Download Genetic Diseases - คณะแพทยศาสตร์ มหาวิทยาลัยนเรศวร

1/29/2014
Topics
Genetic Diseases
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3 กุมภาพันธ พ.ศ. 2557
Introduction
Single gene disorders
Chromosomal disorders
Multifactorial diseases
Somatic Cell Genetic Disorders (neoplasia)
นายแพทย ดร. ณตพล ศุภณัฐเศรษฐกุล
ภาควิชาพยาธิวิทยา
คณะแพทยศาสตร มหาวิทยาลัยนเรศวร
Email : [email protected]
http://www.uga.edu/srel/kidsdoscience/images/genetics-puppets.gif
http://www.uwo.ca/biology/images/undergraduate/chromosome.jpg
Gregor Mendel
1822-1884
James D. Watson
1928 http://history.nih.gov/exhibits/nirenberg/images/photos/01_mendel_pu.jpg
http://www.scq.ubc.ca/wp-content/mendel.jpg
Structure of DNA
1953
Nobel prize in 1962
Francis H.C. Crick
1916 - 2004
http://tesla.desy.de/~rasmus/media/Coherence/PDFs%20and%20high%20res
olution/watson%20and%20crick.jpg
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Structure of DNA
Nucleotide = Nucleoside + Phosphate
Nucleoside = Ribose sugar + Nitrogenous Base
http://th.wikipedia.org/wiki/%E0%B9%84%E0%B8%9F%E0%B8%A5%E0%B9%8C:Nucleotides_1.svg
http://academic.brooklyn.cuny.edu/biology/bio4fv/page/molecular%20biology/16-05-doublehelix.jpg
“Central Dogma”
Cell cycle
Transcription
DNA
Translation
RNA
Protein
Replication
http://ghs.gresham.k12.or.us/science/ps/sci/soph/cells/cycle/cycle.gif
http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg
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Human Genome (chromosomes)
Terminology
In Nucleus
In Mitochondria
3.1 x 109 bp
16,569 bp
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10%
90%
Gene
Non-gene (Extragenetic)
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<10%
Coding
Sequences
(Exon)
>90%
Non coding
Sequences
(Intron)
50%
50%
Repetitive DNA
Non repetitive DNA
Tandem repeats
(satellite, minisatellite, microsatellite)
Interspersed repeats
(SINES, LINES)
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Genotype = genetic constitution of an individual
Phenotype = observed characteristic
Homozygous = identical alleles at a given locus
Heterozygous = two different alleles at a given locus
Autosomes = any chromosomes other than sex
chromosomes
Autosomal inheritance = involve any chromosomes
other than sex chromosomes
Pedigree charts = to illustrate the inheritance
Terminology
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Locus = position of DNA sequences, or gene
on a chromosome
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Allele = possible alternative form of a given
gene
http://ghr.nlm.nih.gov/handbook/illustrations/chromosomallocation.jpg
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http://www.geneticsandhealth.com/wp-content/allele.jpg
http://naturalsciences.sdsu.edu/ta/classes/lab2.4/trait.jpg
http://www.genome.gov/Pages/Hyperion/DIR/VIP/Glossary/Illustration/Images/autosome.gif
http://www.geneticsandhealth.com/wp-content/pedigree%20image_1.gif
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http://www.geneticsandhealth.com/wp-content/pedigree%20image_2.gif
http://www.migeneticsconnection.org/genomics/Family%20History/pedigreeSymbols.jpg
Mutation
Genetic disorders
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Single gene disorders
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Mendelian inheritance
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Non-Mendelian inheritance
Chromosomal disorders
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Autosomal dominant (AD)
Autosomal recessive (AR)
X-linked recessive (X-linked)
Numerical chromosomal abnormality
Structural chromosomal abnormality
Polygenic or multifactorial diseases or
complex genetic disorders
Somatic cell genetic disorders (neoplasia)
หมายถึงกระบวนการที่กอใหเกิดการเปลี่ยนแปลง
ทุกรูปแบบ ที่เกิดขึ้นกับโมเลกุลของ DNA
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“Wild type” and “mutant allele”
Normal variation, polymorphism, inherited disease
Types of mutation
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Base substitution => silent mutation, missense, nonsense
Insertion => frameshift mutation
Deletion => frameshift mutation
Chromosomal abnormality
http://www.layevangelism.com/bastxbk/images/mutation.jpg
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http://www.uic.edu/classes/bms/bms655/gfx/pedigree1.gif
Examples
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Skeletal: Marfan syndrome, Achondroplasia,
Osteogenesis imperfecta
Nervous system: Huntington disease,
Neurofibromatosis
Urinary: Polycystic kidney disease
