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Mutagenesis (mutations) and Teratogenesis (congenital malformations)

Mutagenesis (mutations) and Teratogenesis (congenital malformations). Don’t let this happen to you!!. MUTATIONS. Changes in DNA that affect genetic information. Gene Mutations. Point Mutations – changes in one or a few nucleotides Substitution THE FAT CAT ATE THE RAT

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Mutagenesis (mutations) and Teratogenesis (congenital malformations)

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  1. Mutagenesis (mutations) and Teratogenesis (congenital malformations)

  2. Don’t let this happen to you!!

  3. MUTATIONS Changes in DNA that affect genetic information

  4. Gene Mutations • Point Mutations – changes in one or a few nucleotides • Substitution • THE FAT CAT ATE THE RAT • THE FAT HAT ATE THE RAT • Insertion • THE FAT CAT ATE THE RAT • THE FAT CAT XLW ATE THE RAT • Deletion • THE FAT CAT ATE THE RAT • THE FAT ATE THE RAT

  5. Gene Mutations • Frameshift Mutations – shifts the reading frame of the genetic message so that the protein may not be able to perform its function. • Insertion • THE FAT CAT ATE THE RAT • THE FAT HCA TAT ETH ERA T • Deletion • THE FAT CAT ATE THE RAT • TEF ATC ATA TET GER AT H H

  6. Chromosome Mutations • Changes in number and structure of entire chromosomes • Original Chromosome ABC * DEF • Deletion AC * DEF • Duplication ABBC * DEF • Inversion AED * CBF • Translocation ABC * JKL GHI * DEF

  7. Significance of Mutations • Most are neutral • Eye color • Birth marks • Some are harmful • Sickle Cell Anemia • Down Syndrome • Some are beneficial • Sickle Cell Anemia to Malaria • Immunity to HIV

  8. What Causes Mutations? • There are two ways in which DNA can become mutated: • Mutations can be inherited. • Parent to child • Mutations can be acquired. • Environmental damage • Mistakes when DNA is copied

  9. Chromosome Mutations • Down Syndrome • Chromosome 21 does not separate correctly. • They have 47 chromosomes in stead of 46. • Children with Down Syndrome develop slower, may have heart and stomach illnesses and vary greatly in their degree of inteligence.

  10. Chromosome Mutations • Cri-du-chat • Deletion of material on 5th chromosome • Characterized by the cat-like cry made by cri-du-chat babies • Varied levels of metal handicaps

  11. Sex Chromosome Abnormalities • Klinefelter’s Syndrome • XXY, XXYY, XXXY • Male • Sterility • Small testicles • Breast enlargement

  12. Sex Chromosome Abnormalities • XYY Syndrome • Normal male traits • Often tall and thin • Associated with antisocial and behavioral problems

  13. Sex Chromosome Mutations • Turner’s Syndrome • X • Female • sex organs don't mature at adolescence • sterility • short stature

  14. Sex Chromosome Mutations • XXX • Trisomy X • Female • Little or no visible differences • tall stature • learning disabilities • limited fertility

  15. Some mutations even make it on SNL!

  16. Good news: coffee break  Bad news: 10 minutes 

  17. Causes of Malformations(Teratogenesis or Dismorphology) ? ? ?

  18. Birth defectCongenital malformationCongenital anomaly(Hereditary) abnormality

  19. Types of Abnormalities : • Minor anomalies • Major anomalies • Malformation • Disruptions • Deformations • Syndromes

  20. Principles of Teratology Developmental stage at the time of exposure Dose and duration of exposure to a teratogen

  21. Hereditary (Genetic) causes 15-18% Environmental factors 7-10% Multifactorial 25% Unknown 50%

  22. First week (Resistant period) • Embryonic period • Maximum susceptibility (organ morphogenesis) • Fetal Period • Lowered Susceptibility (functional derangement)

  23. Genetic factors (Numerical Chromosomal Anomalies) Polyploidy Triploidy 69 Tetraploidy 92 Aneuploidy 13 (Patausyndrome) 18 (Edwards syndrome) 21 (Down syndrome) (Klinfeltersyndrome-XXY) Triple X (Superfemale) (Turner syndrome- 45,XO)

