Downloaded 18 times
Uploaded byMunmun Kulsum
Genetics.pptx
This document discusses genetic disorders and their causes at various levels including single gene mutations, chromosomal abnormalities, and multifactorial inheritance. It covers different types of genetic mutations and their implications for resulting proteins and diseases. Various modes of inheritance for genetic disorders are described including autosomal dominant, autosomal recessive, and sex-linked inheritance patterns. Specific examples of genetic disorders are provided for each category. The document also discusses cytogenetic disorders involving abnormalities in chromosome number or structure.
More Related Content
Genetics.pptx
- 1. Genetic Disorders Dr. UmmeKulsum Munmun Assistant Professor Department of Pathology Cumilla Medical College
- 2. Genome • The genomeis the entire set of DNA instructions found in a cell. • In humans, the genome consists of 23 pairs of chromosomes located in the cell's nucleus, as well as a small chromosome in the cell's mitochondria. • A genome contains all the information needed for an individual to develop and function.
- 6. • An exonis a region of the genome that ends up within an mRNA molecule. • Some exons are coding, in that they contain information for making a protein, • whereas others are non-coding. Genes in the genome consist of exons and introns.
- 7. • An intronis a region that resides within a gene but does not remain in the final mature mRNA molecule following transcription of that gene • does not code for amino acids that make up the protein encoded by that gene.
- 8. Genetic Diseases • Geneticdisorders encountered in medical practice represent only the tip of iceberg • 50% of spontaneous abortuses during early months of gestation have a demonstrable chromosomal abnormality
- 9. Genetic Disorders • Broadlyclassified in three categories: - Disorders related to single gene mutations with large effects (Mendelian disorders) - Chromosomal disorders - Complex multigenic disorders (interactions of multiple variant forms of genes and environmental factors)
- 11. Two major categoriesof mutations • Germline mutations occur in gametes. They can be transmitted to offspring and every cell in the offspring will have the mutation. • Somatic mutations occur in other cells of the body, are confined to just one cell and its daughter cells. Somatic mutations cannot be passed on to offspring.(Cancer and other congenital malformations) • Mutations may change the structure of a chromosome or just change a single nucleotide.
- 12. GENE MUTATION • POINTMUTATION (single base substitution) within a coding sequence: VAL-GLU • MUTATIONS in NON-coding sequences defective transcription, regulation • DELETIONS/INSERTIONS frameshift mutation, involvement is NOT a multiple of 3 • Tri-nucleotide REPEATS, e.g., CGG repeats many times in fragile X syndrome
- 14.
- 15. GENE MUTATIONS • INTERFEREwith protein synthesis • SUPPRESS transcription, DNARNA • PRODUCE abnormal mRNA • DEFECTS carried over into TRANSLATION • ABNORMAL proteins WITHOUT impairing syntheses
- 16. GENETIC DISORDERS •SINGLE genemutations, following classical MENDELIAN inheritance patterns the most •MULTIFACTORIAL inheritance •CHROMOSOMAL disorders
- 17. MENDELIAN inheritance patterns •AUTOSOMAL DOMINANT • AUTOSOMAL RECESSIVE • SEX-LINKED (recessive), involving “X” chromosome
- 18. AUTOSOMAL DOMINANT • Diseaseis in HETEROZYGOTES • NEITHER parent may have the disease (NEW mut.) • Both male and female are affected , both can transmit • If an affected person marries an unaffected one, every conception has 50% chance of having the disease • Variation in PENETRANCE (environment?, other genes?) • VARIABLE EXPRESSIVITY (environment?, other genes?) • May have a DELAYED ONSET • Usually result in a REDUCED PRODUCTION or INACTIVE protein
