Biochemistry - Cellular Structure & Biomechanics Block (II) Flashcards
A deficiency of what enzyme will lead to types A and B Niemann-Pick disease?
Acid sphingomyelinase
What substance builds up in Niemann-Pick disease types A and B?
This results in what type of cell?
Sphingomyelin;
foam cells
In what organ systems are foam cells found in cases of Niemann-Pick disease?
The spleen, liver, and CNS
What disease is characterized by acid sphingomyelinase defects and associated foam cell deposits in the CNS, spleen, and liver?
Niemann-Pick disease types A and B
Cytokine-related overactivation of what enzyme may contribute to development of multiple sclerosis?
Acid sphingomyelinase
Defects in acid sphingomyelinase lead to what disease?
Overactivation of acid sphingomyelinase may lead to what disease?
Niemann-Pick disease (types A and B);
multiple sclerosis
What effect does excess sphingomyelin have on erythrocytes?
This is commonly seen in what disease?
Acanthocytosis;
abetalipoproteinemia
What is a hematologic result of abetalipoproteinemia?
This is due to an excess of what lipid?
Acanthocytosis;
sphingomyelin
How does abetalipoproteinemia appear on a peripheral smear?
This is due to a defect involving what substance?
Acanthocytosis;
sphingomyelin (on the RBC E-face)
Cystic fibrosis involves transport of what ion into the mucus?
Chloride
What are the three main organs affected by cystic fibrosis?
Lungs, pancreas, liver
Absence of chloride movement in cystic fibrosis leads to what effect on the mucus?
Less H2O movement –> thick, dry mucus
Cystic fibrosis results as a genetic mutation in which channel?
The gene for this channel is found on which chromosome?
The CFTR
(cystic fibrosis transmembrane regulator);
7
A young child presents with progressive muscle weakness and new cardiac arrythmias. You suspect myotonic dystrophy.
What genetic results would confirm your suspicions?
CTG repeats
(in the DMPK gene on chromosome 19)
A man presents with microcephaly, cognitive deficits, indistinct philtrum, epicanthal folds, a low nasal bridge, and a short nose.
What do you suspect?
What cellular mechanism caused the issue?
Fetal alcohol syndrome;
impaired lipid rafts and signaling proteins
What effect does phalloidin (found in death cap mushrooms) have on cellular structures?
(What is the primary clinical presentation)
Stabilizes F-actin (prevents its degradation)
(acute, extreme hunger due to liver necrosis)
Cytochalasins mess with microfilaments and cause what outcome?
Apoptosis
Hereditary spherocytosis is caused by a deficiency of what protein(s)?
Spectrin, ankyrin, or band-3 proteins
Primary ciliary dyskinesia (immotile cilia syndrome) is an autosomal recessive disease known by what other name and caused by a defect in the gene coding for what protein?
Kartagener’s syndrome;
axonemal dynein
How does Kartagener’s syndrome present?
Chronic respiratory infections, situs inversus, infertility
With what cytoskeletal element does colchicine interact? How?
With what cytoskeletal element do vincristine and vinblastine interact? How?
With what cytoskeletal element does paclitaxel interact? How?
Microtubules, inhibits polymerization;
microtubules, inhibits polymerization;
microtubules, inhibits depolymerization
What stain would be most useful in diagnosing the most common type of primary brain tumor?
GFAP
(astrocytomas)
A two-year-old female toddler presents with steady loss of cognitive ability. Her father notes that she seemed cognitively normal and met all her milestones up until she was 18 mo. of age. You notice her near constant hand wringing.
What is the likely diagnosis?
Rett syndrome
What biochemical defect can lead to Rett’s syndrome?
Mutations in MECP2
(this HDAC-recruiting protein -MECP2- is no longer available upon histone methylation);
leading to inappropriate gene expression
(manifesting clinically as cognitive decline and persistent hand wringing)
Mutation in the MECP2 gene has what effect?
What is this condition called?
A lack of MECP2 protein –> inability to recruit HDAC –> inability to condense DNA –> excessive gene expression;
Rett’s syndrome
How does Rett syndrome typically present in the clinic?
Cognitive decline
(after ~18 mo. of seemingly normal childhood development);
hand wringing
An embryo is missing one autosomal chromosome. What will the result be?
This is a lethal mutation
An embryo is missing one chromosome and is 45,XO. What will the result be?
Turner’s syndrome
What are some clinical presentations of Turner’s syndrome?
Webbed neck,
widely spaced nipples,
swollen hands and feet,
short stature,
widespread nevi
Are individuals with Turner’s syndrome female or male?
