γδβ-Thalassemia due to a de novo mutation deleting the 5' β-globin gene activation-region hypersensitive sites

M. C. Driscoll, C. S. Dobkin, B. P. Alter

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Abstract

γδβ-Thalassemia is a rare disorder of hemoglobin biosynthesis, characterized molecularly by partial or complete deletions of the β-globin gene complex of 100 kilobases (kb) or greater. Common to all mutants described has been the deletion of the most-5' sequences of the β-globin complex. We have used the techniques of pulsed field gel electrophoresis and polymerase chain reaction to study a patient with a clinical γδβ-thalassemia phenotype. This subject developed a de novo deletion on a maternally inherited β-globin gene chromosome involving ~30 kb of sequences 5' to the ε gene; the deletion extends from -9.5 kb to -39 kb 5' of ε and includes three of the four DNase I hypersensitive sites (at -10.9 kb, -14.7 kb, and -18 kb 5' of ε). The remaining sequences of the β-globin complex, including the DNase I hypersensitive sites at -6.1 kb and all structural genes in cis to the deletion are physically intact, but presumably nonfunctional, as evidenced by the presence of a β(s)-globin gene that is not expressed as a sickle hemoglobin. Deletion of DNase I hypersensitive sites on a previously functional β-globin gene complex confirms the significance of these sites in regulating globin gene expression.

Original languageEnglish (US)
Pages (from-to)7470-7474
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume86
Issue number19
DOIs
StatePublished - 1989

ASJC Scopus subject areas

  • General

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