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Beta Globin and Mutations

Beta Globin and Mutations. Alexandra Childs and Ryan Edwards. Beta Globin. Chromosome position: 11p15.5 DNA nucleotides position: 5246696..5248301 To the left of this gene in HBD or Delta globin and to the right of this gene is OR51v1 or Olfactory Receptor. HBB Location.

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Beta Globin and Mutations

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  1. Beta Globin and Mutations Alexandra Childs and Ryan Edwards

  2. Beta Globin • Chromosome position: 11p15.5 • DNA nucleotides position: 5246696..5248301 • To the left of this gene in HBD or Delta globin and to the right of this gene is OR51v1 or Olfactory Receptor

  3. HBB Location • http://ghr.nlm.nih.gov/gene=HBB

  4. Sequence of Beta Globin Green: introns Red: exons Blue: Everything that is transcribed but non-coding

  5. Mature mRNA and Translated protein Sequence • Nucleotide Sequence (444 nt): ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAATranslation (147 aa): MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH

  6. Beta Globin Mutations • Shepherd’s Bush • Hb Mainz • M Saskatoon • Thalassemia Mutation on the Initiation Codon ATG to ATA • Hb Rocky Mountain

  7. Shepherd’s Bush

  8. Gly and Asp Glycine Aspartic Acid →

  9. SB Mutated Sequence • Mutated Nucleotide Sequence (444 nt): ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGACCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAAMutatedTranslation (147 aa): MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDALAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH

  10. Shepherds Bush Changes to Protein

  11. Shepherds Bush Physical Signs • According to the variant database, this mutation manifests itself as an increase in oxygen affinity. It also results in a decreased bpg (2,3-dpg). • Moreover, the mutation causes the hemoglobin to be unstable and hemolytic anemia

  12. Schematic Diagram of Hb-Mainz

  13. Val and Glu Valine Glutamic Acid • 

  14. Hb-Mainz Mutated Sequence • Mutated Nucleotide Sequence (444 nt): ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGACCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGAGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAAMutatedTranslation (147 aa): MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDALAHLDNLKGTFATLSELHCDKLHEDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH

  15. Hb-Mainz Changes to Protein

  16. Hb-Mainz Physical Effects • According to the variant database, Hb-Mainz causes hemoglobin to become unstable and also causes hemolytic severe anemia.

  17. Hb M-Saskatoon Mutation

  18. M-Saskatoon Detailed Sequence • (Mutated) Nucleotide Sequence (444 nt): ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTTATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA • (Mutated) Translation (147 aa): MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAYGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYHCAT becomes TAT H becomes Y

  19. Amino Acid Change Histidine Tyrosine →

  20. 3D Protein Sequence of Hemoglobin Histidine is a positively charged hydrophilic amino acid Tyrosine is an uncharged hydrophilic amino acid What do you notice about where this mutation is near to? We will come back to this…

  21. M-Saskatoon, Methemoglobinemia • Special class of low O2 affinity hemoglobin variant • Iron in the heme is in an abnormal oxidation state • Known as methemoglobin. • useless in O2 binding. • Has a brown pigment • Causes cyanosis • Mutation may also cause Dissociation of Dimers

  22. Thalassemias Mutation of Initiation Codon ATG -> ATA beta0 • (Original) Nucleotide Sequence (444 nt): ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA • (Original) Translation (147 aa): MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH • RED – Initiation Codon that changes to ATA which no longer begins the reading frame • Blue- Region of nucleotide base pairings, amino acids, and protein that is not read because of the mutation to the START codon • Orange- Codon which becomes the START codon but originally is split into two codons before the mutation. All subsequent amino acids change in the translation • Green- New Stop Codon

  23. Amino Acid Change Methionine Isoleucine →

  24. New Sequence Details • (Mutated) Nucleotide Sequence (444 nt): ATGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA • (Mutated) Translation (aa): MKLVVRPWAGCWWSTLGPRGSLSPLGICPLLMLLWATLR(STOP)

  25. Hb Rocky Mountain

  26. Sequence Detail of Hb Rocky Mountain • (Mutated)Nucleotide Sequence (444 nt): ATGGTGCATCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGTTGAAGTTGGTGGTGAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAA • (Original)Translation (147 aa): MVHLTPEEKSAVTALWGKVNVVEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYHGAT becomes GTT Aspartic Acid (D) becomes Valine (V)

  27. Amino Acid Change Aspartic Acid Valine →

  28. Protein Structure and Description of Effects of Mutation • Aspartic Acid is hydrophilic and negatively charged polar • Valine is hydrophobic and non polar making it mildly unstable • The change in the protein sequence may affect Hb function in cells as it causes an alteration in the protein shape

  29. Effects of Hb Rocky Mountain • Those with an Hb Rocky Mountain mutation (a.k.a. Hb Paddington) develop Microcytosis • Smaller red blood cells • Those with mutation are at higher risk of being anemic • Why do you think that is if the red blood cell count is the same as a healthy person?

  30. Useful Sites for Sheperds Bush/ Biblography • http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=387 • http://globin.cse.psu.edu/html/huisman/variants/beta/Shepherds.Bush.html • http://books.google.com/books?id=H85dwxYTKLwC&lpg=RA1-PA1623&ots=A9ufCRxiMW&dq=Shepherds%20Bush%20mutat&pg=RA1-PA1623#v=onepage&q=shepherds%20bush&f=false

  31. Sources for Hb-Mainz • http://www.umm.edu/blood/anehemol.htm • http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=451 • http://www.ncbi.nlm.nih.gov/pubmed/17356397

  32. Useful Sites of Hb Rocky Mountain • http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=925 • http://www.pdb.org/pdb/explore/jmol.do?structureId=2HHB&bionumber=1 • http://en.wikipedia.org/wiki/Mean_corpuscular_volume • http://en.wikipedia.org/wiki/Microcytosis

  33. Sites On Hb M-Saskatoon • http://web2.airmail.net/uthman/hemoglobinopathy/hemoglobinopathy.html • http://www.ncbi.nlm.nih.gov/pubmed/7663000 • http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=359

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