Female
What is the most common human trisomy?
How does it present?
Trisomy 16;
it is lethal
(fetal death in the first trimester)
What is the most common birth defect?
How does it present?
Trisomy 21;
Down syndrome
What is unique about the 21st chromosome?
It is the smallest autosome
Do viable (non-lethal) trisomies usually happen in large or small autosomal chromosomes?
Small
Patau’s syndrome is caused by what defect?
Trisomy 13
Edward’s syndrome is caused by what defect?
Trisomy 18
Trisomy of what chromosome in particular leads to fetal death in the first trimester?
Trisomy 16
Trisomy 16 is incompatible with life and results in fetal death at what point?
The first trimester
The sphingomyelin affected in abetalipoproteinemia is found in which leaflet of the plasma membrane?
The E-face
Defects in occludins may result in severe neurological disorders do to disruption of what structure(s)?
The fetal blood-brain barrier (tight junctions disrupted)
Loss of expression of what protein can disrupt the zona adherens and lead to increased malignancy and invasiveness of a developing carcinoma?
E-cadherins
Autoimmunity against the protein desmoglein I can lead to skin disorders characterized by reduced intercellular cohesion of what in particular?
This is due to disruption of what epithelial cell junction?
Epidermal cells
Macula adherens (desmosome)
Mutations of what protein are related to types of epidermolysis bullosa (blistering skin lesions)?
This is due to disruption of what?
Keratins 5 and 14;
hemidesmosomes
Mutations in various connexin genes have been linked to what issues?
This is due to a defect in what type of cell junction?
Peripheral neuropathy and deafness
(both in very specific situations, not just any PN and deafness);
gap junctions
What pathogens act on proteins of the zona occludens to make cell junctions more permeable?
Cholera toxin;
CMV
Cholera toxins and CMV both act on what structure to increase permeability between cells?
The zona occludens
What disease is characterized by antibody attacks on proteins of the hemidesmosome?
What disease is characterized by antibody attacks on the desmosome (specifically desmoglein I and III)?
Bullous pemphigoid;
pemphigus vulgaris
Antibody attacks on what might cause bullous pemphigoid?
Hemidesmosome proteins
Antibody attacks on what might cause pemphigus vulgaris?
Proteins of the desmosome
(e.g. desmoglein I and III)
Define aneusomy.
What are the three types?
Aberrant number of chromosomes (due to loss or addition);
nullisomy, monosomy, trisomy
Define euploidy.
Correct number of chromosome pairs
What is the term if an embryo is missing both chromosomes of one chromosomal pair?
What is the term if an embryo is missing one chromosome of a chromosomal pair?
What is the term if an embryo has both chromosomes of one chromosomal pair?
What is the term if an embryo has an extra chromosome in addition to one chromosomal pair?
Nullisomy (-2);
monosomy (-1);
eusomy (-0; just right);
trisomy (+1);
What will happen to an embryo with nullisomy of any chromosomal pair?
Embryonic death
What will happen to an embryo with monosomy of any autosomal chromosome pair?
Embryonic death
What is the only survivable true monosomy?
Turner’s syndrome
(any other survivable monosomy is only a partial deletion of a chromosome)
What is the term if an embryo has three entire, homologous sets of chromosomes?
What is the term if an embryo has four entire, homologous sets of chromosomes?
Triploidy;
tetraploidy
Which usually presents earlier in life, aneuploidy or chromatin remodeling abnormalities?
Aneuploidy
What is the typical treatment for Turner’s syndrome?
To address what issues?
Hormonal therapy (GH and estrogen);
the slow growth and lack of sexual development
True/false.
Trisomies of the sex chromosomes (e.g. XXX, XXY, XYY) are all typically associated with only minor problems and a full life span.
True
Which type of autosomal trisomy is most likely to result in a viable fetus?
Those of small autosomes (e.g. 13, 18, 21)
What is the most common human trisomy?
How does it present?
Chromosome 16;
fetal death in the first trimester
Describe the typical clinical presentation of Rett syndrome.
Normal development during first 18 months of life
Temporary stagnation
Neurodegenerative
Loss of communication skills
Constant hand-wringing
Loss of purposeful hand function
How does Rett syndrome present in males?
Embryonic death
Why is Rett syndrome extremely rare in viable males?
The MECP2 gene is on the X chromosome, so it is normally lethal in males (who only have one X chromosome)
The MECP2 gene is found on which chromosome?
The X chromosome
A tall patient with tapering fingers presents to the clinic with visual problems related to subluxation of the lens of his right eye. Three days later, he dies of a cardiovascular event.
