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Molecular pathology: Physiopathology effect of Mutations

Molecular pathology: Physiopathology effect of Mutations. Dr Pupak Derakhshandeh, PhD Ass Prof of Medical Science of Tehran University. Mutations. changes to the either DNA or RNA caused by copying errors in the genetic material: Cell division Ultraviolet Ionizing radiation

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Molecular pathology: Physiopathology effect of Mutations

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  1. Molecular pathology:Physiopathology effect of Mutations Dr PupakDerakhshandeh, PhD Ass Prof of Medical Science of Tehran University

  2. Mutations • changes to the either DNA or RNA • caused by copying errors in the genetic material: • Cell division • Ultraviolet • Ionizingradiation • chemical mutagens • Viruses

  3. By aspect of phenotype affectedMorphological mutations • usually affect the outward appearance of an individual • Mutations can change the height of a plant or change it from smooth to rough seeds. • Biochemical mutations result in lesions stopping the enzymatic pathway • Often, morphological mutants are the direct result of a mutation due to the enzymatic pathway

  4. Special classesConditional mutation • wild-type or less severe phenotype under certain "permissive" environmental conditions • a mutant phenotype under certain "restrictive" conditions • For example: a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deletirious consequences at a lower temperature (permissive condition).

  5. Nomenclature • Nomenclature of mutations specify the type of mutation • and base or amino acid changes • Amino acid substitution: (e.g. D111E) • The first letter is the one letter code of the wildtype amino acid • the number is the position of the amino acid from the N terminus • the second letter is the one letter code of the amino acid present in the mutation • If the second letter is 'X', any amino acid may replace the wild type

  6. Nomenclature • Amino acid deletion: (e.g. ΔF508) • The Greek symbol Δ or 'delta' indicates a deletion • The letter refers to the amino acid present in the wildtype • the number is the position from the N terminus of the amino acid were it to be present as in the wildtype

  7. Harmful mutations • Changes in DNA caused by mutation can cause errors in protein sequence • creating partially or completely non-functional proteins • To function correctly, each cell depends on thousands of proteins to function in the right places at the right times • a mutation alters a protein that plays a critical role in the body • A condition caused by mutations in one or more genes is called a genetic disorder • only a small percentage of mutations cause genetic disorders • most have no impact on health • For example, some mutations alter a gene's DNA base sequence but don’t change the function of the protein made by the gene

  8. DNA repair system • Often, gene mutations that could cause a genetic disorder • repaired by the DNA repair system of the cell • Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA • Because DNA can be damaged or mutated in many ways: • the process of DNA repair is an important way in which the body protects itself from disease

  9. Beneficial mutations • A very small percentage of all mutations : • have a positive effect • lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment: • For example, a specfic 32 base pair deletion in human Chemokine ReceptorCCR5 (CCR5-32) confers HIV resistance to homozygotes • delays AIDS onset in heterozygotes • The CCR5 mutation is more common in those of European descent • One theory for the etiology of the relatively high frequency of CCR5-32 in the european population is that it conferred resistance to the bubonic plaque in mid-14th century Europe

  10. Selection at the CCR5 locus • CCR532/CCR532 homozygotes are resistant to HIV and AIDS • The high frequency and wide distribution of the 32 allele suggest past selection by an unknown agent

  11. The Role of the Chemokine Receptor Gene CCR5 and Its Allele (del32 CCR5) • Since the late 1970s • 8.4 million people worldwide • including 1.7 million children, have died of AIDS • an estimated 22 million people are infected with human immunodeficiency virus (HIV)

  12. CCR5 and Its Allele ( del32 CCR5) monocyte/macrophage (M), T-cell line (Tl) a circulating T-cell (T)

  13. Mutations In multicellular organisms • can be subdivided into: • Germline mutations • can be passed on to descendants • Somatic mutations • cannot be transmitted to descendants in animals

  14. Germ & Somatic cell • a mutation is present in a germ cell • can give rise to offspring that carries the mutation in all of its cells • Such mutations will be present in all descendants of this cell • This is the case in hereditary disease • a mutation can occur in a somatic cell of an organism • certain mutations can cause the cell to become malignant • cause cancer

  15. ClassificationBy effect on structure • Gene mutations have varying effects on health: • where they occur • whether they alter the function of essential proteins

  16. Structurally, mutations can be classified as:

  17. Point mutations • caused by chemicals/malfunction of DNA replication • exchange a single nucleotide for another • Most common is the transition that exchanges a purine for a purine (A ↔ G) • or a pyrimidine for a pyrimidine, (C ↔ T)

  18. Transition • caused by: • Nitrous acid • base mispairing • 5-bromo-2-deoxyuridine (BrdU): • mutagenic base analogs

  19. base analog(C ↔ T)

