2 MISSENSE MUTATIONS IN THE BETA-GLOBIN GENE CAN CAUSE SEVERE BETA-THALASSEMIA - HEMOGLOBIN MEDICINE LAKE (BETA-32[B14]LEUCINE-]GLUTAMINE 98[FG5]VALINE-]METHIONINE)

We studied the molecular basis of transfusion-dependent hemolytic anem ia in an infant who rapidly developed the phenotype of beta thalassemi a major. DNA sequence of one beta-globin gene of the proband revealed two mutations, one for the moderately unstable hemoglobin (Hb) Koln an d another for a novel codon 32 osine-thymidine-guanine-->cytosine-aden ine-guanine transversion encoding a leucine-->glutamine mutation. A hy drophilic glutamine residue at beta 32 has an uncharged polar side cha in that could potentially distort the B helix and provoke further mole cular instability. This new hemoglobin was called Hb Medicine Lake. Bi osynthesis studies showed a deficit of beta-globin synthesis with earl y loss of beta-globin chains. An abnormal unstable hemoglobin, globin chain, or tryptic globin peptide was not present, demonstrating the ex treme lability of this novel globin. Hb Medi cine Lake mRNA was presen t, but an aberrantly spliced message was not. Absence of an abnormal b eta-globin gene in the mother makes it likely that a de novo mutation occurred in the proband. The molecular pathogenesis of Hb Medicine Lak e illustrates a mechanism whereby the phenotype of a genetic disorder, like the mild hemolytic anemia associated with a hemoglobinopathy, ca n be modulated by a coincident mutation in the same gene,