Transcript Mutagenesis (mutations) and Teratogenesis

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!