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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
3 กุมภาพันธ พ.ศ. 2557
Genetic Diseases
Topics
Introduction Single gene disorders Chromosomal disorders Multifactorial diseases Somatic Cell Genetic Disorders (neoplasia)
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http://history.nih.gov/exhibits/nirenberg/images/photos/01_mendel_pu.jpg
http://www.scq.ubc.ca/wp-content/mendel.jpg
Gregor Mendel 1822-1884
http://tesla.desy.de/~rasmus/media/Coherence/PDFs%20and%20high%20resolution/watson%20and%20crick.jpg
James D. Watson 1928 -
Francis H.C. Crick 1916 - 2004
Structure of DNA 1953
Nobel prize in 1962
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Structure of DNA
http://academic.brooklyn.cuny.edu/biology/bio4fv/page/molecular%20biology/16-05-doublehelix.jpg
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
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“Central Dogma”
DNA RNA Protein
Translation Transcription
Replication
Cell cycle
http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg
http://ghs.gresham.k12.or.us/science/ps/sci/soph/cells/cycle/cycle.gif
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Human Genome (chromosomes)
In Nucleus 3.1 x 109 bp
In Mitochondria 16,569 bp
Gene
Coding Sequences
(Exon)
Non coding Sequences
(Intron)
Non-gene (Extragenetic)
Repetitive DNA
Tandem repeats (satellite, minisatellite, microsatellite)
Interspersed repeats (SINES, LINES)
Non repetitive DNA
10% 90%
<10% >90% 50% 50%
Terminology 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
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Terminology Locus = position of DNA sequences, or gene on a chromosome 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
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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
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Genetic disorders
Single gene disorders Mendelian inheritance
Autosomal dominant (AD) Autosomal recessive (AR) X-linked recessive (X-linked)
Non-Mendelian inheritance Chromosomal disorders
Numerical chromosomal abnormality Structural chromosomal abnormality
Polygenic or multifactorial diseases or complex genetic disorders Somatic cell genetic disorders (neoplasia)
Mutation หมายถึงกระบวนการที่กอใหเกิดการเปลี่ยนแปลง
ทุกรูปแบบ ที่เกิดขึ้นกับโมเลกุลของ DNA
“Wild type” and “mutant allele” Normal variation, polymorphism, inherited disease Types of mutation
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
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Examples
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
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
Achondroplasia
- Fibroblast growth factor receptor 3 (FGFR3) - Abnormality in cartilage formation
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http://www.nhlbi.nih.gov/health/dci/images/Marfan_lowres.gif
http://www.homoeopathiker.de/homoeopathik/syphilis/bilder/marfan3.jpg
Marfan syndrome
Marfan syndrome 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)
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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
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
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http://home.kku.ac.th/acamed/kanchana/p7.jpg
Thalassemia 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.buzzle.com/images/diagrams/hemoglobin-structure.jpg
http://www.microscopyu.com/galleries/pathology/images/sicklecell/sicklecellanemia40x02small.jpg
http://www.irondisorders.org/News/SickleCell.jpg
β globin chain point mutation [missense mutation, Glu -> Val]
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http://www.health.state.mn.us/divs/fh/mcshn/ncfu/images/pkupath.gif
http://www.uic.edu/classes/bms/bms655/lesson7.html#RECESSIVE
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Example
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
Gower’s sign
http://medicalimages.allrefer.com/large/x-linked-recessive-genetic-defects.jpg
Duchenne muscular dystrophy
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Genetic disorders
Single gene disorders Mendelian inheritance
Autosomal dominant (AD) Autosomal recessive (AR) X-linked recessive (X-linked)
Non-Mendelian inheritance Chromosomal disorders
Numerical chromosomal abnormality Structural chromosomal abnormality
Polygenic or multifactorial diseases or complex genetic disorders Somatic cell genetic disorders (neoplasia)
Terminology 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.asklenore.info/miscarriage/bick/images/fig3.jpg
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http://www.ucl.ac.uk/~ucbhjow/bmsi/lec7_images/47_xx_21.gif
http://www.myoops.org/cocw/tufts/courses/20/content/D293242/C293223.jpg
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http://www.anselm.edu/homepage/jpitocch/genbio/nondisjunction.JPG
http://www.nature.com/onc/journal/v24/n33/images/1208711f1.jpg
Spectral Karyotyping (SKY) Analysis
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Introduction 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)
Numerical disorders
Autosomal disorders : Trisomy 21 (Down syndrome) Trisomy 18 (Edwards syndrome) Trisomy 13 (Patau syndrome)
Sex chromosome disorders : 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
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Down’s syndrome
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
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Structural Chromosome Abnormalities
Result from breakage and limitations of DNA repair systems Mechanisms
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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http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen30.gif
mental retardation, low birth weight, low set ears, cat-like cry
Genetic disorders
Single gene disorders Mendelian inheritance
Autosomal dominant (AD) Autosomal recessive (AR) X-linked recessive (X-linked)
Non-Mendelian inheritance Chromosomal disorders
Numerical chromosomal abnormality Structural chromosomal abnormality
Polygenic or multifactorial diseases or complex genetic disorders Somatic cell genetic disorders (neoplasia)
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Multifactorial Inheritance
Normal human characteristics : Blood pressure, height, finger ridges, and intelligence Congenital malformations : neural tube defects, cleft lip and palate, and congenital heart disease Common disorders of adult life : DM, Hypertension, peptic ulcer, and schizophrenia
Heritability and Environmental factors
Heritability : percentage denoting that the genetic contribution of a given disease
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
http://www.uic.edu/classes/bms/bms655/gfx/figure18.gif (Tendency)
Example
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
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The age of expression of the major types of genetic disease