L2 - Molecular Basis Of Disease

Question 1

Explain disease at molecular level

Answer 1

Change at DNA, RNA, and protein level

Question 2

What leads to changes in the protein quality, quantity, and function

Answer 2

Mutation of genes and changes during transcription,translation, and post translation level

Question 3

Disease at gross or microscopic level

Answer 3

Morphology and biochemical alterations in body fluids

Question 4

Genetic changes in germ cells

Answer 4

Transmitted to progeny
Lead to inherited diseases (hereditary disorders)
Familial/ congenital

Question 5

Genetic changes in somatic cells

Answer 5

Not transmitted to progeny
Still responsible for disease cause
Not familial

Question 6

Mutation in DNA

Answer 6

Permanent change in DNA sequence

Question 7

Chromosomal alteration

DELETION

Answer 7

Loss of chromosomal fragment - gene loss or deficiency

Question 8

Chromosomal alteration

DUPLICATION

Answer 8

Fusion of proteins or amplification of genes

Question 9

Chromosomal alteration

INVERSION

Answer 9

Segment of chromosome reversed end by end

Question 10

Chromosomal alteration

TRANSLOCATION

Answer 10

Exchange two chromosome segments = fusion of proteins + altered gene expression

Question 11

Aneuploidy

Answer 11

Whole chromosome gains or loses

Question 12

Epigenetic changes

Answer 12

Modulation of gene/ protein expression in absence of alteration in DNA sequence or structure

• DNA methylation
• histone modification
• non coding RNAs
• protein modification

Question 13

DNA methylation of cytosine @ gene promoters

Answer 13

Promoters become inaccessible to RNA polymerase = transcriptional silencing

Question 14

Histone modifications

Answer 14

Methylation and acetylation of secondary and tertiary DNA structure + regulate gene transcription

Question 15

Non coding RNAs - miRNA and IncRNA

Answer 15

miRNA - doesn’t encode proteins but inhibit translation of target mRNAs into corresponding proteins
IncRNA - binding to chromatin and modulate gene expression, restrict access of RNA polymerase to coding genes

Question 16

Protein modification

Answer 16

Folding and phosphorylation

Question 17

Sickle cell disease molecular pathogenesis

Answer 17

Normal( CTC ) in the beta-globn chain changes to ( CAC ) and change of (glutamine) to (valine)

Beta-globin chain -> sickle beta-globin

Question 18

What type of mutation is SCD

Answer 18

Point mutation

Valine for glutamine @ 6th amino acid = structurally abnormal molecule ( hemoglobin S)

Question 19

What happens when hg S is polymerized?

Answer 19

Cytoplasm become rigid filamentous gel and leads to less deformable sickles erythrocytes

Question 20

What does the rigidity of sickles erythrocytes lead to?

Answer 20

• obstruction of the microcirculation, tissue hypoxia and ischemic injury in many organs
• because sickle cells are inflexible this leads to hemolysis in spleen during circulation

Question 21

What are the two primary manifestations of sickle cell diseas

Answer 21

recurrent ischemic events and hemolytic anemia

Question 22

SCD clinical manifestations

Answer 22

Retinopathy- blindness
Stroke
Pneumonia -lung infarcts- acute chest syndrome 
Iron overload in heart and liver 
Spleen atrophy 
Osteomyelitis 
Skin ulcers 
Kidney lower ability

Question 23

Molecular pathogenesis of chronic myeloid leukemia (CML)

Answer 23

BCR-ABL fusion gene by translocation =(Philadelphia chromosome)
The fusion makes signals that mimic effect of growth factor activation =CML cells grow and reproduce
(Gene 9 and 22)

Question 24

Diagnosis of CML

Answer 24

Using translocation bcz its available in most CML patients

Question 25

Treatment of CML

Answer 25

Tyrosine kinase inhibitor (Imatinib)

Question 26

Signal pathways of BCR-ABL

Answer 26

Transforming hematopoietic cells to cancer cells

Question 27

Acute promyelocytic leukemia molecular pathogenesis

Answer 27

translocation between chromosomes 15 and 17 = fusion of PML and RARa gene PML/RARa = blocking myeloid differentiation at promyelocytic stage

Question 28

APL treatment

Answer 28

all-trans retinoic acid (ATRA) survival higher than cytotoxic therapy - Mechanism: binds to PML\RARa causes neoplastic promyelocytes to rapidly differentiate into neutrophils bcz neutrophils die after 6hrs= clearing the tumor (If AML doesn’t have RARa translocation it wont respond to ATRA)

Question 29

Cystic fibrosis cause

Answer 29

mutations of the CF transmembrane Conductance Regulator (CFTR) gene

Question 30

What is the CFTR

Answer 30

anion channel that regulates the transmembrane ion transport

Question 31

Mutation in CFTR

Answer 31

= defective electrolyte transport (chloride ion) in epithelial cells which affects salt absorption, fluid absorption ,and anion-mediated fluid secretion -complex multi system disease

Question 32

Pathogenesis of respiratory and intestinal complications in CF

Answer 32

Low-volume of surface fluid layer -> dehydration in lungs ->accumulation of secretions -> obstruction of air passage and pulmonary infections ( cause of mortality in CF)

Question 33

CFTR defect in sweat duct

Answer 33

High chloride and sodium concentration in sweat

Question 34

CFTR defect in lung

Answer 34

- Low chlorine and high sodium and water reabsorption= dehydration of mucus layer and defect in mucociliary action - mucous plugging and tracheobrachial dilation - greenish discoloration bcz of bacterial infection

Question 35

diabetes mellitus cause

Answer 35

insulin resistance and beta cell dysfunction = insulin deficiency (doesn’t involve autoimmunity)

Question 36

Insulin resistance

Answer 36

Failure of tissue to respond normally to insulin caused by reduction in phosphorylation dependent activation of the insulin receptor and its components = signal transduction

Question 37

Lack of insulin

Answer 37

=catabolic state effects glucose fat and protein metabolism | -bad glucose storage= hyperglycemia

Question 38

Hyperglycemia = ?

Answer 38

-activation of the mitogen activated protein kinase (MAPK) pathway and oxidative stress=clinical presentations

Question 39

Genetics and DM

Answer 39

Diabetogenic | Obesity related genes

Question 40

Environmental influences and DM

Answer 40

Obesity | Sedentary life style

Question 41

How does obesity lead to insulin resistance

Answer 41

Adipose tissues release cytokines and FFAs affect activity of key insulin signaling proteins -FFAs= beta cell dysfunction and release of pro inflammatory cytokines

Question 42

Viruses - mechanism of disease (3 ways)

Answer 42

1. Direct cytopathy-> virus kills cell by stopping synthesis of macromolecules, producing toxins, and apoptosis 2. Antiviral immune response inflammation =tissue damage 3. Transform infected cells to tumor cells

Question 43

Cancer

Answer 43

Multiple gene abnormalities

Question 44

Breast cancer biomarkers

Answer 44

1. Estrogen receptor in breast carcinoma (good prognosis) - Tamoxifen targets estrogen receptor and blocks it 2. HER-2 in breast carcinoma (worse prognosis) - herceptin blocks HER-2 growth signals