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Genes and Disease. Genes and Disease. Genes transmit inherited traits (including mutations that cause disease) from one generation to the next Genetic factors play a major role in the development and severity of many, if not most, diseases. Atherosclerosis Cancer, Alzheimer's Diabetes.

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genes and disease1
Genes and Disease
  • Genes transmit inherited traits (including mutations that cause disease) from one generation to the next
  • Genetic factors play a major role in the development and severity of many, if not most, diseases.
      • Atherosclerosis
      • Cancer,
      • Alzheimer's
      • Diabetes.
      • Infections
  • Damage to the genes by radiation, chemicals and the like may accumulate over a lifetime and contribute to the changes associated with aging.
genetic control
Genetic Control



Cell structure and function

Health or disease

gene environment interaction
Gene Environment Interaction




Cell structure and function

Health or disease

genes and diseases
Genes and Diseases

Genetic disorders may be

  • Inherited
    • Congenital (Down Syndrome)
    • Late onset (Huntington’s Chorea)
  • Acquired
    • Congenital (fetal damage)
    • Late onset (cancer)
  • Polygenic/Multifactorial
    • Result from genetic interactions with environmental factors (diabetes mellitus, coronary artery disease, cleft lips and palates)
genetic disorders
Genetic Disorders

Three Major Categories

  • Single Gene Mutations
      • Point mutations
      • Frameshift mutation
      • Trinucleotide repeats
  • Multifactorial disorders
  • Chromosomal Disorders
    • Numerical
    • Structural
genetic mutations
Genetic Mutations
  • Mutations are a permanent change in DNA and may be inherited or acquired.
  • Mutations may occur from errors in meiosis and mitosis or from damage to DNA.
  • Mutations that affect gamates will be passed on to offspring
  • Mutations that affect somatic cells will not be passed on to offspring but they are passed on to daughter cells and are an important cause of a variety of disorders including cancer, aging and some congenital defects.
  • Not all mutations matter
  • Mutations are not necessarily bad

Mechanisms of Single Gene MutationsPoint Mutation: NonsensePremature stop codon causes a protein product that is short and often non-functional


Mechanisms of Single Gene Mutation Point Mutation: MissenseIncorrect nucleotide causes an incorrect amino acid to beInserted into the protein product


Mechanisms of Single Gene Mutation: Frameshift MutationLoss or gain of 1-2 nucleotides cause affected codon and all subsequent codons to be misread leading to different and often non-functional proteins

mechanisms of single gene mutation tri nucleotide deletion
Mechanisms of Single Gene MutationTri-nucleotide Deletion
  • If the number of base pairs in a deletion is three (or a multiple of three) a protein missing one or more amino acids will be synthesized
mechanism of single gene mutation tri nucleotide repeats
Mechanism of Single Gene Mutation Tri-nucleotide Repeats
  • One three base sequence is amplified or repeated over and over
  • Disrupts the function of the gene
  • Examples include
      • Fragile X syndrome
      • Huntington disease
      • Spinocerebellar ataxia
  • The number of repeats is significant. For example, in Fragile X Syndrome
      • 20-35 repeats -- normal
      • 50-200 repeats– permutation but phenotypically normal
      • Over 200 repeats– disease manifested
single gene mutations
Single Gene Mutations

The effect of single gene mutation depends on

  • Type of protein encoded by the gene
  • The extent to which it is affected by the mutation
single gene mutations clinical example sickle cell syndrome
Single Gene MutationsClinical Example: Sickle Cell Syndrome
  • Single base mutation in the 6th codon (CTC to CAC) of the beta-hemoglobin gene
  • Results in substitution of valine for glutamic acid in beta chain
  • Autosomal recessive disorder
  • If both parents carry an abnormal gene
    • 1 in 4 chance that child will have the disease
    • 2 in 4 chance child will have sickle cell trait and be a carrier
    • 1 in 4 chance child will be normal
sickle cell disease
Normal Hemoglobin

Hemoglobin AA (adult)

Hemoglobin F (fetal)

Sickle Cell Hemoglobin

Hemoglobin AS


Hemoglobin SS (disease)

