Chapter 5 Flashcards
Most common examples of complex multigenic disorders
[those in which no single gene is necessary or sufficient to produce disease]
Atherosclerosis
Diabetes
Hypertension
Autoimmune disease
2 most common cardiovascular lesions in Marfan’s syndrome
Mitral valve prolapse
Dilation of ascending aorta
Most common form of GM2 gangliosidosis
Tay Sachs disease
Which type of Niemann Pick disease is most common?
Type C
What is the most common lysosomal storage disorder?
Gaucher disease (Type 1 is most common subset)
Most common isochromosome present in live births
Long arm of X [i(X)(q10)]
Leads to monosomy for genes on short arm of X and trisomy for genes on long arm of X
Differentiate missense from nonsense point mutations
Missense = single base substituted for another base (conservative or nonconservative)
Nonsense = single base change that changes amino acid to a premature stop codon
Effect of mutations involving noncoding sequences
Point mutations in promoters or ehnacers may interfere with TF binding, leading to reduction/lack of transcription
Point mutations in introns may lead to defective splicing and thus interfere with normal processing of initial mRNA transcripts —> failure to form mature mRNA and gene product not synthesized
2 potential effects on protein encoding associated with deletions and insertions
- If # of base pairs involved is in multiples of 3, the reading frame remains intact and an abnormal protein lacking or gaining 1+ amino acids will be synthesized (CF)
- If # of base pairs involved is not in multiples of 3, result is frameshift mutation, usually resulting in premature stop codon (Tay Sachs)
Characterize mutations associated with trinucleotide repeats and give major example
Amplifications of a sequence of 3 nucleotides; almost all affected sequences share nucleotides G and C
Degree of amplification increases during gametogenesis
Ex: Fragile X syndrome with 250-4000 tandem repeats of CGG within FMR1 when there should only be 29
Inheritance of marfan syndrome, ehlers-danlos syndrome (some variants), and familial hypercholesterolemia
Autosomal dominant
Manifestations and chance of inheritance of autosomal dominant conditions
Manifested in heterozygous state, so at least one parent of an index case is usually affected
Affected+unaffected parent = 50% chance of inheritance
Discuss concept of “new mutation” as it relates to autosomal dominant conditions
With every autosomal dominant disorder, some proportion of patients do not have affected parents, meaning they have a new mutation involving either egg or sperm from which they derived; siblings are not at risk; usually seen in germ cells of older fathers
Define penetrance — what does it mean to have 50% penetrance, and what is incomplete penetrance?
50% penetrance = 50% of those who carry the gene express the trait
Incomplete penetrance = inherited the gene but are phenotypically normal
Define variable expressivity
Trait is seen in all individuals carrying mutant gene but expressed differently in each
Biochemical mechanisms associated with loss of function mutations
Those involved in regulation of complex metabolic pathways subject to feedback inhibition (familial hypercholesterolemia - loss of LDL receptors)
Key structural proteins like collagen and cytoskeletal elements of red cell membrane
Even a single mutant in the collagen chain leads to marked deficiency in collagen, known as a ____ _____ mutant because it impairs function of the normal allele
Dominant negative
Which is more common, gain of function mutations or loss of function mutations?
Loss of function
Inheritance of lysosomal storage diseases, glycogen storage diseases, ehlers danlos syndrome (some variants), and alkaptonuria
Autosomal recessive
Contrast autosomal recessive conditions from autosomal dominant
Expression of defect tends to be more uniform than in autosomal dominant
Complete penetrance is common
Onset usually early in life
T/F: for X-linked disorders, almost all are recessive
True
In terms of X-linked disorders, sons of heterozygous women have ___% chance of inheritance
50
Examples of X-linked recessive conditions
Fragile X syndrome DMD Hemophilia A and B CGD G6PD deficiency Agammaglobulinemia Wiskott aldrich syndrome Diabetes insipidus Lesch-nyhan syndrome
Example of x-linked dominant disorder
Vitamin D-resistant rickets
Enzyme mutations may result in synthesis of an enzyme with reduced activity or a reduced amount of normal enzyme leading to 3 potential consequences:
- Accumulation of substrate
- Metabolic block and decreased amount of end product necessary for normal function
- Failure to inactivate a tissue-damaging substrate
What are 2 conditions in which accumulation of substrate is a problem?
Galactosemia (deficiency in GIP uridyltransferase)
Lysosomal storage diseases (deficiency in degradative enzymes)
Enzyme mutations may result in synthesis of an enzyme with reduced activity or a reduced amount of normal enzyme leading to 3 potential consequences:
- Accumulation of substrate
- Metabolic block and decreased amount of end product necessary for normal function
- Failure to inactivate a tissue-damaging substrate
What are 2 conditions in which metabolic block leads to decreased amount of end product necessary for normal function?
Albinism = lack of tyrosinase —> melanin deficiency
Lesch-Nyhan syndrome = deficiency of end product —> overproduction of intermediates that are injurious at high concentrations
Enzyme mutations may result in synthesis of an enzyme with reduced activity or a reduced amount of normal enzyme leading to 3 potential consequences:
- Accumulation of substrate
- Metabolic block and decreased amount of end product necessary for normal function
- Failure to inactivate a tissue-damaging substrate
What is an example of failure to inactivate a tissue-damaging substrate?
Alpha-1-antitrypsin deficiency = destruction of elastin in walls of lung alveoli d/t inability to inactivate neutrophil elastase —> emphysema
How do single-gene defects affect membrane receptors in terms of familial hypercholesterolemia?
