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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

 

TEF ATC ATA TET GER AT

H

Chromosome Mutations

 Changes in number and structure of entire chromosomes  Original Chromosome ABC * DEF  Deletion AC * DEF  Duplication  Inversion  Translocation 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 5 th 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 92 Triploidy Tetraploidy Aneuploidy (Patau syndrome) 13 ) Edwards syndrome (

) Down syndrome (

18

21 ) Klinfelter syndrome-XXY ( Triple X (Superfemale)

) Turner syndrome- 45,XO (

Patau Syndrome

1/20000 cleft-lip-baby

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 D own 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 Drugs Agents

(& Hormonic Agents)

Chemical Agents Physical Agents

(& other disease)

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 hypoplasia & parasis., hydrocephaly. Mental retardation, cataract limb  HIV After 35 th 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  methotrexate  Busulfan  Phenytoin  Triazolam  Warfarin  Isotretinoin  Diethylstilbestrol  Ethisterone  Norethindrone  Nicotine  Alcohol



Category X

Thalidomide

drugs

   

 Thalidomide

 Aminopterin  Methotrexate  Busulfan

Category X drugs



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



Valsuroic acid



Diazepam



doxycycline



lorazepam



Streptomycin



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 18 th week (activation of immune system)

Thank you!