Sickle Cell Disease
sickle cell trait
Sickle Cell Trait
  • In sickle cell trait (Hgb AS) 35-45% of hemoglobin is affected
  • Usually does not cause symptoms
  • Prolonged or severe deoxygenation (such as extreme exercise or depressurized airplane) may be associated with symptoms
basic defect
Basic Defect
  • Normally hemoglobin stays dissolved even at physiologic extremes of PO2, pH, temperature and osmolarity
  • Hemoglobin S comes out of solution and become rigid and deformed at low PO2, low pH, low temperature and increased osmolarity
  • Sickled cells have shortened lifespan (16-20 days compared to 120) resulting in chronic anemia
  • Microvascular occlusion leads to impaired delivery of oxygen to tissues and chronic tissue damage
  • Sickled cells also cause endothelial damage to larger vessels resulting in thickened walls, stenosis, occlusion and thrombus formation
effect of other genes
Effect of Other Genes

Although the basic defect is the same in sickle cell anemia, the severity of the disease varies.

Other factors, controlled by other genes, may influence severity

  • Role of endothelial inflammation
  • Role of increased expression of adhesion molecules on endothelium
  • Role of NO-binds to Hgb of damaged RBCs, decreases availability for endothelial vasodilation
effect of environment
Effect of Environment
  • Hydration
  • Altitude
  • Basic hygiene
  • Prevention of decreased tissue oxygenation
  • Access/quality of health care
sickle cell disease management
Sickle Cell DiseaseManagement
  • Experimental treatments include
    • Hydroxyurea and butyrates increase production of Hgb F
    • Bone marrow transplant
    • Modulation of endothelial activation
    • Chelation therapy to prevent iron overload from repeated transfusions
single gene disorder cystic fibrosis
Single Gene DisorderCystic Fibrosis
  • Like sickle cell disease, CF is a single gene disorder (sounds simple)
  • Unlike sickle cell disease (in which the basic genetic mutation is always the same) in CF there are over 1200 possible mutation in the gene (pretty complex)
cystic fibrosis
Cystic Fibrosis
  • The disease is characterized by
    • Chronic pulmonary disease
    • Pancreatic insufficiency
    • Complications of viscous secretions in other organs including the small intestine, liver and reproductive organs
cystic fibrosis1
Cystic Fibrosis
  • One in 2500 newborns is affected
  • About 1 in 25-29 adults are carriers.
  • Approximately 95% of those affected are white.
  • The disease occurs rarely in Blacks and almost never in Asians.
  • Both parents must carry the mutated gene
  • Parents are usually unaffected
cystic fibrosis2
Cystic Fibrosis
  • The gene responsible for CF is located on the long arm of chromosome 7 (7q31)
  • Named the cystic fibrosis transmembrane conductance regulator gene (CFTR)
  • Most common mutation of gene is 508
  • Over 1200 other mutations have been identified
cystic fibrosis3
Cystic Fibrosis
  • The relationship between CF genotype and clinical disease is complicated by
    • sheer number of possible mutations
    • potential interactions between mutations, other genes and the environment
  • Even patients with the exact same genetic mutations have variations in the presentation and progression of disease, presumably due to other genetic and environmental factors.
normal cftr
Normal CFTR
  • CFTR is a transmembrane protein is located in epithelial cells of exocrine glands
  • Forms an ion channel for the chloride ion to pass through
    • cell membrane of glandular mucous cells
    • inracellular membrane of secretory granules
  • The protein is found in epithelial cells lining the lungs, pancreatic ducts, bile ducts, sweat glands as well as other locations.
mutated cftr
Mutated CFTR
  • Depending on the type of mutation
    • Blocked synthesis of CFTR: premature STOP codon in the gene causing early termination of transcription
    • Errors in Processing: Mutant proteins may be marked as defective and degraded in the endoplasmic reticulum or inappropriate sugars may be added.
    • Mutant CFTR may be released from ER or golgi but not migrate to the cell membrane and instead accumulate in the cytoplasm
    • Mutant CFTR may be produced and inserted in cell membrane but not function adequately
  • The degree of synthesis and function of CFTR will determine signs and symptoms of disease
cystic fibrosis4
Cystic Fibrosis


new therapies

Decreased transport of chloride through CFTR resulting in thick mucous in airway

Sodium reabsorption in airway epithelial cells may be increased, contributing to the thick and dehydrated mucous