Reduced synthesis of functional LDL receptors —> defective transport of LDL into cells —> excessive cholesterol synthesis
How do single-gene defects affect transport systems in cystic fibrosis?
Defective Cl- transport —> injury to lungs and pancreas
What happens when those with G6PD deficiency are given antimalarial drugs?
Severe hemolytic anemia
D/t single-gene defect leading to enzyme defiency that is unmasked after exposure to certain drugs
Etiology of Marfan syndrome
Usually autosomal dominant inherited defect in fibrillin, inhibiting polymerization of fibrillin fibers (dominant negative effect)
[missense mutation in FBN1 gene encoding fibrillin-1; found on Chr 15q.21.1]
2 fundamental mechanisms by which loss of fibrillin leads to clinical manifestations of Marfan syndrome
Loss of structural support in microfibril rich CT — fibrils provide a scaffolding on which tropoelastin is deposited to form elastic fibers; particularly abundant in the aorta, ligaments, and ciliary zonules of lens
Excessive activation of TGF-b signaling — normal microfibrils sequester TGF-b, can lead to deleterious effects on vascular smooth muscle development and increases activity of MMPs, leading to loss of ECM
Skeletal abnormalities in Marfan syndrome
Unusually tall with long extremities and long, tapering fingers and toes
Lax joint ligaments
Dolichocephalic with bossing of frontal eminences and prominent supraorbital ridges
Spinal deformities
Chest is classically deformed with either pectus excavatum or carinatum
Ocular changes with Marfan syndrome
Ectopia lentis - bilateral subluxation or dislocation of lens
Cardiovascular lesions are the most life threatening complications associated with Marfans. What are some examples?
Mitral valve prolapse
Dilation of asending aorta d/t cystic medionecrosis potentially leading to aortic dissection
Describe effect of valve lesions in Marfan syndrome
Valve lesions + lengthening of chordae tendinae lead to mitral regurg
Etiology of Ehlers-Danlos syndrome
Defect in synthesis or structure of fibrillar collagen
Mode of inheritance encompasses all 3 mendelian patterns
Describe classic type (I/II) of Ehlers-Danlos syndrome
Skin and joint hypermobility, atrophic scars, easy bruising; complications include diaphragmatic hernia
Autosomal dominant inheritance
Gene defects: COL5A1, COL5A2 —> abnormalities in type V collagen
Describe kyphoscoliosis type (VI) Ehlers-Danlos syndrome
Hypotonia, joint laxity, congenital scoliosis, ocular fragility; complications include rupture of cornea and retinal detachment
Autosomal recessive
Gene defects: lysyl hydroxylase (responsible for cross-linking so collagen lacks stability)
Describe vascular type (IV) Ehlers-Danlos syndrome
Thin skin, arterial or uterine rupture, bruising, small joint hyperextensibility; complications include rupture of colon and large arteries
Autosomal dominant
Gene defects: COL3A1 —> abnormalities in type III collagen (heterogenous effects)
Etiology of familial hypercholesterolemia
Mutation in gene encoding receptor for LDL which is involved in transport and metabolism of cholesterol
Why do people with familial hypercholesterolemia have increased synthesis of LDL?
Because IDL, the immediate precursor of plasma LDL, also uses hepatic LDL receptors (apoprotein B-100 and E) for its transport into the liver. Impaired transport of IDL secondarily diverts a greater proportion of plasma IDL into the precursor pool for plasma LDL
Familial hypercholesterolemia involves a marked increase in scavenger-receptor-mediated traffic of LDL cholesterol into the cells of the mononuclear phagocyte system and possibly the vascular walls. This increase is responsible for what 2 complications of familial hypercholesterolemia?
Xanthomas
Premature atherosclerosis
Different classes of mutations leading to familial hypercholesterolemia
Class I = no synthesis Class II = no transport Class III = no binding Class IV = no clustering Class V = no recycling
Describe class I mutations leading to familial hypercholesterolemia
No synthesis
Relatively uncommon
Complete failure of synthesis of the receptor protein (null allele)
Describe class II mutations leading to familial hypercholesterolemia
No transport!
Fairly common
Encode receptor proteins that accumulate in the ER because their folding defects make it impossible for them to be transported to golgi
Describe class III mutations leading to familial hypercholesterolemia
No binding!
Affect LDL binding domain of receptor
Encoded proteins reach the cell surface but fail to bind LDL (or do so poorly)
Describe class IV mutations leading to familial hypercholesterolemia
No clustering!
Encode proteins that are synthesized and transported to cell surface efficiently and bind LDL normally but fail to localize in coated pits, so LDL is not internalized
Describe class V mutations leading to familial hypercholesterolemia
No recycling!
Encode proteins that are expressed on cell surface, can bind LDL, and can be internalized, but pH-dependent dissociation of receptor and bound LDL fails
Such receptors are trapped in the endosome where they are degraded (not recycled)
Types of lysosomal storage diseases
Glycogenoses Sphingolipidoses Sulfatidoses Mucopolysaccharidoses Mucolipidoses Fucosidoses Mannosidoses Aspartylglycosaminuria Wolman disease Acid phosphate deficiency
Enzyme defect in Tay Sachs disease
Mutations in alpha subunit locus on Chr15 causing severe deficiency of hexosaminidase A
[most affect protein folding, but over 100 mutations have been identified; triggers unfolded protein response leading to apoptosis]
