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Hb Palencia: a novel δβδ-type two-way fusion variant with β-globin-like expression levels

Abstract

Aims Fusion proteins of unequal recombination events at the β-globin locus have pathological effect. The haemoglobin (Hb) variants of type Lepore are fusion proteins characterised by β-like globin chains with a δ-globin (HBD) N-terminus and a β-globin (HBB) C-terminus, whereas reciprocal products of underlying crossover events hold a HBB N-terminus and HBD C-terminus instead. Finally, Hb Parchman contains a β-like globin chain with a central HBB fragment and HBD-derived N-termini and C-termini, whereas reciprocal hybrid proteins are as yet unknown.

Methods The propositus was an 80-year-old Caucasian man, whose HbA1c quantification by HPLC (Variant II turbo) for exclusion of type-2 diabetes revealed an abnormal peak. Haemoglobins were analysed by ion-exchange HPLC (Variant II) and capillary electrophoresis (Sebia Capillarys Flex) and DNA by automatic Sanger sequencing of δ-globin and β-globin genes.

Results Sequencing showed an HBB-HBD-HBB hybrid gene, with HBD-derived central codons 9–31, and HBB-derived UTRs and complementary coding regions. The corresponding new hybrid haemoglobin (Hb Palencia) is represented at ≈40%, similar to HbA.

Conclusion Hb Palencia contains the first globin variant with internal HBD sequences and HBB-derived N-terminal and C-terminal and regulatory sequences. Relative quantity of the new βδβ-type variant suggests transcriptional control by HBB elements and a half-life similar to normal HBB.

  • HPLC
  • electrophoresis capillar
  • hemoglobinopathies
  • molecular diagnosis
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