Post on 13-Apr-2017
transcript
Mutation
Present by;Naseem bhurgri Ph.D. scholar ( biotechnology university of Sindh)
MUTATIONA mutation is a change in genetic material. A mutation is a change in the DNA sequence or chromosomal
mutation. Most mutation are the result of error during DNA replication
process/ error during DNA repair. Some types of mutations are known to be caused by certain
chemicals and ionizing radiation, UV
mutation
Type of mutation
Types of mutation
Molecular chromosomal
Substation Insertion Deletion frameshift
Inversion Duplication translocation
“
”
Mutation typesTwo types of mutation
Spontaneous Mutations
Induced mutations
SPONTANEOUS MUTATION
they are mainly caused during dna replication or by incorporation of incorrect nucleotide in the growing dna chain .
They occur naturally by changes in DNA sequence during replication.
induced mutation
are caused by the changes in DNA brought about by some environmental factor called mutagens.
E.g.- UV light,x-rays,gamma rays etc…,
Types of Mutation on molecular basis
Substitution •Insertion •Deletion •Frameshift
Substitution
A substitution is a mutation that exchanges one base for another (i.e., a change in a single "chemical letter" such as switching an A to a G).
Insertion
Insertions are mutations in which extra base pairs are inserted into a new place in the DNA
Deletion mutation
Frameshift Mutations
a mutation caused by the addition or deletion of a base pair or base pairs in the DNA of a gene resulting in the translation of the genetic code in an unnatural reading frame from the position of the mutation to the end of the gene
EFFECT OF MUTATION ON PROTEIN FUNCTION
“
”
EFFECT OF MUTATION ON PROTEIN Function
Mutation exert their phenotypic effects by one of the two mechanism.
Loss of functionGain of function
Mutations are also classified by their impact on protein function
Loss of function Complete loss of the protein: E.g null, loss-of-function, amorph Reduction of protein’s ability to work: e.g hypomorph, reduction-of-function
Gain of function
Inrcease in the protein’s function: E.g hypermorph, gain-of-function A protein that interferes with the wild-type protein’s
function: E.g antimorph, dominant negative
Disease due to mutation
Sickle cell trait
A case study of the effects of mutation:
Sickle cell anemia Sickle cell anemia is a genetic disease with severe symptoms, including pain and anemia.
The disease is caused by a mutated version of the gene that helps make hemoglobin —a protein that carries oxygen in red blood cells.
People with two copies of the sickle cell gene have the disease. People who carry only one copy of the sickle cell gene do not have the disease, but may
pass the gene on to their children.
How Does a Child Get Sickle Cell DIsease? • Sickle cell disease is inherited through genes. For a child to have any form of sickling disease, each parent will have an abnormal
hemoglobin. One possibility is that each parent has sickle cell trait (AS). Another possibility is when one parent has the disease (SS) and the other parent has sickle
cell trait (AS). In hemoglobin SC disease, one parent has sickle cell trait and the other parent has a
different trait (hemoglobin C). In sickle beta-thalassemia, one parent has sickle cell trait (or sickle cell anemia) and the
other parent carries the trait for beta thalassemia (or has thalassemia major).
How Does a Child Get Sickle Cell DIsease? •
sickle-cell anemia is caused by a single point mutation in the nucleotide sequence of β-globin.
The seventh triplet should read GAG which colds for glutamic acid, but the middle nucleotide has changed to a thymine, which changes the triplet to GTG, which codes for valine.
Replacement of the normally charged glutamic acid with the hydrophobic valine
Replacement of the normally charged glutamic acid with the hydrophobic valine alters the solubility of hemoglobin, so that at a lower oxygen concentration, the altered protein changes the red blood cell to a sickle shape that is unable to carry oxygen. This causes the symptoms of sickle-cell anemia.
Hemoglobinopathies
Disorders of the human hemoglobins Most common single gene disorders in the world
WHO: 5% of the world’s population are carriers for clinically significant hemoglobinopatihies
Well understood at biochemical and molecular levels
Hemoglobinopathies?
What are they? Disorders where the production of normal adult
hemoglobin in partly or completely suppressed or replaced by a variant hemoglobin.
Broad Classification System for Hemoglobin Disorders
Qualitative:
Characterized by decreased production of hemoglobin resulting from decreased synthesis of one particular globin chain
Hemoglobins differ in sequence of amino acids composing globin chain
Disorders called hemoglobinopathies
Quantitative:
•Thalassemia.
Thalassemia is an inherited blood disorder in which the body produces an abnormal form of hemoglobin which results in excessive destruction of red blood cells and further leads to anemia.
Thalassemia
ALPHA THALASSEMIA BETA
THALASSEMIA
Alpha Thalassemia
Alpha Thalassemia Alpha thalassemia is the result of changes in the genes for the alpha globin component of hemoglobin.
Pathophysiology
Therefore, alpha thalassemia occurs when there is a disturbance in production of α-globin from any or all four of the α-globin genes.
When functional point mutations, frame shift mutations, nonsense mutations, and chain termination mutations occur within or around the coding sequences of the alpha-globin gene cluster hemoglobin is impaired
.When that occurs, protein synthesis may be inhibited.
