Letter | Published:

Globin structural mutant α125Leu→Pro is a novel cause of α-thalassaemia

Nature volume 296, pages 864865 (29 April 1982) | Download Citation

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Abstract

The duplicated human α-globin structural loci lie on chromosome 16 and are arranged in the order 5′ α2−αl 3′. Although the most common molecular mechanism for α-thalassaemia is deletion of segments of DNA that contain one or both of these α-globin structural loci1, two molecular lesions that are not due to gross gene deletion have been defined. In one, a point mutation in the termination codon of the α2 gene results in the production of an elongated α-globin chain2,3. As only a small amount of the mutant globin chain is produced, α-thalassaemia results. The second lesion, which is caused by a 5-base pair (bp) deletion in the first intervening sequence of the α2 gene, results in abnormal mRNA processing and α-globin chain deficiency4. We now describe a novel mechanism for α-thalassaemia not involving deletion. A single nucleotide mutation in the coding region of the α2 gene results in the substitution of proline (Pro) for leucine (Leu) in a region of the H helix of the α-globin chain, which is critical for αl−βl contact. This probably impedes α1−β1 dimer formation, the initial step of haemoglobin tetramer assembly, and produces an α-thalassaemia phenotype.

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Author information

Author notes

    • Michel Goossens
    •  & Stephen A. Liebhaber

    Present addresses: Département de Biochimie, Hôpital Henri Mondor, Créteil, France (M.G.); Department of Human Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA (S.A.L.).

Affiliations

  1. The Howard Hughes Medical Institute Laboratory and the Division of Molecular Hematology, Department of Medicine, University of California, San Francisco, California 94143, USA

    • Michel Goossens
    • , Kathleen Y. Lee
    • , Stephen A. Liebhaber
    •  & Yuet Wai Kan

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https://doi.org/10.1038/296864a0

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