  24. Patau Syndrome 1/20000 cleft-lip-baby

  25. Edwards Syndrome 1/5000

  26. Down syndrome • Maternal nondisjunction (95%) • Mosaism • Translocation

  27. Monosomy • Nondisjunction in sperm (80%) • X chromosome only • Nondisjunction in mitosis (Mosaicism)

  28. Structural Chromosomal Anomalies • Isochromosome • Crossing over : • Translocation 21,13,14, 15in Down syndrome • Partial Deletion Cri du chat 5(microcephal, mental, cardiovas) • Microdeletion Angelman15 (speech, mental, movement) Prader- willi15 (fatty, mental, hypogonad) • Inversion

  29. Gene Mutation Anomalies • Marphan syndrome • Crigler-Najjarsyndrome • Roberts syndrome • Alportsyndrome • Aarskog-Scott syndrome • Savant syndrome • Treacher-Collinssyndrome • Niemann–Pick disease • Cystic Fibrosis • DMD

  30. Environmental factors • Infectious Agents (& other disease) • Drugs Agents (& Hormonic Agents) • Chemical Agents • Physical Agents

  31. Infectious Agents • A) Viral infections • Rubella virus (German Measles) 1month-From placenta- atrioventricularseptsl defect, cataract. Weight ↓ • Cytomegalovirus(CMV) From Placenta,Cervix,Vagina (& Lactation) - microephaly, deafness, mental retardation, hepatospleenomegally ,cardiac defect,cerebral calcification, blue spot on skin • Herpes simplex virus(HSV) From Placenta,Vagina(85%)-Defect in CNS,liver, pancreas,ren,suprarenal glands, infection on skin, Eyes or mouth – no treatment=40-50% death • Varicella-zoster virus(VZV)first 3 month-From Placenta- limb hypoplasia & parasis., hydrocephaly. Mental retardation, cataract • HIV After 35th week- Systematic Chronic infection(fungus,bacterial,viral,protozoan)

  32. Infectious Agents • B)Nonviral infections • Toxoplasma in each three munth - death, microcephaly, hydroceohaly, cerebral calcification • Treponemapallidum Syphilis, rhinitis, eye defect (cataract), icterus,abnormal teeth, splenohepatomegaly

  33. Chronic Diseases • Diabetes Coudaldisgenesis, death • PKU mental retardation, microcephaly, cardiac defect • Nutrient deficiency Iodine deficiency coused cretinism • Obesity ONTD, cardiac defect, … • Hypoxy

  34. Drugs Agents • Category X drugs • Category D drugs

  35. Category X drugs • Clomiphen • Diethylstilbestrol • Ethisterone • Norethindrone • Nicotine • Alcohol • Thalidomide • Aminopterin • methotrexate • Busulfan • Phenytoin • Triazolam • Warfarin • Isotretinoin

  36. Category X drugs • Thalidomide antinauseant drug داروی ضد تهوع • limb defect (Amelia,Meromelia) • Cardiac defect • GIT atresy • Optic & otic defect

  37. Thalidomide

  38. Category X drugs • Aminopterin • Methotrexate • Busulfan • Used in chemotererapy • Dawerfism • Myelomeningocele • palate clef • Growth retardation • ophtalmic defect

  39. Category X drugs • Aminopterin • Methotrexate • Busulfan • Used in chemotererapy • Dawerfism • Myelomeningocele • palate clef • Growth retardation • ophtalmic defect

  40. Category X drugs • Phenytoin • Antileptic drug • microcephaly • Growth & mental retardation • palate clef • Finger & nail Hypoplesia • Skull defect

  41. Category X drugs • Warfarin • Anti couagulant drug • Mental retardation • microcephaly • optic n. atrophy • Fetal bleeding

  42. Category X drugs • Clomiphen • Non-steroidal drug • Used for stimulus ovulation • Maybe Malformatin

  43. Category X drugs isotretinoin, 13-cis-retinoic acid • Retinoids (vitamin A) • Used for Cystic acne • severe craniofacial defects • cardiac defects • neural tube defects (NTD) • Palate cleft tretinoin (Retin-A)

  44. Category X drugs • Nicotine • Mental retardation • Wheight loss • Fetal Hypoxy • Premature Parturition

  45. Category X drugs • Alcohol • Fetal Alcholic Syndrome (FAS) • Mental retardation • microcephaly • Cardivascular defect • Limb & Face malformation • Hairsutism

  46. Valsuroicacid • Diazepam • lorazepam • Lithium • Hydrochlorothiazide Category D drugs • Tetracycline • doxycycline • Streptomycin • Phenobarbital • Pentobarbital

  47. Category D drugs • Phenobarbital & Pentobarbital • paliative drug • Fetal malformation

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