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1/29/2014 Topics Genetic Diseases z z z z z 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 1 1/29/2014 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 2 1/29/2014 Human Genome (chromosomes) Terminology In Nucleus In Mitochondria 3.1 x 109 bp 16,569 bp z z z 10% 90% Gene Non-gene (Extragenetic) z z <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) z z 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 z Locus = position of DNA sequences, or gene on a chromosome z Allele = possible alternative form of a given gene http://ghr.nlm.nih.gov/handbook/illustrations/chromosomallocation.jpg 3 1/29/2014 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 4 1/29/2014 http://www.geneticsandhealth.com/wp-content/pedigree%20image_2.gif http://www.migeneticsconnection.org/genomics/Family%20History/pedigreeSymbols.jpg Mutation Genetic disorders z Single gene disorders z Mendelian inheritance z z z z Non-Mendelian inheritance Chromosomal disorders z z 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) หมายถึงกระบวนการที่กอใหเกิดการเปลี่ยนแปลง ทุกรูปแบบ ที่เกิดขึ้นกับโมเลกุลของ DNA z z z z “Wild type” and “mutant allele” Normal variation, polymorphism, inherited disease Types of mutation z z z z Base substitution => silent mutation, missense, nonsense Insertion => frameshift mutation Deletion => frameshift mutation Chromosomal abnormality http://www.layevangelism.com/bastxbk/images/mutation.jpg 5 1/29/2014 http://www.uic.edu/classes/bms/bms655/gfx/pedigree1.gif Examples z z z z z z 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 6 1/29/2014 Marfan syndrome Marfan syndrome z z z z z 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 7 1/29/2014 Example z z z z 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 z z z z z http://home.kku.ac.th/acamed/kanchana/p7.jpg z 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) 8 1/29/2014 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 9 1/29/2014 Gower’s sign Example z z z z z 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 z Single gene disorders z Mendelian inheritance z z z z Non-Mendelian inheritance Terminology z z z z Chromosomal disorders z z 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 z z 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 10 1/29/2014 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 11 1/29/2014 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 z z z z z 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 : z z z z Sex chromosome disorders : z z z z z 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 12 1/29/2014 http://www.virtualsciencefair.org/2004/mcgo4s0/public_html/t2/dwn_chromo.gif http://www.suriyothai.ac.th/en/node/1005 Down’s syndrome z z z z z 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 13 1/29/2014 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 z Result from breakage and limitations of DNA repair systems z Mechanisms z z z z z Translocation Inversion Duplication Deletion and ring chromosome Isochromosome http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=107050&screenWidth=1280&screenHeight=800 14 1/29/2014 Genetic disorders z Single gene disorders z Mendelian inheritance z z z mental retardation, low birth weight, low set ears, cat-like cry z Non-Mendelian inheritance Chromosomal disorders z z 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 z Normal human characteristics : Blood pressure, height, finger ridges, and intelligence Heritability and Environmental factors z Heritability : percentage denoting that the genetic contribution of a given disease z z z Congenital malformations : neural tube defects, cleft lip and palate, and congenital heart disease Common disorders of adult life : DM, Hypertension, peptic ulcer, and schizophrenia z 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 15 1/29/2014 Threshold model for Multifactorial disorders Example z z z z z z z z (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 16