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Part 2
Haemophilia A An X-linked recessive disorder in which blood clotting does not
occur due to deficiency of clotting factor VIII. In most cases the mutation is the result of insertion of a large
segment, consisting of about 3800 bp, in the coding region of the factor VIII.
This results in total inactivation of the protein.
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Inherited as a sex linked recessive trait with bleeding manifestations only in males.
Genes which control factor VIII and IX production are located on the x chromosome
Affected male marries a normal female: none of sons will be affected, all daughters will be carriers
Female carrier marries normal male: 50% chance sons will be affected and 50% chance daughters will be carriers
Haemophilia A
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Deletion
CTGGAG
C T A G
Deletions involve removal of one or more base pairs. They vary greatly in size from deletion of a single base
to deletion of a whole gene. The clinical effects often depend on the size and
location of the deleted part of the gene.
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What will happen to the amino acids?
Mutated DNA: CGA – TCA- TC
A guanine was deleted, thereby pushing all the bases down a frame.
Alanine – Threonine – stop
Alanine – Serine
Deletion MutationsNormal DNA: CGA – TGC – ATC
This is called a deletion mutation, also a type of frameshift mutation.
What has happenedto the DNA?
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Muscular Dystrophy
Deletions of Dystrophin Gene
Dystrophin is a protein that is an important component of skeletal muscle.
The dystrophin gene is located on the p arm of the X chromosome (Xp21.2).
It is a very large gene spanning 2.5 million bp of genomic DNA and consists of 79 exons coding for a protein of approximately 3600 amino acids (11kb).
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Muscular Dystrophy
Deletions of Dystrophin Gene
Deletion of the whole or most of the dystrophin geneDystrophin may not be produced at all Or produce in in abnormal forms,
Resulting in Duchenne muscular dystrophy This is a severe X-linked recessive disorder that affects boys and is
transmitted by carrier females. X linked Recessive disorder. In affected boys there is almost complete lack of dystrophin, muscle
weakness beginning in childhood and increasing progressively in severity so that the individual is wheel-chair bound at the age of about 15 years.
Death usually ensues in the early twenties due to respiratory muscle involvement.
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X linked Recessive disorder
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Becker Muscular Dystrophy(BMD)Deletions involving a small non-critical part of the gene result in
altered dystrophin.This causes the clinical condition of Becker muscular dystrophy
in BMD muscle weakness begins in adolescence and is very slowly progressive, and affected individuals may lead an almost normal life.
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Cystic Fibrosis.
Cystic fibrosis (CF) is a genetic condition that affects many organs in the body: especially the lungs, pancreas and sweat glands.
Cystic fibrosis is caused by a mutation in the Cystic Fibrosis Trans-membrane Regulator (CFTR) gene, that is located on chromosome 7.
This gene Produces a trans-membrane protein that regulates the flow of chloride ions into the cells.
The most common mutation is termed the ∆508 mutation, which is a deletion of a single codon at position number 508 in exon 10 of the CFTR gene.
Homozygotes(both parents need to be the carriers of the defective gene) for a ∆508 mutation have cystic fibrosis disease.
Gene That Encodes CFTR The gene that encodes the CFTR protein is found on
the human chromosome 7, on the long arm at position q31.2.
Mutations consist of replacements, duplications, deletions or shortenings in the CFTR gene.
This may result in proteins that may not function, work less effectively, are more quickly degraded, or are present in inadequate numbers
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Cystic Fibrosis.
The defective gene produces a defective protein leading to a blockage in the transportation of the salt, thus leading to production of thick, sticky mucus.
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Presentation
The secretion of very thick, sticky mucus causes Obstruction of the bronchi and predisposing to pulmonary infections, Pancreatic duct obstruction leads to problems with digestion. Intestinal and liver problems and When it blocks the sweat glands, it leads to loss of excessive salt
through sweat. This leads to imbalance of minerals within the body.
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• Paroxysmal nocturnal hemoglobinuria is a disorder of blood cells in which absence of specific molecule(GPI anchor protein, CD55 [Decay Accelerating Factor (DAF)], and CD59 [Membrane Inhibitor of Complement Lysis (MIRL)] on the surface of the cells (particularly RBC) leads to premature destruction of the cells by the complement system.
