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Changes in DNA that affect genetic information

Gene MutationsPoint Mutations – changes

in one or a few nucleotidesSubstitution

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 MutationsFrameshift 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

Chromosome MutationsChanges in number and structure of entire

chromosomes Original Chromosome ABC * DEFDeletion AC * DEFDuplication ABBC * DEFInversion AED * CBFTranslocation 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 childMutations can be acquired.

Environmental damage Mistakes when DNA is copied

Chromosome MutationsDown 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 MutationsCri-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 AbnormalitiesKlinefelter’s

SyndromeXXY, XXYY, XXXYMaleSterilitySmall testiclesBreast enlargement

Sex Chromosome AbnormalitiesXYY Syndrome

Normal male traitsOften tall and thinAssociated with antisocial and behavioral

problems

Sex Chromosome MutationsTurner’s

SyndromeXFemalesex organs don't

mature at adolescence

sterilityshort stature

Sex Chromosome MutationsXXX

Trisomy XFemaleLittle or no visible differencestall staturelearning disabilitieslimited 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 :

MalformationDisruptionsDeformationsSyndromes

• Minor anomalies

• Major anomalies

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

Triploidy 69 Tetraploidy 92

Aneuploidy 13 (Patau syndrome)

18( Edwards syndrome) 21( Down syndrome)

(Klinfelter syndrome-XXY) Triple X (Superfemale)

(Turner syndrome- 45,XO)

Patau Syndrome 1/20000

cleft-lip-baby

Edwards Syndrome 1/5000

Maternal nondisjunction (95%)MosaismTranslocation

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

Structural Chromosomal AnomaliesIsochromosomeCrossing over : Translocation

21,13,14, 15 in Down syndromePartial 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 syndromeCrigler-Najjar syndromeRoberts syndromeAlport syndromeAarskog-Scott syndromeSavant syndromeTreacher-Collins syndromeNiemann–Pick diseaseCystic FibrosisDMD

Environmental factors

• Infectious Agents (& other disease)

• Drugs Agents (& Hormonic Agents)

• Chemical Agents

• Physical Agents

A) Viral infectionsRubella 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

Infectious AgentsB) 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 DiseasesDiabetes

Coudal disgenesis, death

PKUmental retardation, microcephaly, cardiac defect

Nutrient deficiency Iodine deficiency coused cretinism

ObesityONTD, cardiac defect, …

Hypoxy

Drugs AgentsCategory X drugs

Category D drugs

Category X drugs Thalidomide

Aminopterin

methotrexate

Busulfan

Phenytoin

Triazolam

Warfarin

Isotretinoin

Clomiphen

Diethylstilbestr

ol

Ethisterone

Norethindrone

Nicotine

Alcohol

Category X drugs

Thalidomide

Category X drugsAminopterin MethotrexateBusulfan

Used in chemotererapy

Dawerfism Myelomeningocele palate clef Growth retardation ophtalmic defect

Category X drugs

Aminopterin MethotrexateBusulfan

Used in chemotererapy

Dawerfism Myelomeningocele palate clef Growth retardation ophtalmic defect

Category X drugs

Phenytoin

Antileptic drug microcephalyGrowth & mental

retardationpalate clefFinger & nail

HypoplesiaSkull defect

Category X drugsWarfarin

Anti couagulant drugMental retardation microcephaly optic n. atrophy Fetal bleeding

Category X drugs

Clomiphen

Non-steroidal drug Used for stimulus ovulation

Maybe Malformatin

Category X drugs

Retinoids (vitamin A)

Used for Cystic acne

severe craniofacial defects

cardiac defects

neural tube defects (NTD)

Palate clefttretinoin (Retin-A)

isotretinoin, 13-cis-retinoic acid

Category X drugs

Nicotine

Mental retardationWheight lossFetal HypoxyPremature Parturition

Category X drugs

Alcohol

Fetal Alcholic Syndrome (FAS)Mental retardationmicrocephalyCardivascular defectLimb & Face malformationHairsutism

Category D drugsTetracycline

doxycycline

Streptomycin

Phenobarbital

Pentobarbital

Valsuroic acid

Diazepam

lorazepam

Lithium

Hydrochlorothiazid

e

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

Ultrasonography

Maternal Serum Screening (AFP,hCG)

AFP : Trisomy↓- NTD,GIT atresia,amniotic band↑

Amniocentesis

Chorionic Villus Sampling (CVS)

Prenatal Diagnosis

Fetal Transfusion

Fetal Medical Treatment

Fetal Surgery

Stem Cell Transplantation and Gene Therapy

Befor 18th week (activation of immune system)

Fetal Therapy

Thank you!