Chapter 5 Robbins - Genetic stuff Flashcards
Marfans Syndrome (AD)
AD, connective disease
skeleton eyes cardiovascular system
inherited defect in extracellular glycoprotein - fibrillin 1
FBN1 gene (15q21) –>
70-85% sporadic the remainder arise de novo.
excessive loss of microfibrils also give rise to abnormal and excessive activation of TGF-B
excessive TGF-B has deleterious effects on vascular Smooth muscle development and integrity of the ECM
angiotensin blockers - block the function of TGF-B and improve cardiac and aortic function
Ehlers Danlos syndrome (AD and AR - lots of different types)
group of diseases associated with defective collagen synthesis or structure
all are single gene disorders.
mode of hesitance both AD and recessive
tissues which are rich in collage such as skin, ligaments, and joints are the most frequently effected in EDS.
skin stretchability
structural failure of organ disease - large arteries, rupture of colon, retinal detachment
Three of the more common variants:
Deficient synthesis of type 3 collagen - mutations in COL3A1 = vascular EDS, autosomal dominant (bowel wall and blood vessels)
Deficiency of type 5 collagen - mutations in COL5A1 and COL5A2 AD - results in classical EDS
Familial hypercholesterolemia:
Receptor disease - loss of function of the LDH receptor - involved in the transport and metabolism of cholesterol.
Elevated cholesterol and premature atherosclerosis results.
Increased risk of MIs particularly.
Pathogenesis - familiaal hypercholesterolemia mutations in the LDL receptor protein impaired the intracellular transport and catabolism of LDL resulting in accumulation of LDL cholesterol in the plasma.
Both heterozygotes and homozygotes are affected.
Moe than 900 different mutations
Class one - uncommon - complete losss of receptor synthesis
CLass 2 - the receptor protein I synthesised but it’s transport from the endoplasmic reticulum to the Golgi is impaired because of defects in protein folding (THE MOST COMMON TYPE)
Class 3 - produce receptors that are transported to the cell surface but fail to bind LDL normally
Class IV receptor - given rise to receptors that fail to internalise within clathrin pits after binding to LDL
Class 5…dissociation between trapped in endoscopes because of disccosiation of the receptor and bound LDL does not occur.
……..
Normal cholesterol metabolism - cholesterol is derived from the diet or from endogenous synthesis - dietary triglycerides and cholesterol are incorporated into chylomicrons and in the intestinal mucosa travel to the gut lymphatics into the blood.
Then hydrolysed by endothelial lipoprotein lipase and in the capillaries of muscle and fat.
The chylomicrons remnants rich in cholesterol are delivered to the liver
PCSK9 - enzyme
Activating mutations (lot less common) can cause a similar phenotype to familial hypercholesterolemia
Therapeutic role PCSK9 inhibitors
a post - translational regulation of plasma LDL has been elucidated. PCSK9 causes intracellular degradation of LDL receptors before they reach the cell surface. With fewer LDL receptor there is reduced uptake of plasma LDL - leading to hypercholesterolemia
A
HMGCOA reductase inhibitors?
Cystic fibrosis (Autosomal recessive)
Mutations in the CFTR gene encoding the CF transmembrane regulator.
Defect in chloride ion transport = high salt concentration in sweat and viscous luminal secretions.
Most common severe mutation= deletion of 3 x nucleotides coding for phenylalanine at amino acid position 508 (found in around 70% of patients) with CF
Phenylketonuria - autosomal recessive
mutations that cause a severe lack of phenylalanine hydroxyls (PAH)
1/10,000 live newborn white infants.
numerous disease causing alleles.
Lack of the above enzyme - hyperphenylalaninemia and PKU
after birth rising plasma phenylalanine level –> impairs brain developement
also usually enzyme converts to tyrosine (important for melanin development -)
by 6 months–> severe mental retardation
other: seizures, other neurologic manifestations, decreased pigmentation of hair, and skin and eczema can develop.
