma ratio of 4:1, whereas carriers of the G gamma + ((A) gamma delta beta)(0)-thal deletion show in their peripheral blood a considerably higher (15%) percentage of Hb F. Both defects interact in the compound heterozygotes for G gamma + ((A) gamma delta beta)(0)-thal and delta(0)-HPFH producing a further increase (up to 24%) of fetal Hb consisting entirely of G gamma chains. Molecular characterization of the (G) gamma + ((A) gamma delta beta)(0)-thal by means of Southern analysis showed that the deletion spans about 50 kb, removing the 3′ end of the A gamma- gene, the psi beta-, delta-, and beta-genes. A number of possible mechanisms leading to the overproduction of Hb F in HPFH and (G) gamma + ((A) gamma delta beta)(0)-thal will be discussed.

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Interaction of two different disorders in the beta-globin gene cluster associated with an increased hemoglobin F production: a novel deletion type of (G) gamma + ((A) gamma delta beta)(0)-thalassemia and a delta(0)-hereditary persistence of fetal hemoglobin determinant

Blood ◽

10.1182/blood.v77.4.861.861 ◽

1991 ◽

Vol 77 (4) ◽

pp. 861-867 ◽

Cited By ~ 7

Author(s):

M Losekoot ◽

R Fodde ◽

EJ Gerritsen ◽

I van de Kuit ◽

A Schreuder ◽

...

Keyword(s):

Gene Cluster ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Beta Globin ◽

Gamma Delta ◽

Hemoglobin F ◽

Beta Globin Gene ◽

Globin Gene Cluster ◽

Hereditary Persistence

Abstract We report two different disorders of the beta-globin gene cluster segregating in a Belgian family: a novel deletion that results in (G) gamma + ((A) gamma delta beta)(0)-thalassemia (thal) and a heterocellular hereditary persistence of foetal hemoglobin of the Swiss type linked to a delta(0)-thal gene (delta (0)-HPFH). Heterozygosity for the heterocellular HPFH brings about a moderate (3.4% to 8.24%) increase of hemoglobin (Hb) F having a G gamma/A gamma ratio of 4:1, whereas carriers of the G gamma + ((A) gamma delta beta)(0)-thal deletion show in their peripheral blood a considerably higher (15%) percentage of Hb F. Both defects interact in the compound heterozygotes for G gamma + ((A) gamma delta beta)(0)-thal and delta(0)-HPFH producing a further increase (up to 24%) of fetal Hb consisting entirely of G gamma chains. Molecular characterization of the (G) gamma + ((A) gamma delta beta)(0)-thal by means of Southern analysis showed that the deletion spans about 50 kb, removing the 3′ end of the A gamma- gene, the psi beta-, delta-, and beta-genes. A number of possible mechanisms leading to the overproduction of Hb F in HPFH and (G) gamma + ((A) gamma delta beta)(0)-thal will be discussed.

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The entire beta-globin gene cluster is deleted in a form of gamma delta beta-thalassemia

Blood ◽

10.1182/blood.v61.6.1269.1269 ◽

1983 ◽

Vol 61 (6) ◽

pp. 1269-1274 ◽

Cited By ~ 28

Author(s):

ER Fearon ◽

HH Jr Kazazian ◽

PG Waber ◽

JI Lee ◽

SE Antonarakis ◽

...

Keyword(s):

Gene Cluster ◽

Mexican American ◽

Globin Gene ◽

Dna Polymorphisms ◽

Beta Thalassemia ◽

Beta Globin ◽

Gamma Delta ◽

Beta Globin Gene ◽

Globin Gene Cluster ◽

Endonuclease Mapping

Abstract We have used restriction endonuclease mapping to study a deletion involving the beta-globin gene cluster in a Mexican-American family with gamma delta beta-thalassemia. Analysis of DNA polymorphisms demonstrated deletion of the beta-globin gene from the affected chromosome. Using a DNA fragment that maps greater than 40 kilobases (kb) 5′ to the epsilon-gene as a probe, reduced amounts of normal fragments were found in the DNA of affected family members. Similar analysis using radiolabeled DNA fragments located 3′ to the beta-globin cluster has shown that the deletion extends more than 17 kb 3′ to the beta-gene, but terminates before the 3′ endpoint of the Ghanian HPFH deletion. Hence, this gamma delta beta-thalassemia deletion eliminates over 105 kb of DNA and is the first report of a deletion of the entire beta-globin gene cluster.