. Pathophysiology
Normal production of alpha chains is absent which results in excess production of gamma- globin chains in the fetus and newborn or beta- globin chains in children and adults.
The β-globin chains are capable of forming soluble tetramers (beta-4, or HbH) This form of hemoglobin is still unstable and precipitates within the cell, forming
insoluble inclusions called Heinz bodies These Heinz bodies damage the red blood cells. This further results in damage to erythrocyte precursors and ineffective erythropoiesis in
the bone marrow, hypochromia and microcytosis of circulating red blood cells
Mutated Thalassemia
Alpha (0) thalassemia – More than 20 mutations have been found .Those that result in the functional depletion of both pair of α -globin genes Individuals with this disorder are not able to produce any functional α -globin and thus
are unable to make any functional hemoglobin A, F, or A2. This leads to the development of hydrops fetalis or hemoglobin Bart (excess buildup of
fluid before birth)
Clinical Presentation
Enlarged liver and spleen
Weakness
Pale skin
Shortage of red blood cells- Anemia
Clinical Presentation
Abnormalities of the urinary system or genitalia
Abnormal bleeding
Hb Bart syndrome can
cause complications in pregnancy such
as
Premature delivery
High blood pressure•
Treatment of Alpha Thalassemia
Treatment for thalassemia often involves regular blood transfusions and folate supplements.•
If you receive blood transfusions, you should not take iron supplements. Doing so can cause a high amount of iron to build up in the body, which can be harmful.
Persons who receive significant numbers of blood transfusions need a treatment called chelation therapy to remove excess iron from the body.
Bone marrow transplant may help treat the disease in some patients, especially children.
Medications•
FOLIC ACID- ORAL• FOLIC ACID - INJECTION• DEFEROXAMINE - INJECTION
BETA THALASSEMIA
Beta thalassemia is a genetic blood disorder that reduces the production of hemoglobin.
Beta Thalassemia• Specifically, it is characterized by a genetic deficiency in the synthesis of beta- globin chains
.• Beta-globin is a component (subunit) of hemoglobin.
There are 3 types of Beta Thalassemia
Thalassemia Minor
Thalassemia Intermediate
Thalassemia Major or Cooley's Anemia
Symptoms of Beta Thalassemia
It is characterize by severe anemia that can
begin months after birth
Delays in growth and development Paleness
Bone marrow expansion.
Untreated Beta Thalassemia major can lead to child death due
to heart failure
Treatment of Beta Thalassemia
Regular blood transfusion helps prevent severe anemia and allows for more normal growth and development
There are various medications that target the production of red blood cells (i.e. erythropoeitin)
“
”ANEMIA
What is anemia
Anemia is a condition that develops when your blood lacks enough healthy red blood cells or hemoglobin.
ANEMIA is the most common blood condition in the U.S. It affects about 3.5 million Americans. Women, young children, and people with chronic diseases are at increased risk of anemia
TYPES OF ANEMIA
Iron deficiency anemia.
hemolytic anemia.
Megaloblastic anemia
aplastic anemia.
thalassemmia anemia.
Hemorrhagic anemia
Pernicious anemia
.Iron deficiency anaemia
excessive loss of iron
Women are at risk.
For menstrual blood and growing
fetus.
2.Megaloblastic anemia
Red bone marrow produces abnormal
RBC.
Less intake of vitamin B 12
CANCER DRUGS.
3.Pernicious anemia
Inability of stomach to absorb vitamin B 12 in small intestine
4.Hemorrhagic anemia
Excessive loss of RBC through
-bleeding
stomach ulcers
menstruation
5.Hemolytic anemia
RBC plasma membrane ruptures
may be due to
parasites,toxins,antibodies.
6.Thalassemmia anemia
Less synthesis of hemoglobin.
.Aplastic anemia
destruction of red bone marrow ♣ caused by toxins,gamma radiation . ♣ enzymes needed for blood production.
SIGN SYMPTOMS
Irritability
Lack of Concentration
Weakness
InfectionFatigue
DIFFICULTIES IN
CONCENTRATE
HAIR LOSS
TREATMENT
TREA
TMEN
TBLOOD
TRANSFUSION
PARENTAL
ORAL IRON
HUMAN RECOMBINANT EROTHROPROTEIN
INJECTABLE IRON
References
First Known Heart Attack Associated With Beta- thalassemia Major Reported." Heart Disease Weekly February 22, 2004: 10.
Bowden, Vicky R., Susan B. Dickey, and Cindy Smith Greenberg. Children and Their Families: The continuum of care . Philadelphia: W.B. Saunders Company, 1998.
"Thalassemias." In Principles and Practice of Medical Genetics , Volume 2, edited by Alan E.H. Emery, MD, PhD, and David L. Rimoin, MD, PhD. New York: Churchill Livingstone, 1983.
Thompson, M.W., R. R. McInnus, and H. F. Willard. Thompson and Thompson Genetics in Medicine , Fifth Edition. Philadelphia: W.B. Saunders Company, 1991.
Olivieri, N. F. "The Beta Thalassemias." The New England Journal of Medicine 341 (1999): 99-109.