Two missense mutations in the beta-globin gene can cause severe beta thalassemia. Hemoglobin Medicine Lake (beta 32[B14]leucine-->glutamine; 98 [FG5] valine-->methionine).

Abstract

We studied the molecular basis of transfusion-dependent hemolytic anemia in an infant who rapidly developed the phenotype of .8thalassemia major. DNA sequence of one /3-globin gene of the proband revealed two mutations, one for the moderately unstable hemoglobin (Hb) Koln and another for a novel codon 32 cytosine-thymidine-guanine-cytosineadenine-guanine transversion encoding a leucine-glutamine mutation. A hydrophilic glutamine residue at /332 has an uncharged polar side chain that could potentially distort the B helix and provoke further molecular instability. This new hemoglobin was called Hb Medicine Lake. Biosynthesis studies showed a deficit of j8-globin synthesis with early loss of /3-globin chains. An abnormal unstable hemoglobin, globin chain, or tryptic globin peptide was not present, demonstrating the extreme lability of this novel globin. Hb Medicine Lake mRNA was present, but an aberrantly spliced message was not. Absence of an abnormal .8-globin gene in the mother makes it likely that a de novo mutation occurred in the proband. The molecular pathogenesis of Hb Medicine Lake illustrates a mechanism whereby the phenotype of a genetic disorder, like the mild hemolytic anemia associated with a hemoglobinopathy, can be modulated by a coincident mutation in the same gene. (J. Clin. Invest. 1995. 95:503-509.)

Molecular epidemiology, pathogenicity, and structural analysis of haemoglobin variants in the Yunnan province population of Southwestern China

“…Similarly, the Hb Galliera I variant, has been found expressed in an Italian family (irretrievable published literature), while the Hb D-Los Angeles variant has been found widespread globally 32 . Notably, the Hb Köln variant was found sporadically distributed around the world as a de novo mutation 33 . Additionally, the Hb G-Copenhagen variant was found expressed in European populations 34 , and the Hb G-Coushatta and Hb Hope variants fortuitously prevalent in both European and Asian populations 35,36 .…”

Tertiary structural analysis of the elongated part of an abnormal hemoglobin, hemoglobin Pakse

“…Indeed, the structural aberration relating to the helix part of the globin chain shows some possible correlation with hemolysis. Coleman et al (1995) studied the molecular basis of transfusion-dependent hemolytic anemia in Hb Medicine Lake and noted that the potentially distorted B helix might provoke further molecular instability, including the presentation of mild hemolytic anemia. The developed molecular structure will be useful in further studies on the molecular structure and molecular action in this disorder.…”

Diverse hematological phenotypes of β‐thalassemia carriers

“…Another group of variant hemoglobins that can lead to β‐thalassemia trait in varying degrees of disease severity is the highly unstable variant hemoglobins. One example is Hb Medicine Lake, which harbors two mutations within the same β‐globin gene, codon 32 CTG>CAG and codon 98 GTG>ATG ( HBB :c.[295G>A;98T>A]) or Leu32Gln and Val98Met …”