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

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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

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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)

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”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.