• This destruction is intermittent (paroxysmal).
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Paroxysmal Nocturnal Hemoglobinurea
Paroxysmal Nocturnal Hemoglobinurea
GPI anchor protein on the surface of red blood cells produced by the bone marrow stem cells
This is caused by a mutation of PIG-A gene, PIG-A gene is present on the X chromosome important in
making GPI protein anchors. Defect makes the red cells in susceptible to destruction
by the complement system.
The PIG-A mutation occurs in a bone marrow stem cell.
All the blood cells made by this defective stem cell are deficient in GPI-anchored proteins. (glycosyl-phosphatidylinositol GPI).
The GPI-anchored proteins are present on the surface of red blood cells that protect red cells from the activity of the complement system.
When they are absent , no protection from complement and this lead to intravascular haemolysis.
Paroxysmal Nocturnal Hemoglobinurea
Genetics• PIGA gene(phosphatidylinositol glycan class A) is
present in in the X chromosome and can have several mutations, from deletions to point mutations.
• The genetic mutation leading to the inability to synthesize the glycosyl-phosphatidylinositol (GPI) anchor proteine.
RBC Lysis
Normal RBCs PNH RBC
Intact RBC
ComplementActivation
Lysed PNH RBCs and free hemoglobin in the plasma
Chronic Hemolysis
CD59
Lectin Pathway Classical Pathway Alternative Pathway Carbohydrate structure Antibody bound to antigen Microbial membranes Pathogen/Damaged cell Immune complexes Bacterial LPS C3 convertase C4b2a, C3bBb C3 C3a Weak anaphylatoxin
C3b CD55 C5 convertases C4b2a3b, C3bBb3b CD55 C5 C5a Inflammation Cell Activation C6,C7,C8,C9 CD59
C5b-9 Microorganism Destruction Red Blood Cell Lysis Platelet Activation
Role of CD55 &CD 59
• The term "nocturnal" refers to the belief that hemolysis is triggered by acidosis during sleep and activates complement to hemolyze an unprotected and abnormal RBC membrane.
• However, this observation was later disproved. Hemolysis has been shown to occur throughout the day and is not actually paroxysmal, but the urine concentrated overnight produces the dramatic change in color.
Paroxysmal Nocturnal Hemoglobinurea
Deletion of 6 codons in the -globin gene resulting in a variant Hemoglobin
The codons 92 to 97 of the -globin gene are deleted. This results in a shortened -globin protein that produces
a haemoglobin variant termed Haemoglobin Gun Hill. In homozygotes it produces mild clinical; symptoms.
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Codon no Codon Amino acid
91 CUG Leucine
92 CAC Histidine
93 UGU Cysteine
94 GAC Aspartic acid
95 AAG Lysine
96 CUG Leucine
97 CAC Histidine
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Frame shift mutations
Frame shift mutations involve a deletion or insertion of one or two base pairs within a coding sequence of a gene.
As the coding message is read in triplets codons and deletions will altered the the reading frame of mRNA
This results in a non-sense sequence of amino acids till stop codon. Original= T H E FAT C A T AT E T H E W E E R AT
Frame-shift= T H E FAT C A A T E T H E W E E R AT
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Frame Shift Mutations(Deletion)
An example occurs in the -globin gene in which one nucleotide of codon 39 is deleted leads to altered sequence.
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Frame Shift Mutations(Insertion)
Insertion of a sequence of bases into a coding sequence of a gene.
Sometimes a whole gene sequence may be duplicated.
1. Hereditary motor and sensory neuropathy type I
A DNA segment at locus 17p11 is duplicated.
2. Tay-Sachs Disease
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Tay-Sachs Disease
Tay-sachs disease is an autosomal recessive disorder This genetic defect is located in the HEXA (hexosaminidase)
gene, which is found on chromosome 15. The hexa gene makes part of an enzyme called beta-
hexosaminidase A This enzyme helps break down a fatty substance called GM2
ganglioside in nerve cells. Mutations in the HEXA gene disrupt the activity of beta-
hexosaminidase A, preventing the breakdown of the fatty substances.