- 19. AUTOSOMAL DOMINANT • HUNTINGTONDISEASE • NEUROFIBROMATOSIS • MYOTONIC DYSTROPHY • TUBEROUS SCLEROSIS • POLYCYSTIC KIDNEY • HEREDITARY SPHEROCYTOSIS • VON WILLEBRAND DISEASE • MARFAN SYNDROME • EHLERS-DANLOS SYNDROMES (some) • OSTEOGENESIS IMPERFECTA • ACHONDROPLASIA • FAMILIAL HYPERCHOLESTEROLEMIA • ACUTE INTERMITTENT PORPHYRIA
- 20. AUTOSOMAL DOMINANT PEDIGREE 1) BOTHSEXES INVOLVED 2) GENERATIONS NOT SKIPPED
- 21. AUTOSOMAL RECESSIVE • Diseaseis in HOMOZYGOTES • More UNIFORM expression than AD • The trait usually does not affect the parent of the individual but siblings may have the disease • 25% chance of being affected in each birth • Often COMPLETE PENETRANCE • Onset usually EARLY in life • Affected individual is most likely the product of consanguineous marrage • NEW mutations rarely detected clinically • Proteins show LOSS of FUNCTION • Include ALL inborn errors of metabolism • MUCH more common that autosomal dominant
- 22. AUTOSOMAL RECESSIVE • CF •PKU • GALACTOSEMIA • HOMOCYSTINURIA • LYSOSOMAL STORAGE • Α-1 ANTITRYPSIN • WILSON DISEASE • HEMOCHROMATOSIS • GLYCOGEN STORAGE DISEASES • Hgb S • THALASSEMIAS • CONG. ADRENAL HYPERPLASIA • EHLERS-DANLOS (some) • ALKAPTONURIA • NEUROGENIC MUSC. ATROPHIES • FRIEDREICH ATAXIA • SPINAL MUSCULAR ATROPHY
- 23. AUTOSOMAL RECESSIVE PEDIGREE 1)BOTH SEXES INVOLVED 2) GENERATIONS SKIPPED
- 24. SEX (“X”) LINKED •MALES ONLY • HIS SONS are healthy • ALL his DAUGHTERS are CARRIERS • The “Y” chromosome is NOT homologous to the “X”, i.e., the concept of dominant/recessive has no meaning here • HETEROZYGOUS FEMALES have no phenotypic expression (carriers)….usually, this means autosomal “recessive”
- 25. SEX (“X”) LINKED •DUCHENNE MUSCULAR DYSTROPHY • HEMOPHILIA , A and B • G6PD DEFICIENCY • AGAMMAGLOBULINEMIA • WISKOTT-ALDRICH SYNDROME • DIABETES INSIPIDUS • LESCH-NYHAN SYNDROME • FRAGILE-X SYNDROME
- 26. SEX LINKED PEDIGREE •MALES ONLY, sons of affected males are OK
- 27. SINGLE GENE DISORDERS •ENZYME DEFECT (Most of them, e.g., PKU) • Accumulation of substrate • Lack of product • Failure to inactivate a protein which causes damage • RECEPTOR/TRANSPORT PROTEIN DEFECT (Familial Hypercholesterolemia) • STRUCTURAL PROTEIN DEFECT (Marfan, Ehl-Dan) • Structure • Function • Quantity • ENZYME DEFECT WHICH INCREASES DRUG SUSCEPTIBILITY: G6PDPrimaquine
- 28. STRUCTURAL PROTEIN DEFECTS •Marfan Syndrome • Fibrillin-1 defect (not -2 or -3) • Tall, dislocated lens, aortic arch aneurysms, etc. • Ehlers-Danlos Syndromes) • Multiple (6?) different types • Various collagen defects • Hyperelastic skin, hyperextensible joints
- 29. RECEPTOR PROTEIN DEFECTS •FAMILIAL HYPERCHOLESTEROLEMIA • LDL RECEPTOR defect • Cholesterol TRANSPORT across liver cell impaired • CHOLESTEROL BUILDUP IN BLOOD • “Scavenger System” for CHOL kicks in, i.e., MACROPHAGES • YOU NOW KNOW WHY MACROPHAGES are “FOAMY”
- 30. ENZYME DEFICIENCIES •BY FAR,THE LARGEST KNOWN CATEGORY • SUBSTRATE BUILDUP • PRODUCT LACK • SUBSTRATE could be HARMFUL •LYSOSOMAL STORAGE DISEASES comprise MOST of them
- 31. LYSOSOMAL STORAGE DISEASES •GLYCOGEN STORAGE DISEASES • SPHINGOLIPIDOSES (Gangliosides) • SULFATIDOSES • MUCOPOLYSACCHARIDOSES • MUCOLIPIDOSES
- 32. GLYCOGEN STORAGE DISEASES •MANY TYPES • Storage sites: Liver, Muscle, Heart
- 33. SPHINGOLIPIDOSES • MANY types,Tay-Sachs most often referred to • GANGLIOSIDES are ACCUMULATED, due to a hexoseaminidase A deficiency • Ashkenazi Jews (1/30 are carriers) • CNS neurons a site of accumulation • CHERRY RED spot in Macula