Some mutations result in premature STOP codon that prevents transcription of CFTR gene


Other chloride channels (calcium dependent channels) continue to function in CF. Activity of these channels can be increased by use of tricyclic nucleotides, UTP or ATP, delivered to the airway by aerosol

Drugs such as amiloride may inhibit sodium and water absorption by the epithelial cell, thereby hydrating mucous in the airway

Topical administration of some aminoglycosides may suppress these nonsense mutations and allow formation of full mRNA

New Therapies
new therapies1
The mutant CFTR protein may be improperly folded in the ER or incorrectly processed in the golgi

Some mutant CFTRs reach the cell membrane but function inadequately

Normally chemical chaperones associate with new proteins and facilitate proper folding and transport to the cell membrane. Several potential chaperones that would promote proper processing of mutant CFTR are under trial including phenylbutyrate, genistein, CPX, others

Milrinone and amrinone may improve mutant CFTR activity by increasing cAMP (normal activator of CFTR)levels.Phosphodiesterase breaks down cAMP. These drugs inhibit phosphodiesterase thereby prolonging cAMP action

Other new drugs such as genistein seem to improve chloride transport by activating CFTR directly. phosphodiesterase thereby prolonging cAMP action. Other new drugs such as genistein seem to improve chloride transport by activating CFTR directly

New Therapies
new therapies2
Tissue damage due to inflammatory immune response

Genetic mutations in CFTR gene lead to clinical disease

Progressive destruction of lung

Use of non-steroidal antiinflammatory medications is under study. Steroids have shown some benefit but side effects are problematic.

Introduce correct copy of gene into epithelial cells. This has been tried using an inactivated adenovirus (that typically infects airway epithelial cells) that carries a normal copy of the gene. The gene was successfully transferred to the airway cells but the virus stimulated an inflammatory response.

Lung transplant or heart and lung transplant

New Therapies
chromosomal disorders
Chromosomal Disorders
  • Human genome contains 46 chromosomes
    • 23 pairs of autosomes
    • 1 pair of sex chromosomes
chromosomal disorders1
Chromosomal Disorders
  • Numerical (aneuploidy)
    • Monosomies (loss of one copy of chromosome)
      • If autosome affected, usually incompatible with life
      • Sex chromosome monosomies are compatible with life
    • Trisomies (extra copy of chromosome)
  • Structural
    • Result form chromosome breakage followed by loss or rearrangement of genetic material
chromosomal disorders2
Chromosomal Disorders

Aneuploidy of Sex Chromosomes

  • Turner’s Syndrome (45, X0)
  • Poly X Female (45 XXX)
  • Kleinfelter’s Syndrome (47, XXY)
  • XYYMales

Trisomy of Autosomes

  • Trisomy 21 (Down Syndrome)
  • Trisomy 13 (Patau’s Syndrome)
  • Trisomy 18 (Edward’s Syndrome)
chromosomal disorders3
Chromosomal Disorders
  • Loss of chromosomal material produces more severe defects than does gain
  • Excess chromosomal material may result for complete chromosome (trisomy) or part of a chromosome
  • Imbalances of sex chromosomes are better tolerated than imbalances of autosomes
chromosomal mutations
Chromosomal Mutations
  • Duplication: during replication a gene or group of genes may be copied more than once within a chromosome
  • Deletion: gene may be lost during replication
  • Inversions: segments of DNA are removed from chromosome and reinserted in opposite direction
chromosomal mutations translocations
Chromosomal Mutations: Translocations

Breakage and repositioning of chromosomal segments

Chromosome 18 14

Chromosomal Mutations: AmplificationMany copies of a segment of a chromosome are produced leading to multiple copies of selected genes.
  • What are the patterns of gene expression in disease?
  • What are the patterns of gene expression in health?
  • What are patterns of gene interaction?