Variant Hemoglobin: Abnormal Fusion Genes

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Variant Hemoglobin Abnormal Fusion Genes

• David Chow

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Road Map

• History
• Chromosomal Re-arrangements
• Hb Lepore
• Hb Kenya

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• Survey looking at the relatives of kids with
  thalassemia
• In one family
• Mother and child had a variant hemoglobin
• RBCs have the appearance of classical
  thalassemia
• Marked anisocytosis poikilocytosis
• ? MCV, ? Hct, ? HgB A2

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Starch Gel Electrophoresis

• pH 8.6
• New HgB variant
• Between A2 and F
• 11 of total HgB in mother

Mother Child Cord
blood
(Control)
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Peripheral Smear
ß Thal
Lepore Trait (Mother)
Double heterozygote(Lepore ß Thal) (Child)
Normal
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Pedigree
ß Thal
Double heterozygote (Lepore trait ß thal)
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Chromosomal Crossover

• Genetic information is swapped between two
  chromosomes
• Occurs during metaphase 1
• Formation of a chiasmata is required for proper
  segregation of homologous chromosomes during
  meiosis

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Chromosomal Crossover

• Line up
• Homologous
• Chiasmata
• Bridge
• Exchange strands
• Detach

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Chromosomal Crossover
Chiasmata
Pairing
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Abnormal Hb Fusion Genes

• Hb Lepore and Kenya
• Abnormal pairing!

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Hb Lepore

• Anti-Lepore
• ßd fusion gene
• Longer than the original
• Lepore
• dß fusion gene
• Shorter than the original

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Hb Kenya

• Anti-Kenya
• ß-A? fusion
• (much) longer than the original
• Kenya
• A?- ß fusion
• (much) shorter than the original

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Hb Lepore

• Falls in A2
• Much higher than expected for ß thalassemia

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Clinical Importance

• Hb Lepore
• Although ß chain variant
• Makes up approximately 15 of Hb
• Less stable than aß
• Similar to ß thalassemia in phenotype
• Makes sense because only 1 normal ß chain, while
  the other is a dß fusion chain
• Hb Kenya
• Hereditary persistence of fetal hemoglobin
• Hb F 10
• Hb Kenya 7-23
• Enhancer that normally ? ß globin production is
  now positioned closer to the ? promoter