A review of the molecular genetics of the human alpha-globin gene cluster

Higgs, DR; Vickers, MA; Wilkie, Andrew O.M.; Pretorius, I M; Jarman, Andrew P.; Weatherall, D. J.

doi:10.1182/blood.v73.5.1081.1081

Cited by 426 publications

(87 citation statements)

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“…a + -Thalassaemia in the developing fetus may impair its survival by two physiological mechanisms. Activation of the aglobin locus occurs at the end of the third week of gestation and both the embryonic haemoglobin Gower II and fetal haemoglobin comprise a-globin chains (Higgs et al, 1989;Weatherall & Clegg, 2001). Therefore, a + -thalassaemia may impair haemoglobin synthesis in the fetus.…”

Section: Discussionmentioning

confidence: 99%

“…Allen 1,2 associated with maternal anaemia (Allen et al, 1998). Although it is possible that a + -thalassaemia in the mother may favour pregnancy by affording protection against malaria, it could also reduce reproductive fitness; a + -thalassaemia in the developing fetus results in a deficiency of a-globin chains early in gestation which could impair fetal oxygenation and result in miscarriage, a phenomenon that is well documented for the severe forms of a + -thalassaemia (Higgs et al, 1989).…”

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α⁺‐Thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea

et al. 2006

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SummaryThe effect of maternal a + -thalassaemia on pregnancy was assessed in the north coastal region of Papua New Guinea (PNG), where malaria is hyperendemic and a + -thalassaemia is extremely common. In a prospective study of 987 singleton hospital deliveries, we correlated maternal a-globin genotype with markers of reproductive fitness (age in primigravidae, gravidity, pregnancy interval and the number of miscarriages and stillbirths), Plasmodium falciparum (P. falciparum) infection of the mother and placenta, maternal haemoglobin, preterm delivery and birthweight. The frequency of the )a genotype in mothers was 0AE61. Markers of reproductive fitness were similar in women with and without a + -thalassaemia. Median haemoglobin concentration during pregnancy and after delivery was about 1AE0 g/dl lower in homozygous a + -thalassaemia than in women with a normal a-globin genotype (P £ 0AE001). The frequency of placental P. falciparum infection and systemic malaria infection after delivery showed no consistent relationship to a-globin genotype. The frequency of preterm delivery and low birthweight did not vary significantly according to maternal a-globin genotype. Maternal a + -thalassaemia does not affect reproductive fitness or susceptibility to malaria during pregnancy. Although median haemoglobin concentration was significantly lower in mothers homozygous for a + -thalassaemia than those with a normal a-globin genotype, this did not result in an adverse outcome of pregnancy.

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α⁺‐Thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea

et al. 2006

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“…The HBA and HBB genes are expressed at high levels in erythroid cells in a cell type-and developmental stage-specific manner (Higgs et al, 1989;Stamatoyannopoulos et al, 2001). These genes encode aand b-globin chains that are assembled to form HbA, the most abundant adult haemoglobin tetramer.…”

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Regulation of the humanHBAgenes by KLF4 in erythroid cell lines

et al. 2010

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SummaryKLF1/EKLF and related Krueppel-like factors (KLFs) are variably implicated in the regulation of the HBB-like globin genes. Prompted by the observation that four KLF sites are distributed in the human a-globin gene (HBA) promoter, we investigated if KLFs could also act to modulate the expression of the HBA genes. Among the KLFs tested, only KLF4/GKLF bound specifically to three out of four a-globin KLF sites. The occupancy of the same sites by KLF4 in vivo was confirmed by chromatin immunoprecipitation assays with KLF4-specific antibodies. In luciferase reporter assays in MEL cells, high levels of the wild type HBA promoter, but not mutated promoters bearing point mutations that disrupted KLF4-DNA binding, were transactivated by over-expression of KLF4. In K562 cells, induced KLF4 expression with a Tet-off regulated cassette stimulated the expression of the endogenous HBA genes. In a complementary assay in the same cell line, knocking down KLF4 with lentiviral delivered sh-RNAs caused a parallel decrease in the transcription of the HBA genes. All experiments combined support a regulatory role of KLF4 in the control of HBA gene expression.

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“…They are the most common single-gene diseases in the world. The a-globin genes are duplicated (a1 and a2) and located within the a gene cluster f2)wf1)wa2)wa1)a2)a1)h1 on the distal short arm region of chromosome 16 (Higgs et al, 1989). This cluster contains four genes and three pseudogenes.…”

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Determination of the breakpoint and molecular diagnosis of a common α‐thalassaemia‐1 deletion in the Indian population

Shaji¹,

Eunice²,

Baidya

et al. 2003

Br J Haematol

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Summary. The previously described South African type a-thalassaemia-1 mutation was identified in Indian HbH patients using a polymerase chain reaction (PCR) strategy. A multiplex PCR assay was devised to detect heterozygotes and homozygotes. This a-thalassaemia-1 mutation was found to be the commonest determinant causing HbH disease in this population. In one family this mutation was found in combination with a novel splice donor mutation a2 IVS I-1 (G fi A). Characterization of the breakpoint junction sequence revealed, in addition to a 23 kb deletion, that there was an addition of 160 bp bridging the breakpoints. Similar to other deletions in the a-globin gene cluster, there is an Alu repeat-mediated mechanism for the origin of the deletion. Keywords: a-thalassaemia, PCR, India, AluThe a-thalassaemias are genetic defects characterized by the decrease or complete suppression of synthesis of the a-globin polypeptide chains of haemoglobin. They are the most common single-gene diseases in the world. The a-globin genes are duplicated (a1 and a2) and located within the a gene cluster f2)wf1)wa2)wa1)a2)a1)h1 on the distal short arm region of chromosome 16 (Higgs et al, 1989). This cluster contains four genes and three pseudogenes. Deletions of one ()a) or both () ) )) of these cis-linked genes are the most common causes of the a-thalassaemias. Around 25 different two-gene cis deletions () )) and eight single-gene deletions ()a)

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A review of the molecular genetics of the human alpha-globin gene cluster

Cited by 426 publications

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α⁺‐Thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea

α⁺‐Thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea

Regulation of the humanHBAgenes by KLF4 in erythroid cell lines

Determination of the breakpoint and molecular diagnosis of a common α‐thalassaemia‐1 deletion in the Indian population

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A review of the molecular genetics of the human alpha-globin gene cluster

Cited by 426 publications

References 0 publications

α+‐Thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea

α+‐Thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea

Regulation of the humanHBAgenes by KLF4 in erythroid cell lines

Determination of the breakpoint and molecular diagnosis of a common α‐thalassaemia‐1 deletion in the Indian population

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α⁺‐Thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea

α⁺‐Thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea