We report here a new frameshift mutation in exon 3 of the b-globin gene, a single nucleotide deletion (-C) in between codons 140/141 (GCC/CTG?GCC/TG), found in an 8-year-old Argentinean girl with clinical picture of thalassemia intermedia. It leads to a b-chain that is elongated to 156 amino acids [(141)Trp-Pro-Thr-Ser-Ile-Thr-Lys-Leu-Ala-Phe-Leu-Leu-Ser-Asn-Phe-(156) Tyr-COOH]. The resulting hemoglobin, which we named Hb Florida, was not detected in peripheral blood; however, erythroid hyperplasia and dyserythropoiesis with large inclusion bodies on methyl violet staining were observed in bone marrow, suggesting that this is a hyperunstable variant producing a dominant b-thalassemia phenotype, since the other b-allele was completely normal. Am. J. Hematol. 81:358-360, 2006. V V C 2006 Wiley-Liss, Inc.
We describe here the molecular and hematological characteristics of novel frameshift mutations in exon 2 of the HBB gene (in heterozygous state) found in two Argentinean pediatric patients with dominant β-thalassemia-like features. In Hb Wilde, HBB:c.270_273delTGAG(p.Glu90Cysfs*67), we detected the deletion of the third base of the codon 89 (T) and the codon 90 (GAG), whereas in Hb Patagonia, HBB:c.296_297dupGT(p.Asp99Trpfs*59), the frameshift mutation was due to a duplication of a 'GT' dinucleotide after the second base of codon 98 (GTG). The Hb Patagonia and Hb Wilde mutations would result in elongated β-globin chains with modified C-terminal sequences and a total of 155 and 157 amino acids residues, respectively. Based on bioinformatics and structural analysis, as well as protein modeling, we predict that the elongated β-globins would affect the formation of the αβ dimers and their stability, which would further support the mechanism for the observed clinical features in both patients.
An elongated C-terminal β-globin variant, due to the deletion of one nucleotide (-C) in between codons 140/141 (GCC/CTG→GCC/TG), which modified the C-terminal sequence and added 10 more residues to the β-chain [(141)Trp-Pro-Thr-Ser-Ile-Thr-Lys-Leu-Ala-Phe-Leu-Leu-Ser-Asn-Phe-(156)Tyr-COOH], was found in an 8-year-old Argentine girl of Spanish descent with clinical picture of β-thalassemia intermedia. The patient presented chronic moderate hemolytic anemia (RBC=3.8x10¹²/L, Hb=8.6 g/dL, Hct=28%), with pallor, jaundice and liver and spleen enlargement, having required blood transfusion for 5 times, during viral and bacterial infections; peripheral blood analysis revealed a remarkable degree of anisocytosis with microcytosis (RDW=28%, MCV=73.0 fl), poikilocytosis (with ovalocytes and schistocytes), hypochromia (MCH=22.6pg), 13% of reticulocytes and 2% of erythroblasts, punctate basophilia, elevated Hb A2 and Hb F levels (5% and 13%, respectively), without any detectable abnormal Hb (Hb and globin chain electrophoreses/HPLC). Tests for unstable hemoglobins were weakly positive, but the staining of the bone marrow cells with methyl violet allowed the visualization of many inclusion bodies, suggesting that this is probably a hyperunstable variant whose proteolysis in the bone marrow precursors results in dominant β-thalassemia phenotype, since the other β-locus showed no alteration. Mother’s carrier was completely normal and the father, although not available for studying, was also probably normal.
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