The molecular basis of α-thalassemias: Frequent occurrence of dysfunctional α loci among non-Asians with Hb H disease

Orkin, Stuart H.; Old, John; Lazarus, Herbert; Altay, Çiğdem; Gürgey, Aytemiz; Weatherall, D. J.; Nathan, David G.

doi:10.1016/0092-8674(79)90292-7

Cited by 170 publications

(75 citation statements)

References 29 publications

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“…This data implies that the low expression of the Constant Spring gene is due, at least in part, to a relative instability of the Constant Spring mRNA (i.e. a2-globin S. A. Liebhaber and Y. W. Kan In the nondeletion hemoglobin-H syndromes, (14,32,33), physically intact a-globin genes produce a decreased amount of a normal a-globin protein. We have previously described a Chinese subject with nondeletion hemoglobin-H disease with an intact al and a2 gene on one chromosome (--/aa"T) (14).…”

Section: (5) Although It Ismentioning

confidence: 99%

Differentiation of the mRNA transcripts originating from the alpha 1- and alpha 2-globin loci in normals and alpha-thalassemics.

Liebhaber¹,

Kan²

1981

J. Clin. Invest.

136

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A B S T R A C T The a-globin polypeptide is encodedby two adjacent genes, al and a2. In the normal diploid state (aa/aa) all four a-globin genes are expressed. Loss or dysfunction of one or more of these genes leads to deficient a-globin production and results in a-thalassemia. We present a technique to differentially assess the steady-state levels of the al-and a2-globin messenger RNA (mRNA) transcripts and thus delineate the relative level of expression of the two a-globin loci in a variety of a-thalassemia states. Only ail mRNA was produced in the a-thalassemia-2 haplotype (-a) (one of the two a-globin genes deleted from chromosome 16). This confirms previous gene mapping data which demonstrate deletion of the a2 gene. The triple a-globin gene haplotype (caca) is the reciprocal of the a-thalassemia-2 haplotype and thus contains an extra a2-globin gene. RNA from this haplotype contained a greater than normal level of a2-relative to alglobin mRNA. This data implies that the extra a2 gene in the triple a-globin haplotype is functional. We detected a relative instability of the a2-globin mRNA encoding the a-globin structural mutant Constant Spring. This instability may contribute to the low level of expression of the a-Constant Spring protein. In a Chinese patient with nondeletion hemoglobin-H disease (--/aaT) (both a-globin genes are present but not fully functional) a normal ratio was maintained between the levels of al-and a2-globin mRNA, implying that mRNA production from both a-globin genes is suppressed in a balanced manner. These observations extend previous findings concerning the structural rearrangements in the deletion types of athalassemia and the pathophysiology of two nondeletion variants.

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Section: (5) Although It Ismentioning

confidence: 99%

Differentiation of the mRNA transcripts originating from the alpha 1- and alpha 2-globin loci in normals and alpha-thalassemics.

Liebhaber¹,

Kan²

1981

J. Clin. Invest.

136

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“…The finding of the --/aa genotype in Chinese a-thalassemia-1 subjects explains the occurrence of homozygous a-thalassemia in this group. This disease is not found in the black population because the a-thalassemia-1 phenotype is a result of the deletion of the two a-globin loci on opposite chroml-osomiies (-a/-a) (15 (18,19). It thus seems likely that, as in 8-thalassemia, the mechanism that leads to abnormal gene function in a-thalassemia is heterogeneous.…”

Section: Introductionmentioning

confidence: 99%

Organization of the alpha-globin genes in the Chinese alpha-thalassemia syndromes.

Embury¹,

Lebo²,

Dozy³

et al. 1979

J. Clin. Invest.

174

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“…In blacks, only one of the two a-globin genes on a given chromosome may be deleted, giving rise to the silent carrier state in the heterozygote and a-thalassemia trait in the homozygote (16). In southeast Asia, the double deletion occurs on some chromosomes leading to a-thalassemia trait in the heterozygote and total a-globin deficiency (hydrops fetalis) in the homozygote (17).…”

Section: Resultsmentioning

confidence: 99%

Genetic analysis of C4 deficiency.

1981

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The molecular basis of α-thalassemias: Frequent occurrence of dysfunctional α loci among non-Asians with Hb H disease

Cited by 170 publications

References 29 publications

Differentiation of the mRNA transcripts originating from the alpha 1- and alpha 2-globin loci in normals and alpha-thalassemics.

Differentiation of the mRNA transcripts originating from the alpha 1- and alpha 2-globin loci in normals and alpha-thalassemics.

Organization of the alpha-globin genes in the Chinese alpha-thalassemia syndromes.

Genetic analysis of C4 deficiency.

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