Gastrointestinal: Familial polyposis coli
Hematopoietic: Von Willebrand disease
Metabolic: Familial hypercholesterolemia,
Acute intermittent porphyria
Achondroplasia
- Fibroblast growth factor receptor 3 (FGFR3)
- Abnormality in cartilage formation
http://www.sciencemuseum.org.uk/on-line/genes/images/1-3-5-1-4-2-1-1-1-3-0.jpg
http://www.commonwealthadoption.org/images/johnston.jpg
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Marfan syndrome
Marfan syndrome
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http://www.nhlbi.nih.gov/health/dci/images/Marfan_lowres.gif
Antoine Marfan, a french pediatrician, 1896
Fibrillin-1 (FBN1) gene mutation on chromosome 15
Fibrillin-1 is an extracellular matrix glycoprotein,
secreted by fibroblasts
Structural component of microfibrils in the formation
of elastic fibers in connective tissue
Skeletal abnormality, subluxation of the lens (ectopia
lentis), CVS abnormalities (mitral valve prolapse,
aortic aneurysm, aortic dissection)
http://www.homoeopathiker.de/homoeopathik/syphilis/bilder/marfan3.jpg
http://www.uic.edu/classes/bms/bms655/lesson5.html
http://upload.wikimedia.org/wikipedia/commons/thumb/3/3e/Autorecessive.svg/300px-Autorecessive.svg.png
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Example
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Metabolic: Cystic fibrosis, Phenylketonuria,
Hemochromatosis, Glycogen storage
disease, Galactosemia, Homocystinuria
Hematopoietic: Thalassemia, Sickle cell
disease
Endocrine: Congenital adrenal hyperplasia
Nervous: Friedreich ataxia
http://healthnet.md.chula.ac.th/text/forum1/thalassemia2/picture/thalassemia.jpg
Thalassemia
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http://home.kku.ac.th/acamed/kanchana/p7.jpg
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Hemoglobinopathy
Hemoglobin (Hb): iron-containing oxygen
transport protein in the red blood cells
Four globular protein subunits – Heme group
containing Fe
Two alpha(α) and two beta(β) subunits:
[Heterotetramer; α2β2 = Hemoglobin A]
Alpha thalassemia: HBA1 and HBA2 (16p13.3)
Beta thalassemia: HBB (11p15.5)
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http://www.microscopyu.com/galleries/pathology/images/sicklecell/sicklecellanemia40x02small.jpg
β globin chain point mutation
[missense mutation, Glu -> Val]
http://www.buzzle.com/images/diagrams/hemoglobin-structure.jpg
http://www.health.state.mn.us/divs/fh/mcshn/ncfu/images/pkupath.gif
http://www.irondisorders.org/News/SickleCell.jpg
http://www.uic.edu/classes/bms/bms655/lesson7.html#RECESSIVE
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Gower’s sign
Example
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Duchenne muscular dystrophy
Musculoskeletal: Duchenne muscular
dystrophy, Becker muscular dystrophy
Blood: Glucose-6-phosphate dehydrogenase
(G6PD) deficiency, Hemophilia A and B
Metabolic: Diabetes insipidus, Lesch-Nyhan
syndrome
Nervous: Fragile-X syndrome
Immune: Agammaglobulinemia
http://www.neurologyarticles.com/sitebuilder/images/Scan10106-176x315.jpg
Genetic disorders
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Single gene disorders
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Mendelian inheritance
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Non-Mendelian inheritance
Terminology
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Chromosomal disorders
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Autosomal dominant (AD)
Autosomal recessive (AR)
X-linked recessive (X-linked)
Numerical chromosomal abnormality
Structural chromosomal abnormality
Polygenic or multifactorial diseases or
complex genetic disorders
Somatic cell genetic disorders (neoplasia)
http://medicalimages.allrefer.com/large/x-linked-recessive-genetic-defects.jpg
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Karyotype = the chromosome constitution of an individual,
normal human karyotype is 46,XY (male) and 46,XX (female)
Polyploidy = the number of hapoloid chromosome sets is
greater than two (2n), triploidy, tetraploidy
Aneuploidy = chromosome number is not an exact multiple of
haploid number, monosomies, trisomies
Trisomy = three representatives of a given chromosome, trisomy
21 in Down dyndrome
Monosomy = one member of a chromosome pair is missing,
Turner syndrome (45,X)
Translocation = the transfer of one segment of a chromosome
to another
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http://www.transtutors.com/Uploadfile/CMS_Images/4026_Karyotype%20of%20human%20(Male).JPG
http://www.ucl.ac.uk/~ucbhjow/bmsi/lec7_images/47_xx_21.gif
