بسم ا الرحمن الرحيم Hemoglobinopathies - Lecture 1
HEMOGLOBIN MOLECULE GENES AND PROTEINS
Akram Al-Hilali 2009 08/06/14
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4 of po Hb ly A pep m t id ol e ec s ul e
Polypeptide Genes Îą-like genes
Chromosome 16
β-like genes
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Chromosome 11
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SYNTHETIC PATHWAY OF HAEMOGLOBIN ACETATE Kreb’s Cycle SUCCINATE CoA Mg++ ATP SUCCINYL CoA ALA-S : Synthetase ALA-DH : Dehydratase PD : Deaminase US : Synthetase UD : Decarboxylase UO : Oxidase F-CH : Ferrochelatase HS : Haemoglobin Synthetase GSH : Reduced Glutathione
PORPHOBILINOGEN PD US
GLYCINE+PUIDOXAL PO4
ALA-DH
PD US
+
GSH
ALA-S
AMINOLAEVULINIC ACID (ALA) UROPORPHYRINOGEN I
UROPORRPHYRINOGEN III UD
UD
COPROPORPHYRINOGEN III UO
PROTOPORPHYRIN IX
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+ Fe++ + GLOBIN
F-CH HS GSH
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H A E M O G L O B IN
COPROPORPHYRINOGEN
Hb molecules Adult Hb (HbA)
Foetal Hb (HbF) HbA2 08/06/14
Polypeptides
Diseases
β CHAIN
β s in sickle
α CHAIN
Suppressed in β thalassemia Relatively increased in β thalassemia
γ CHAIN α CHAIN
Suppressed in λ thalassemia
δ CHAIN
Suppressed in α thalassemia
α CHAIN
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GENE STRUCTURE
Promoter
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2
3 GENE
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Splicing Sites
EXONS
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INTRONS
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HEMOGLOBIN MOLECULE Alpha chain
α chain- genes are on chromosome 16 141 amino acids in the chain. Common to all hemoglobins, except first embryonic molecule There are two active genes: α1 and α2 There is an inactive gene as well. Inheritance of α thalassemia could be by one of the genes on one chromosome (silent), two genes on the same chromosome (cis-trait), one gene on each of the 2 chromosomes (trans-trait), 2 genes on one chromosome and one on the second (Hb H disease) or 2 genes on each chromosome (Barts hydrops fetalis).
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Îą Thalassemia-Inheritance and outcome Parents
Parents
Offspring
Offspring
Normal (25%) Silent (50%) Trait (25%)
Silent (50%) Trait (50%)
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Parents
Offspring Normal (25%) Silent (25%) Trait (25%) Hb H disease (25%)
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Hb H Disease & Barts hydrops Inheritance
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HEMOGLOBIN MOLECULE Beta chain
β-chain gene on chromosome 11 within βgene cluster. 146 amino acids Gene cluster includes active and inactive βchains, ɣ-chain and λ-chain genes. Some deletions are large enough to remove more than one gene or part of two genes (like ɣ and β) to lead to fusion of remnants of the two genes.
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GENE ABNORMALITIES THAT MAY GIVE A HEMOGLOBINOPATHY Point mutations-These may give an abnormal structure only or stop transcription altogether (non-sense) Deletions Gene fusions Changes in transcription or slicing of the gene. Changes affecting translation of the mRNA
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EXAMPLES OF α GENE STRUCTURAL ABNORMALITIES Hb-Constant Spring- Structural + suppression of production. Hb G-Philadelphia- causes diagnostic problems in presence of HbS. Other Hb-G Hb-I
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EXAMPLES OF α GENE QUANTITATIVE ABNORMALITIES
Hb Constant Spring. α chain is elongated by addition of 31 extra amino acids. This slows transcription of the gene. α thalassemia due to deletions:
SE Asian deletions Mediterranean deletions African deletions
α thalassemia due to mutations
Many have been described but α-thal-2 mutations are common in SE Asia and Mediterranean regions.
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RESULTS OF THE GENE CHANGES
Normal quantity, abnormal structure (structural hemoglobinopathies)
Low quantity, normal structure (thalassemias)
No clinical disease- discovered by chance. Anemia Erythrocytosis or methemoglobinemia Various levels of severity
Low quantity and abnormal structure (HbE and Hb Constant Spring). Abnormal structure and low production Combined hemoglobinopathies of any 2 of the above.
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EXAMPLES OF β GENE STRUCTURAL ABNORMALITIES
Sickle cell mutation at position # 6 in the β chain Hb C mutation at position # 6 in β chain Hb O Arab at position 121 on β chain Hb E at position 26 on β chain Hb D Los Angeles at position 121 on β chain Hb Köln- unstable. Mutation at position 98 Hb Zurich- unstable. Mutation at position 63 in β chain (histidine to arg) Hb M- methemoglobinemia. Tyrosine replaces histidine at many possible sites. Some are α gene variants.
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EXAMPLES OF β GENE QUANTITATIVE ABNORMALITIES
Hb E: thalassemia-like depression of β chain due to the mutation causing abnormal mRNA. Hb Lepore and Hb Kenya: caused by a combination of λ and β chains due to unequal crossing over in the genes. Mutations affecting the sequence of the gene itself (non-sense mutations), splice sites or promoter of the gene leading to β thalassemia. Deletions affecting the sequence of the gene, like deletion 619 bp.
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Is gene defect the only factor leading to disease? Gene for the actual polypeptides is the main factor. However, other inherited changes outside the exons can play a role in deciding severity Also other controllers of gene expression affect disease severity
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What other factors can modify expression of hemoglobinopathy gene? Gene promotor and other tools affecting transcription. mRNA splicing- speed may be affected by low enzyme activity that slows down splicing. Polymorphism is the introns of the gene. mRNA translation in ribosomes may be affected by local factors.
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