Triple Nucleotide Repeat Abnormality and its Pathology

1. Triple Repeat
Abnormalities and its
Pathology

2. CONTENTS
1. Introduction to the topic
2. About Genes
3. Types of Abnormalities
4. Triple Repeat Abnormality
5. Pathogenesis
6. Disorders

3. Introduction

4. Chromosome
Thread like structures in which DNA is tightly
packed within the nucleus.
Gene
A specific sequence of nucleotides in DNA or RNA
that is usually located on a chromosome that codes
for a molecule that has function and is the
functional unit of inheritance.
Genome
A genome is an organism’s complete set of DNA,
including all its genes.
DNA
A molecule composed of two chains that coil
around each other to form a double helix
carrying the genetic instructions
Nucleosome
Segment of 147 base pairs of DNA
wrapped around 8 histone protein cores.
Chromatin
DNA – Histone complex, resembling
a series of beads joined by short DNA
linkers.

5. MUTATION
•A single bp is
substituted with a
different bp.
•Conservative
missense
•NonConservative
missense
•Nonsense
•Point mutations
or Deletions in
regulatory
sequences.
•Defective
splicing .
•Resulting in
failure to form
mature mRNA.
•Two possible
outcomes
•Intact reading
framework and
abnormal protein
synthesis.
•Frameshift
Mutation.
•Amplification of a
sequence of 3
nucleotides.
•Almost all
affected
sequences share
the nucleotides
Guanine (G) and
Cytosine (C)
- A mutation is defined as a permanent change in the DNA.
- Mutations that affect germ cells are transmitted to the progeny and can give rise to inherited diseases.
Point
Mutations
within
coding
sequences
Mutations
within
noncoding
sequences
Deletions
and
Insertions
Trinucleotide
– repeat
mutations

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GENETIC DISORDERS
• A genetic disorder is caused by a mutation to a gene, group of genes or entire chromosome.
Disorders related to mutations in single genes with large effects.
Autosomal Dominant disorders - Myotonic Dystrophy, Polycyctic Kidney Disease
Autosomal Recessive diseases - Sickle cell anemia, Cystic Fibrosis.
X-Linked disorders - Hemophilia Aand B, Diabetes Insipidus.
Chromosomal disorders.
1. Structural Abnormalities :
Deletions - Cri-du chat Syndrome.
Duplication - Charcot-Marie-Tooth disease t ype 1A
2. Numerical Abnormalities
Trisomy - Down’s Syndrome.
Monosomy - Turner Syndrome
Complex Multigenic Disorders. Eg. Diabetes Mellitus, Hypertension.

7. MENDELIAN DISORDERS
•Collagen – Osteogenesis Imperfecta
Ehlers-Danlos Syndrome
•Fibrillin – Marfan Syndrome
•Dystrophin – Duchenne Muscular Dystrophy.
•Spectrin/Ankyrin – Hereditary Spherocytosis
Disorders associated with Defects
in Structural Proteins
•Familial Hypercholesterolemia
- Autosomal dominant
- Mutations in gene encoding the
LDL receptor.
Disorders Associated with
Defects in Receptor Proteins
•Lysosomal Storage diseases
•Tay-Sachs Disease
•Niemann-Pick Disease
•Gaucher
•Mucopolysaccharidoses.
•Glycogen Storage Diseases
Disorders associated with
Defects in Enzymes
•Mutations in Proto-oncogenes and tumor
suppressor genes.
•Majority mutations affect somatic cells.
•Approximately 5% of all cancers affect germ line .
•Most familial cancers are inherited in an
autosomal dominant fashion.
Disorders associated with Defects in
Proteins that Regulate Cell Growth
•Mutations in single
gene with large
effect.
•Usually dominant or
recessive.
•Codominance – eg
blood group
antigens.

8. SINGLE-GENE DISORDERS WITH NONCLASSIC INHERITANCE
Diseases caused by trinucleotide-repeat
mutations
Disorders caused by mutations in mitochondrial
genes
Disorders associated with genomic imprinting
Disorders associated with gonadal mosaicism
4 Groups

9. Trinucleotide-Repeat Mutations

10. • Expansion of trinucleotide repeats is an important genetic cause of
human disease, particularly neurodegenerative disorders .
•First discovered in 1991. Since then about 40 diseases have been added.
•Dynamic.
•The causative mutations usually share the nucleotides G and C.
Expansion of repeats
above threshold
Unstable DNA
Impaired gene
function
•The proclivity to expand depends strongly on the sex of the transmitting parent.
eg. In Fragile X Syndrome - expansions occur during oogenesis.
In Huntington Disease – expansions occur during spermatogenesis.

11. Loss of
function
of the
gene
Toxic
gain of
function
Toxic
gain of
function
3 Key
Mechanisms
• By Transcription silencing
• repeats are generally in non
coding part of gene
•Eg Fragile-X Syndrome
• By alterations of protein structure.
• eg. Huntington disease
Spinocerebellar ataxia
• Mediated by mRNA
• eg. Fragile-X tremor-ataxia
syndrome.

12. DISEASES REPEAT NORMAL DISEASE
• Expansions Affecting Noncoding Regions
Fragile X Syndrome CGG 6-55 >230
Friedreich Ataxia GAA 7-34 >100
Myotonic Dystrophy CTG 5-37 >100
• Expansions Affecting Coding Regions
Spinobulbar muscular Atrophy CAG 9-36 36-62
Huntington Disease CAG 6-35 36-121
Dentatorubral-pallidoluysian Atrophy ( Haw River Syndrome) CAG 6-35 49-88
Spinocerebellar Ataxia type 1 CAG 6-44 39-82
Spinocerebellar Ataxia type 2 CAG 15-31 36-63
Spinocerebellar Ataxia type 3 CAG 12-40 55-84
Spinocerebellar Ataxia type 6 CAG 4-18 21-33
Spinocerebellar Ataxia type 7 CAG 4-35 37-306
EXAMPLES OF NEUCLEOTIDE REPEAT DISORDERS

13. Mutations affecting coding region usually involve
CAG repeats
‘Polyglutamine’ expansion leading to toxic gain of
function
Interference by abnormal protein or acquire a
toxic activity
Proteins are misfolded and tend to aggregate,
which may suppress transcription of other genes
Mitochondrial dysfunction or trigger the unfolded-
protein stress response and apoptosis
PATHOGENESIS

14. Thank You