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นายแพทย ดร. ณตพล ศุภณัฐเศรษฐกุล

ภาควิชาพยาธิวิทยา

คณะแพทยศาสตร มหาวิทยาลัยนเรศวร

Email : nsupanat@yahoo.com

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