1. Molecular Biology In Medicine
Chapter 4

2. Inherited Diseases

3. Mutations
Gene mutations can be either inherited from a parent or acquired.
A hereditary mutation is a mistake that is present in the DNA of virtually all body cells.
Hereditary mutations are also called germ line mutations because the gene change exists in the reproductive cells (eggs and sperm) and can be passed from generation to generation, from parent to newborn.
The mutation is copied every time body cells divide.

4. Mutations occur all the time in every cell in the body
Mutations occur all the time in every cell in the body. Each cell, however, has the remarkable ability to recognize mistakes and fix them before it passes them along to its descendants. But a cell's DNA repair mechanisms can fail, or be overwhelmed, or become less efficient with age. Over time, mistakes can accumulate.

5. Down’s Syndrome Caused by non- disjunction of the 21st chromosome.
This means that the individual has a trisomy (i.e. 3 copies) chromosome 21.

6. Down Syndrome or Trisomy 21

8. Symptoms of Down Syndrome
Upward slant to eyes.
Small ears that fold over at the top.
Small, flattened nose.
Small mouth, making tongue appear large.
Short neck.
Small hands with short fingers.
Low muscle tone.

9. Symptoms of Down Syndrome
Single deep crease across center of palm.
Looseness of joints.
Small skin folds at the inner corners of the eyes.
Excessive space between first and second toe.
In addition, down syndrome always involves some degree of mental retardation, from mild to severe. In most cases, the mental retardation is mild to moderate.

10. Sickle Cell Anemia
An inherited, chronic disease in which the red blood cells, normally disc- shaped, become crescent shaped. As a result, they function abnormally and cause small blood clots. These clots give rise to recurrent painful episodes called "sickle cell pain crises".

11. Cystic Fibrosis (CF) Monogenic
Cause: deletion of only 3 bases of a gene on chromosome 7
Fluid in lungs, potential respiratory failure
Common among Caucasians…1 in 20 are carriers
Therefore is it dominant or recessive?

12. Tay-Sachs disease Monogenic, autosomal recessive
Central nervous system degrades, ultimately causing death.
Most common among people of Jewish eastern Europe descent and French Canadians.
May provide resistance to Cholera

13. Muscular Dystrophy
What Is Muscular Dystrophy? Muscular dystrophy is a disease in which the muscles of the body get weaker and weaker and slowly stop working because of a lack of a certain protein (see the relationship to genetics?)
Can be passed on by one or both parents, depending on the form of MD (therefore is autosomal dominant and recessive)

14. Hemophilia, the royal disease
Haemophilia is the oldest known hereditary bleeding disorder.
Caused by a single mutation to a gene on the X chromosome.
There are about 20,000 haemophilia patients in the United States.
One can bleed to death with small cuts or bruises .
The severity of haemophilia is related to the amount of the clotting factor in the blood. About 70% of hemophilia patients have less than one percent of the normal amount and, thus, have severe haemophilia.

15. X-linked Inheritance pedigree chart

16. Huntington’s Disease
Huntington's disease (HD) is an inherited, degenerative brain disorder which results in an eventual loss of both mental and physical control. The disease is also known as Huntington's chorea. Chorea means "dance-like movements" and refers to the uncontrolled motions often associated with the disease.

19. Huntington’s
Scientists have discovered that the abnormal protein produced by the Huntington's disease gene, which contains an elongated stretch of amino acids called glutamines, binds more tightly to HAP-1 than the normal protein does.

20. Phenylketonuria or PKU
People with PKU cannot consume any product that contains aspartame. PKU is a metabolic disorder that results when the PKU gene is inherited from both parents (recessive or dominant? Monogenic or chromosomal?) Caused by a deficiency of an enzyme which is necessary for proper metabolism of an amino acid called phenylalanine.

21. PKU
Phenylalanine is an essential amino acid and is found in nearly all foods which contain protein, dairy products, nuts, beans, tofu, etc.
A low protein diet must be followed.
Brain damage can result if the diet is not followed causing mental retardation and mousy body odor (phenylacetic acid is in sweat).

22. PKU

23. Phenylalanine

24. Color Blindness Cause: x-linked recessive
8% males and 0.64% females affected. Why the difference?
Individuals are unable to distinguish shades of red-green.
Are you color blind?
                                          

26. Genes Are carried on a chromosome The basic unit of heredity
Encode how to make a protein
DNARNA proteins
Proteins carry out most of life’s function.
When altered causes dysfunction of a protein
When there is a mutation in the gene, then it will change the codon, which will change which amino acid is called for which will change the conformation of the protein which will change the function of the protein. Genetic disorders result from mutations in the genome.

27. Picture of a Chromosome

28. What is Gene Therapy
It is a technique for correcting defective genes that are responsible for disease development
There are four approaches:
A normal gene inserted to compensate for a nonfunctional gene.
An abnormal gene traded for a normal gene
An abnormal gene repaired through selective reverse mutation
Change the regulation of gene pairs
Is the most common approach
The abnormal gene would be swapped by homologous recombination
Would cause a return to normal function
Control expression of genes. Similar to epistasis, when one gene affects the expression of another gene.

29. The Beginning…
In the 1980s, Scientists began to look into gene therapy.
They would insert human genes into a bacteria cell.
Then the bacteria cell would transcribe and translate the information into a protein
Then they would introduce the protein into human cells

30. The First Case
The first gene therapy was performed on September 14th, 1990
Ashanti DeSilva was treated for SCID
Sever combined immunodeficiency
Doctors removed her white blood cells, inserted the missing gene into the WBC, and then put them back into her blood stream.
This strengthened her immune system
Only worked for a few months

31. How It Works
A vector delivers the therapeutic gene into a patient’s target cell
The target cells become infected with the viral vector
The vector’s genetic material is inserted into the target cell
Functional proteins are created from the therapeutic gene causing the cell to return to a normal state
A vector is a carrier molecule, usually a virus
The target cells are usually in the liver or lung

33. Viruses Replicate by inserting their DNA into a host cell
Gene therapy can use this to insert genes that encode for a desired protein to create the desired trait
Four different types

34. Retroviruses Created double stranded DNA copies from RNA genome
The retrovirus goes through reverse transcription using reverse transcriptase and RNA
the double stranded viral genome integrates into the human genome using integrase
integrase inserts the gene anywhere because it has no specific site
May cause insertional mutagenesis
One gene disrupts another gene’s code (disrupted cell division causes cancer from uncontrolled cell division)
vectors used are derived from the human immunodeficiency virus (HIV) and are being evaluated for safety

35. Adenoviruses
Are double stranded DNA genome that cause respiratory, intestinal, and eye infections in humans
The inserted DNA is not incorporate into genome
Not replicated though
Has to be reinserted when more cells divide
E.g.: Common cold

36. Adenovirus cont.

37. Adeno-associated Viruses
Adeno-associated Virus- small, single stranded DNA that insert genetic material at a specific point on chromosome 19
From parvovirus family- causes no known disease and doesn't trigger patient immune response.
Low information capacity
gene is always "on" so the protein is always being expressed, possibly even in instances when it isn't needed.
hemophilia treatments, for example, a gene-carrying vector could be injected into a muscle, prompting the muscle cells to produce Factor IX and thus prevent bleeding.
Study by Wilson and Kathy High (University of Pennsylvania), patients have not needed Factor IX injections for more than a year