Don’t let this happen to you!! 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 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 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 H THE FAT CAT ATE THE RAT TEF ATC ATA TET GER AT H Chromosome Mutations Changes in number and structure of entire chromosomes Original Chromosome Deletion Duplication Inversion Translocation ABC * DEF AC * DEF ABBC * DEF AED * CBF ABC * JKL GHI * DEF 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 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 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. 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 Sex Chromosome Abnormalities Klinefelter’s Syndrome XXY, XXYY, XXXY Male Sterility Small testicles Breast enlargement Sex Chromosome Abnormalities XYY Syndrome Normal male traits Often tall and thin Associated with antisocial and behavioral problems Sex Chromosome Mutations Turner’s Syndrome X Female sex organs don't mature at adolescence sterility short stature Sex Chromosome Mutations XXX Trisomy X Female Little or no visible differences tall stature learning disabilities limited fertility Some mutations even make it on SNL! Good news: coffee break Bad news: 10 minutes Causes of Malformations (Teratogenesis or Dismorphology) Birth defect Congenital malformation Congenital anomaly (Hereditary) abnormality Types of Abnormalities: • Minor anomalies • Major anomalies Malformation Disruptions Deformations Syndromes Principles of Teratology Developmental stage at the time of exposure Dose and duration of exposure to a teratogen Hereditary (Genetic) causes 15-18% Environmental factors 7-10% Multifactorial 25% Unknown 50% First week (Resistant period) Embryonic period Maximum susceptibility (organ morphogenesis) Fetal Period Lowered Susceptibility (functional derangement) Genetic factors )Numerical Chromosomal Anomalies( Polyploidy 69 Triploidy 92 Tetraploidy Aneuploidy (Patau syndrome) 13 )Edwards syndrome( 18 )Down syndrome( 21 )Klinfelter syndrome-XXY( Triple X (Superfemale) )Turner syndrome- 45,XO( Patau Syndrome cleft-lip-baby 1/20000 Edwards Syndrome 1/5000 Down syndrome Maternal nondisjunction (95%) Mosaism Translocation •Monosomy •Nondisjunction in sperm (80%) •X chromosome only •Nondisjunction in mitosis (Mosaicism) Structural Chromosomal Anomalies Isochromosome Crossing over : Translocation 21,13,14, 15 in Down syndrome Partial Deletion Cri du chat 5(microcephal, mental, cardiovas) Microdeletion Angelman 15 (speech, mental, movement) Prader- willi 15 (fatty, mental, hypogonad) Inversion Gene Mutation Anomalies Marphan syndrome Crigler-Najjar syndrome Roberts syndrome Alport syndrome Aarskog-Scott syndrome Savant syndrome Treacher-Collins syndrome Niemann–Pick disease Cystic Fibrosis DMD Environmental factors • Infectious Agents (& other disease) • Drugs Agents (& Hormonic Agents) • Chemical Agents • Physical Agents Infectious Agents A) Viral infections Rubella virus (German Measles) 1month-From placenta- atrioventricular septsl 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) Infectious Agents B) Nonviral infections Toxoplasma in each three munth - death, microcephaly, hydroceohaly, cerebral calcification Treponema pallidum Syphilis, rhinitis, eye defect (cataract), icterus,a bnormal teeth, splenohepatomegaly Chronic Diseases Diabetes Coudal disgenesis, death PKU mental retardation, microcephaly, cardiac defect Nutrient deficiency Iodine deficiency coused cretinism Obesity ONTD, cardiac defect, … Hypoxy Drugs Agents Category X drugs Category D drugs Category X drugs Thalidomide Clomiphen Aminopterin Diethylstilbestrol methotrexate Ethisterone Busulfan Norethindrone Phenytoin Triazolam Warfarin Isotretinoin Nicotine Alcohol Category X drugs Thalidomide Thalidomide Category X drugs Aminopterin Methotrexate Busulfan Used in chemotererapy Dawerfism Myelomeningocele palate clef Growth retardation ophtalmic defect Category X drugs Aminopterin Methotrexate Busulfan Used in chemotererapy Dawerfism Myelomeningocele palate clef Growth retardation ophtalmic defect Category X drugs Phenytoin Antileptic drug microcephaly Growth & mental retardation palate clef Finger & nail Hypoplesia Skull defect Category X drugs Warfarin Anti couagulant drug Mental retardation microcephaly optic n. atrophy Fetal bleeding Category X drugs Clomiphen Non-steroidal drug Used for stimulus ovulation Maybe Malformatin 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) Category X drugs Nicotine Mental retardation Wheight loss Fetal Hypoxy Premature Parturition Category X drugs Alcohol Fetal Alcholic Syndrome (FAS) Mental retardation microcephaly Cardivascular defect Limb & Face malformation Hairsutism Category D drugs Tetracycline doxycycline Streptomycin Valsuroic acid Diazepam lorazepam Lithium Phenobarbital Hydrochlorothiazide Pentobarbital Category D drugs Phenobarbital & Pentobarbital paliative drug Fetal malformation Category D drugs Diazepam, Lorazepam , Chlorodiazepoxide antianxiety drug palate & lip clef specially in first 3 months Category D drugs Lithium ,Phenothiazine Antiedepressive CardioVascular defect Chemical Agents (heavy metals) Physical Agents Male-mediated Teratogenesis Chromosomal defects & Mutation in germ cells Environmental agent : transmission of paternal mediated toxicity through seminal fluid Prenatal Diagnosis Ultrasonography Maternal Serum Screening (AFP,hCG) AFP : Trisomy↓- NTD,GIT atresia,amniotic band↑ Amniocentesis Chorionic Villus Sampling (CVS) Fetal Therapy Fetal Transfusion Fetal Medical Treatment Fetal Surgery Stem Cell Transplantation and Gene Therapy Befor 18th week (activation of immune system) Thank you!