MOLECULAR BIOLOGY IN MEDICINEChapter 4
Inherited Diseases
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.
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.
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.
Down Syndromeor Trisomy 21
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.
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.
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".
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?
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
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)
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.
X-linked Inheritance pedigree chart
Huntington’s DiseaseHuntington'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.
Huntington’sScientists 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.
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.
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).
PKU
Phenylalanine
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?
Genes Are carried on a chromosome The basic unit of heredity Encode how to make a protein
DNARNA 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.
Picture of a Chromosome
What is Gene Therapy It is a technique for correcting
defective genes that are responsible for disease development
There are four approaches:1. A normal gene inserted to compensate
for a nonfunctional gene.2. An abnormal gene traded for a normal
gene3. An abnormal gene repaired through
selective reverse mutation4. Change the regulation of gene pairs
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
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
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
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
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
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
Adenovirus cont.
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
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