L2 - Molecular Basis Of Disease Flashcards
Explain disease at molecular level
Change at DNA, RNA, and protein level
What leads to changes in the protein quality, quantity, and function
Mutation of genes and changes during transcription,translation, and post translation level
Disease at gross or microscopic level
Morphology and biochemical alterations in body fluids
Genetic changes in germ cells
Transmitted to progeny
Lead to inherited diseases (hereditary disorders)
Familial/ congenital
Genetic changes in somatic cells
Not transmitted to progeny
Still responsible for disease cause
Not familial
Mutation in DNA
Permanent change in DNA sequence
Chromosomal alteration
DELETION
Loss of chromosomal fragment - gene loss or deficiency
Chromosomal alteration
DUPLICATION
Fusion of proteins or amplification of genes
Chromosomal alteration
INVERSION
Segment of chromosome reversed end by end
Chromosomal alteration
TRANSLOCATION
Exchange two chromosome segments = fusion of proteins + altered gene expression
Aneuploidy
Whole chromosome gains or loses
Epigenetic changes
Modulation of gene/ protein expression in absence of alteration in DNA sequence or structure
- DNA methylation
- histone modification
- non coding RNAs
- protein modification
DNA methylation of cytosine @ gene promoters
Promoters become inaccessible to RNA polymerase = transcriptional silencing
Histone modifications
Methylation and acetylation of secondary and tertiary DNA structure + regulate gene transcription
Non coding RNAs - miRNA and IncRNA
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
Protein modification
Folding and phosphorylation
Sickle cell disease molecular pathogenesis
Normal( CTC ) in the beta-globn chain changes to ( CAC ) and change of (glutamine) to (valine)
Beta-globin chain -> sickle beta-globin
What type of mutation is SCD
Point mutation
Valine for glutamine @ 6th amino acid = structurally abnormal molecule ( hemoglobin S)
What happens when hg S is polymerized?
Cytoplasm become rigid filamentous gel and leads to less deformable sickles erythrocytes
What does the rigidity of sickles erythrocytes lead to?
- 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
What are the two primary manifestations of sickle cell diseas
recurrent ischemic events and hemolytic anemia
SCD clinical manifestations
Retinopathy- blindness Stroke Pneumonia -lung infarcts- acute chest syndrome Iron overload in heart and liver Spleen atrophy Osteomyelitis Skin ulcers Kidney lower ability
Molecular pathogenesis of chronic myeloid leukemia (CML)
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)
Diagnosis of CML
Using translocation bcz its available in most CML patients
Treatment of CML
Tyrosine kinase inhibitor (Imatinib)
Signal pathways of BCR-ABL
Transforming hematopoietic cells to cancer cells
Acute promyelocytic leukemia molecular pathogenesis
translocation between chromosomes 15 and 17 = fusion of PML and RARa gene
PML/RARa = blocking myeloid differentiation at promyelocytic stage
APL treatment
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)
Cystic fibrosis cause
mutations of the CF transmembrane Conductance Regulator (CFTR) gene
What is the CFTR
anion channel that regulates the transmembrane ion transport
Mutation in CFTR
= defective electrolyte transport (chloride ion) in epithelial cells which affects salt absorption, fluid absorption ,and anion-mediated fluid secretion
-complex multi system disease
Pathogenesis of respiratory and intestinal complications in CF
Low-volume of surface fluid layer -> dehydration in lungs ->accumulation of secretions -> obstruction of air passage and pulmonary infections ( cause of mortality in CF)
CFTR defect in sweat duct
High chloride and sodium concentration in sweat
CFTR defect in lung
- 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
diabetes mellitus cause
insulin resistance and beta cell dysfunction = insulin deficiency (doesn’t involve autoimmunity)
Insulin resistance
Failure of tissue to respond normally to insulin caused by reduction in phosphorylation dependent activation of the insulin receptor and its components = signal transduction
Lack of insulin
=catabolic state effects glucose fat and protein metabolism
-bad glucose storage= hyperglycemia
Hyperglycemia = ?
-activation of the mitogen activated protein kinase (MAPK) pathway and oxidative stress=clinical presentations
Genetics and DM
Diabetogenic
Obesity related genes
Environmental influences and DM
Obesity
Sedentary life style
How does obesity lead to insulin resistance
Adipose tissues release cytokines and FFAs affect activity of key insulin signaling proteins
-FFAs= beta cell dysfunction and release of pro inflammatory cytokines
Viruses - mechanism of disease (3 ways)
- Direct cytopathy-> virus kills cell by stopping synthesis of macromolecules, producing toxins, and apoptosis
- Antiviral immune response inflammation =tissue damage
- Transform infected cells to tumor cells
Cancer
Multiple gene abnormalities
Breast cancer biomarkers
- Estrogen receptor in breast carcinoma (good prognosis)
- Tamoxifen targets estrogen receptor and blocks it
- HER-2 in breast carcinoma (worse prognosis)
- herceptin blocks HER-2 growth signals