As a result, the fatty substances accumulate to deadly levels in the brain and spinal cord.
The buildup of GM2 ganglioside causes progressive damage to the nerve cells.
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Tay-Sachs Disease
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Tay-Sachs Disease
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Tay-Sachs Disease
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Loss of hearingPhysical and mental retardationSeizuresDementiaAnd most noticeably detected by the red dots it causes
on the retina of an individuals eye
Tay-Sachs Disease S\S
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Trinucleotide Repeat Expansions
Trinucleotides are triplets of nucleotides that are repeated The number of repeats varies in different individuals. Trinucleotide repeats is - - - CAG CAG CAG CAG CAG - - - - Trinucleotide repeats are widespread in the genome, and may
occur in exons, introns, promoter sequences or non-coding regions.
They are perfectly normal and occur in all individuals However a mutation arises when the repeats become unstable and
undergo expansion, namely an increase in the number of repeats as they are transmitted from one generation to the next.
When the number of repeats exceeds a certain limit, clinical symptoms occur.
An example is the huntingtin gene, which, when mutated, causes Huntington's disease.
Normal range of (CAG)n is 11 to 34 Huntington's disease appear in individuals in whom the number
of repeats is greater than 37.
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Huntington's Disease
Autosomal Dominant InheritanceDue to an excess of C-A-G nucleotide repeats(>37) in
the HTT gene on the short arm of chromosome 4 forms (4p 16.3)Huntington's protein.
Huntington's protein has increase number of glutamine (polyglutamine).
Excess of repeats causes the protein to form aggregates that are deposited within the neurons causing neuronal degeneration
Affects brain and spinal cord, especially the basal ganglia.
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Trinucleotide Repeat Expansions
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Clinical Manifestations Most commonly appear in mid-forties If appear at a younger age, more severe Manifestations occur because of wasting away of brain cells.
1. Sudden jerky, involuntary movements throughout body
2. Difficulties with balance and coordination
3. Dysphasia
4. Hesitant/slurred speech
5. Progressive dysfunction of intellectual and thought processes (dementia)
6. Cognitive deficits
a. Working memory loss
b. Reduced capacity to plan, organize, and sequence
7. Restlessness, irritability
8. Depression or Euphoria 38SDK 2012
What happens to a person who has a mutation?
Most of the time the mutation is harmless because 95% sections of DNA do not code for protein (junk DNA).
But sometimes the mutations can cause disorders such as Huntington’s disease and sickle cell anemia etc.
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Brain Work 5
Which of these is NOT a type of mutation.a) Point mutation
b) Flyaway mutation
c) Frameshift mutation
d) Nonsense mutation
Flyaway Mutation
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Brain Work 61. THE CAT SAW THE FAT RAT
2. THE CAT SAW THE RAT
The change in Statement 1 to form Statement 2 is most similar to what type of mutation?
A. Insertion
B. Deletion
C. Substitution
D. Frameshift
The correct answer is B deletion. Because the sentence is missing the word fat
which occurs in deletion as it is the removal of a section of DNA.
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Brain Work 7
5 AGAUCGAGU3 → 5′ ′ ’ACAUCGAGU3′The chain above represents three codons.
Which of the following changes would be expected in the amino acid chain if the mutation shown
above occurred?
A. The amino acid sequence would be shorter than expected.
B. The identity of one amino acid would change.C. The amino acid sequence would remain
unchanged.D. The identities of more than one amino acid
would change. The correct answer is B because according to the codon chart if G is switched by a C then one amino acid is affected because now instead of coding for Arginine it now codes for Threonine.
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Brain Work 7
5 AGAUCGAGU3 → 5′ ′ ’AGAUGAAGU3′The chain above represents three codons.
Which of the following changes would be expected in the amino acid chain if the mutation shown
above occurred?
A. The amino acid sequence would be shorter than expected.
B. The identity of one amino acid would change.C. The amino acid sequence would remain
unchanged.D. The identities of more than one amino acid
would change. The correct answer is A because according to the codon chart if C G are switched by a G A then one codon will be affected because now instead of coding for Serine it now codes for Stop codon.
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Thank You
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