- 34. SULFATIDOSES • MANY types,but the • metachromatic leukodystrophies (CNS), • Krabbe, • Fabry, • Gaucher, and • Niemann-Pick (A and B) are most common
- 35. ALKAPTONURIA •HOMOGENTISIC ACID •HOMOGENTISIC ACIDOXIDASE •BLACK URINE •BLACK NAILS (OCHRONOSIS), SKIN •BLACK JOINT CARTILAGE (SEVERE ARTHRITIS)
- 37. NEUROFIBROMATOSIS • NF1 andNF2 • Neurofibromas, café-au-lait, Lisch nodules
- 38. MULTIFACTORIAL INHERITANCE • Multi-”FACTORIAL”,not just multi-GENIC • Common phenotypic expressions governed by “multifactorial” inheritance • Hair color • Eye color • Skin color • Height • Intelligence • Diabetes, type II
- 39. FEATURES of multifactorial inheritance •Expression determined by NUMBER of variant genes (polymorphism) • Each variant genes confers a small increase in disease risk • Low penetrance • Environmental interactions are important in the pathogenesis of disease • Expression of CONTINUOUStraits (e.g., height) vs. DISCONTINUOUS traits (e.g., Diabetes I)
- 40. “MULTIFACTORIAL” DISORDERS •Cleft lip,palate •Congenital heart disease •Coronary heart disease •Hypertension •Gout •Diabetes •Pyloric stenosis •MANY, MANY, MANY MORE, perhaps MOST!
- 41.
- 42. COMMON CYTOGENETIC DISEASES (numerical) •AUTOSOMES •TRISOMY-21 (DOWN SYNDROME) • 13 (Patau), 18 (Edwards), • 22q.11.2 deletion • SEX CHROMOSOMES •KLINEFELTER: 47XXY etc. •TURNER: 45XO
- 43. Down Syndrome • Flattenedface. • Small head. • Short neck. • Protruding tongue. • Upward slanting eye lids (palpebral fissures) • Unusually shaped or small ears. • Poor muscle tone. • Broad, short hands with a single crease in the palm.
- 45. SEX CHROMOSOME DISORDERS •Problems related to sexual development and fertility • Discovered at time of puberty • Retardation related to the number of X chromosomes • If you have at least ONE “Y” chromosome, you are male
- 46. KLINEFELTER (XXY, XXXY,etc.) •Hypogonadism found at puberty •#1 cause of male infertility •NO retardation unless more X’s •47, XXY 82% of the time •L----O----N----G legs, atrophic testes, small penis
- 47. TURNER (XO) •45, Xis the “proper” designation •Often, the WHOLE chromosome is not missing, but just part •NECK “WEBBING”, “STREAK “ OVARIES •EDEMA of HAND DORSUM •CONGENITAL HEART DEFECTS most FEARED
- 48. HERMAPHRODITES • GENETIC SEXis determined by the PRESENCE or ABSENCE of a “Y” chromosome, but there is also, GONADAL (phenotypic), and DUCTAL sex • TRUE HERMAPHRODITE: OVARIES AND TESTES, often on opposite sides (VERY RARE) • PSEUDO-HERMAPHRODITE: • MALE: TESTES with female characteristics (XY) • FEMALE: OVARIES with male characteristics (XX)
- 49.
- 50. SINGLE GENE, NON-Mendelian •Tripletrepeats •Fragile X (CGG) syndrome •Others: ataxias, myotonic dystrophy •Mitochondrial Mutations: (maternal) (LEBER HEREDITARY OPTIC NEUROPATHY) •Genomic “IMPRINTING”: (Inactivation of maternal or paternal allele, contradicts Mendel) •Gonadal “MOSAICISM”: (only gametes have mutated cells)
- 51. KARYOTYPING •Defined as thestudy of CHROMOSOMES •46 = (22x2) + X + Y •Conventional notation is “46,XY” or “46,XX” •Short arm = p, long arm = q
- 53. F.I.S.H. (gene “probes”) •FluorescentIn- Situ Hybridization • Uses fluorescent labelled DNA fragments, ~10,000 base pairs, to bind (or not bind) to its complement
- 54.
Editor's Notes
- #49 “Pseudo”-hermaphrodites are MUCH more common that TRUE hermaphrodites.
- #53 The “official” notation for the normal male pattern is: “46, XY”
- #55 This technique is used to identify structural chromosome aberrations in cancer cells and other disease conditions when Giemsa banding or other techniques are not accurate enough. Each chromosome has a different color, sort of, although some of this is digital false color techniques, much in the same way, electron microscopy can generate “false” colors.