http://www.asklenore.info/miscarriage/bick/images/fig3.jpg
http://www.myoops.org/cocw/tufts/courses/20/content/D293242/C293223.jpg
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Spectral Karyotyping (SKY) Analysis
http://www.anselm.edu/homepage/jpitocch/genbio/nondisjunction.JPG
Introduction
http://www.nature.com/onc/journal/v24/n33/images/1208711f1.jpg
Numerical disorders
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Maybe numerical or structural
Nomenclature
Numerical disorders :
[47, XY,+21],
[45,X]
Structural disorders :
[46,XY,t(14;21)(q11,p10)],
[46,XY,dup(5) (q20-q30)],
[46,XY,del(15)(q11-q13)],
(break point, margin, or region)
Autosomal disorders :
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Sex chromosome disorders :
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Trisomy 21 (Down syndrome)
Trisomy 18 (Edwards syndrome)
Trisomy 13 (Patau syndrome)
Klinefelter syndrome (47,XXY)
Turner syndrome (45,X)
XXX = female with an extra X chromosome
XYY = male with an extra Y chromosome
XX male = Y sequences are transferred to the X
chromosome, look like male with Klinefelter
syndrome
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http://www.virtualsciencefair.org/2004/mcgo4s0/public_html/t2/dwn_chromo.gif
http://www.suriyothai.ac.th/en/node/1005
Down’s syndrome
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Down’s syndrome facies
Simian crease
Gap between 1st and 2nd toes
CVS : Endocardial cushion defect
(Atrioventricular septal defect) most common
GI : increase risk of Hirschprung’s diseases
(intestinal stenosis)
http://upload.wikimedia.org/wikipedia/commons/c/c3/Trisomy21_graph.jpg
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http://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm
http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=109400&screenWidth=1280&screenHeight=800
Structural Chromosome
Abnormalities
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Result from breakage and limitations of
DNA repair systems
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Mechanisms
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Translocation
Inversion
Duplication
Deletion and ring chromosome
Isochromosome
http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=107050&screenWidth=1280&screenHeight=800
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Genetic disorders
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Single gene disorders
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Mendelian inheritance
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mental retardation, low birth weight, low set ears, cat-like cry
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Non-Mendelian inheritance
Chromosomal disorders
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Autosomal dominant (AD)
Autosomal recessive (AR)
X-linked recessive (X-linked)
Numerical chromosomal abnormality
Structural chromosomal abnormality
Polygenic or multifactorial diseases or
complex genetic disorders
Somatic cell genetic disorders (neoplasia)
http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen30.gif
Multifactorial Inheritance
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Normal human characteristics : Blood
pressure, height, finger ridges, and intelligence
Heritability and Environmental
factors
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Heritability : percentage denoting that the
genetic contribution of a given disease
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Congenital malformations : neural tube
defects, cleft lip and palate, and congenital
heart disease
Common disorders of adult life : DM,
Hypertension, peptic ulcer, and schizophrenia
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If heritability is high, there is a high correlation in
relatives
Environmental factors : can be manipulated
to reduce an individual’s susceptibility below
than the threshold
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Threshold model for
Multifactorial disorders
Example
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(Tendency)
Diabetes mellitus, type I (Insulin-dependent)
Essential hypertension (62% heritability)
Atherosclerosis (65% heritability)
Peptic ulcer (37% heritability)
Schizophrenia (85% heritability)
Asthma (80% heritability)
Alzheimer disease
Non syndromic cleft lip cleft palate
http://www.uic.edu/classes/bms/bms655/gfx/figure18.gif
The age of expression of the major types of genetic disease
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