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Beta-Globin Gene Cluster Haplotypes of Amerindian Populations from the Brazilian Amazon Region

Human Heredity ◽

10.1159/000154206 ◽

1994 ◽

Vol 44 (3) ◽

pp. 142-149 ◽

Cited By ~ 15

Author(s):

João Farias Guerreiro ◽

Mauro Silvério Figueiredo ◽

Marco Antonio Zago

Keyword(s):

Gene Cluster ◽

Globin Gene ◽

Brazilian Amazon ◽

Amazon Region ◽

Beta Globin ◽

Beta Globin Gene ◽

Globin Gene Cluster ◽

Brazilian Amazon Region

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Z-DNA-forming sites within the human beta-globin gene cluster.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.93.2.780 ◽

1996 ◽

Vol 93 (2) ◽

pp. 780-784 ◽

Cited By ~ 17

Author(s):

V. Muller ◽

M. Takeya ◽

S. Brendel ◽

B. Wittig ◽

A. Rich

Keyword(s):

Gene Cluster ◽

Globin Gene ◽

Beta Globin ◽

Beta Globin Gene ◽

Globin Gene Cluster ◽

Z Dna

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Production of F cells in sickle cell anemia: regulation by a genetic locus or loci separate from the beta-globin gene cluster

Blood ◽

10.1182/blood.v64.5.1053.1053 ◽

1984 ◽

Vol 64 (5) ◽

pp. 1053-1058 ◽

Cited By ~ 29

Author(s):

SH Boyer ◽

GJ Dover ◽

GR Serjeant ◽

KD Smith ◽

SE Antonarakis ◽

...

Keyword(s):

Gene Cluster ◽

Sickle Cell ◽

Genetic Locus ◽

Globin Gene ◽

The United States ◽

Beta Globin ◽

Cell Production ◽

Beta Globin Gene ◽

Globin Gene Cluster ◽

Sib Pairs

Abstract Levels of fetal hemoglobin (HbF) bearing reticulocytes (F reticulocytes) range from 2% to 50% in patients with sickle cell (SS) anemia. To learn whether any portion of such variation in F cell production is regulated by loci genetically separable from the beta- globin gene cluster, percentages of F reticulocytes were compared in 59 sib pairs composed solely of SS members, including 40 pairs from Jamaica and 19 from the United States. We reasoned that differences in F reticulocyte levels might arise (1) from any of several kinds of artifact, (2) via half-sib status, or (3) because one or more genes regulating F cell production segregate separately from beta S. We minimized the role of artifact by assay of fresh samples from 84 SS individuals, including both members of 38 sib pairs. In 78 of the 84 subjects, serial values for percent F reticulocytes fell within 99.9% confidence limits or were alike by t test (P greater than or equal to .05). This left 32 sib pairs for which F reticulocyte levels in each member were reproducible. When sib-sib comparisons were limited to these 32 pairs, percentages of F reticulocytes were grossly dissimilar within 12 Jamaican and 3 American sibships. Within them, the probability that sibs were alike was always less than or equal to .005 and usually less than or equal to 10(-4). We next minimized the contribution of half-sibs among Jamaicans by a combination of paternity testing and sib-sib comparison of beta-globin region DNA restriction fragment length polymorphisms, especially among discordant pairs. We thereafter concluded that at least seven to eight Jamaican pairs were composed of reproducibly discordant full sibs. There is thus little doubt that there are genes regulating between-patient differences in F cell production that are separate from the beta-globin gene cluster. Still unanswered is (1) whether or not these genes are actually linked to beta S, (2) why F reticulocyte levels in Americans tend to be lower than in Jamaicans, and (3) whether or not differences in F cell production among SS patients are regulated by several major loci or by only one.

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