  20. Bromodeoxyuridine & Thymine CH3

  21. Transversion • Less common • exchanges a purine for a pyrimidine • or a pyrimidine for a purine (C/T ↔ A/G)

  22. Point mutations that occur within the protein coding region of a gene • depending upon what the erroneous codon codes for: • Silent mutations: • which code for the same amino acid • Missense mutations : • which code for a different amino acid • Nonsense mutations : • which code for a stop and can truncate the protein

  23. Insertions • add one or more extra nucleotides into the DNA • usually caused by transposable elements • or errors during replication of repeating elements (e.g. AT repeats) • in the non/coding region of a gene may alter: • splicing of the mRNA (splice site mutation) • or cause a shift in the reading frame (frame shift) • significantly alter the gene product • Insertions can be reverted by excision of the Transposable element

  24. Deletion • remove one or more nucleotides from the DNA • Like insertions, these mutations can alter the reading frame of the gene • Deletions of large chromosomal regions, leading to loss of the genes within those regions • They are irreversible

  25. Deletions/insertions/duplications • Out of frame • In frame

  26. Deletions/insertions/duplications • Out of frame: • result in frameshifts giving rise to stop codons. • no protein product or truncated protein product • deletions/insertions in DMD patients : truncated dystrophins of decreased stability • RB1 gene - usually no protein product in retinoblastoma

  27. Deletions/insertions/duplications • In frame: • loss or gain of amino acid(s) • depending on the size and may give rise to altered protein product with changed properties • eg CF Delta F508 loss of single amino acid • In some genes loss or gain of a single amino acid: mild

  28. In frame: • In some regions of RB1 a single amino acid loss: • rise to mild retinoblastoma or incomplete penetrance • BMD patients: • Some times in-frame deletions/duplications • DMD deletions: • mostly disrupt the reading frame

  29. Deletions/insertions/duplications • In untranslated regions: • these might affect transcription/expression and/or stability of the message: • Fragile X • MD expansions

  30. Large-scale mutations in chromosomal structure

  31. Amplifications(gene duplications) • leading to multiple copies of all chromosomal regions • double-minute chromosomes: • Sometimes, so many copies of the amplified region are produced • they can actually form their own small pseudo-chromosomes • increasing the dosage of the genes

  32. Amplifications

  33. Chromosomal translocations: • Fusion genes: • Mutations: to juxtapose previously separate pieces of DNA • potentially bringing together separate genes to form functionally distinct (e.g. bcr-abl) • Chromosomal translocation: • interchange of genetic parts from nonhomologous chromosomes

  34. Lethal mutations • lead to a phenotype: • incapable of effective reproduction

  35. Interstitial deletions: • an intra-chromosomal deletion: • removes a segment of DNA from a single chromosome • For example, cells isolated from a human astrocytoma, a type of brain tumor • have a chromosomal deletion removing sequences between the "fused in glioblastoma" (fig) gene and the receptor tyrosine kinase "ros", producing a fusion protein (FIG-ROS) • The abnormal FIG-ROS fusion protein has constitutively active kinase activity • causes oncogenic transformation (a transformation from normal cells to cancer cells)

  36. Astrocytoma • a primary tumor of the central nervous system • develops from the large, star-shaped glial cells known as astrocytes • Most frequently astrocytomas occur in the brain • but occasionally they appear along the spinal cord • occur most often in middle-aged men • Symptoms of an astrocytoma, similar to other brain tumors: • depend on the precise location of the growth • For instance, if the frontal lobe is affected • mood swings and changes in personality may occur • a temporal lobe tumor is more typically associated with speech and coordination difficulties

  37. Astrocytoma & Astrocyte

  38. AA: anaplastic astrocytomas(60.6%) GBM: glioblastoma multiforme (65%)

  39. Chromosomal inversions: • Reversing the orientation of a chromosomal segment • Loss of heterozygosity: • loss of one allele: • either by a deletion • recombination event

  40. By effect on function • Loss-of-function mutations • Gain-of-function mutations • Dominant negative mutations • Lethal mutations

  41. Loss-of-function mutations • Wild type alleles typically encode a product necessary for a specific biological function • If a mutation occurs in that allele, the function for which it encodes is also lost • The degree to which the function is lost can vary

  42. Loss-of-function mutations • gene product having less or no function: • Phenotypes associated with such mutations are most often recessive: • to produce the wild type phenotype! • Exceptions are when the organism is haploid • or when the reduced dosage of a normal gene product is not enough for a normal phenotype (haploinsufficiency)

  43. Loss-of-function mutations • mutant allele will act as a dominant: • the wild type allele may not compensate for the loss-of-function allele • the phenotype of the heterozygote will be equal to that of the loss-of-function mutant (as homozygote) • to produce the mutant phenotype !

  44. Loss-of-function mutations • Null allele: • When the allele has a complete loss of function • it is often called an amorphic mutation • Leaky mutations: • If some function may remain, but not at the level of the wild type allele • The degree to which the function is lost can vary

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