Disappearance of the protein of a somatic mutation: a possible example of stem cell inactivation.

The low concentration of the hemoglobin variant, Hb Vicksburg (leucine-beta-75 deleted), and a profound deficit of its mRNA led us to postulate that a beta(+)-thalassemia mutation existed in cis to the coding region mutation, suppressing its synthesis. We examined blood from this patient 6, 8, and 10 yr after our initial studies, using methods of analysis unavailable initially. We found 1) mutations causing beta(+)-(-88 C----T) and beta 0-(849 A----G) thalassemia; 2) that the proportion of Hb Vicksburg in erythrocytes fell over time, from 8 to 4%, and ultimately disappeared; and 3) that the mutation causing Hb Vicksburg was not detectable in genomic DNA isolated from blood leukocytes when this variant was present in hemolysate. We postulate that Hb Vicksburg arose from a somatic mutation of a beta(+)-thalassemia gene in an erythroid-committed stem cell. Its gradual disappearance suggests the cycling of stem cells, with inactivation of different clones over time.