What disorder does the patient have, and what causes it?
Of what CV event did he likely die?
Marfan’s syndrome, fibrillin-1 defect (a scaffold for tropo-elastin);
aortic dissection
A teenager presents to the clinic with hyperextensible joints and skin. You notice in his history that he has been diagnosed with a murmur of one of his heart valves in the past. The patient appears well and normal for age.
What is a likely diagnosis for this patient?
What protein is likely not being produced properly?
Ehlers-Danlos syndrome;
collagen
In what layer of the skin are skin cancers most likely to originate?
The stratum basale of the epidermis
(e.g. basal cell carcinomas and melanomas)
A defect in the anchoring fibrils that connect the epidermis to the dermis can result in what condition involving blistering and skin erosion?
Epidermolysis bullosa
What are the two primary causes of albinism?
A defect/deficiency in tyrosinase;
a decreased melanin production rate
Why is the subcutaneous layer of tissue such a useful location for drug administration?
It is highly vascular
What is the term for the layers and sections of fat of the subcutaneous (hypodermic) layer?
What is the layer of striated muscle deep to the subcutaneous tissue?
The panniculus adiposus;
the panniculus carnasus
What substance binds keratin together to create the waterproofing of the skin?
Lack of this substance results in what?
Filaggrin;
ichthyosis
Filaggrin defect/deficiency leads to what immediate effect in the skin and what compensatory effect?
What is this condition called?
Dehydration/scaly skin, hyperkeratosis;
ichthyosis
What blistering condition results from defects in anchoring proteins (e.g. hemidesmosomes)
What blistering condition results as an autoimmune attack on desmosomes (specifically, desmoglein I and III)?
Epidermolysis bullosa;
pemphigus vulgaris
What disease is demonstrated here?
How is this disease classified?
Pemphigus vulgaris;
autoimmune (against desmoglein I, III)
What disease is demonstrated here?
How is this disease classified?
Epidermolysis bullosa;
genetic (hemidesmosome defect)
What disease is demonstrated here?
Psoriasis
What type of skin condition results in universally loose fragile skin? Due to a defect in what?
What type of skin condition results in universally impaired elastic recoil? Due to a defect in what?
Ehlers-Danlos, collagen fibers
cutis laxa, elastic fibers
Cutis laxa results because of a defect in what protein?
Ehlers-Danlos results because of a defect in what protein?
Elastic fibers;
collagen fibers
Cri-du-Chat syndrome is a microdeletion of the short arm of chromosome __.
5
A carrier of a Robertsonian translocation has how many chromosomes?
45
What is another name for DiGeorge syndrome?
It is due to a deletion of what genetic sequence?
Velocardiofacial syndrome;
22q11
What rare type of skin cancer spreads quickly and deeper than BCC, SCC, and melanoma?
Merkel cell carcinomas
List the types of skin cancer from most to least common.
Basal cell carc. > squamous cell carc. >> melanoma
>>>> anything else
What is the most common type of cancer worldwide?
Skin cancer
Genetic defect of hemidesmosomes causes:
Autoantibodies against hemidesmosomes causes:
Autoantibodies against desmosomes causes:
Epidermolysis bullosa;
bullous pemphigoid;
pemphigus vulgaris
Why is acne typically associated with adolescents?
Sebaceous gland activity increases in adolescence
Acne is caused by what?
Plugged hair follicles and their associated sebaceous glands
What wide-spectrum antibiotic is a bacterial topoisomerase inhibitor?
Ciprofloxacin
What is ciprofloxacin?
How does it exert its effect?
A wide-spectrum antibiotic;
inhibiting bacterial topoisomerase
What two eukaryotic topoisomerase inhibitors can be used to treat some colon and ovarian cancers?
Which topoisomerase do they inhibit?
Irinotecan and Topotecan;
type I
What are Irinotecan and Topotecan?
How do they exert their effect?
Chemotherapeutic agents;
type I topoisomerase inhibition
What are Doxorubicin (adriamycin), etoposide, and ellipticine?
How do they exert their effects?
Chemotherapeutic agents;
type II topoisomerase inhibitors
What wide-spectrum antibiotic is a bacterial topoisomerase inhibitor?
What are two chemotherapeutic agents that are type I topoisomerase inhibitors?
What are three chemotherapeutic agents that are type II topoisomerase inhibitors?
Ciprofloxacin;
Irinotecan, Topotecan;
Doxorubicin (adriamycin), etoposide, and ellipticine
By which types of UV ray are we most at-risk of being harmed?
Which UV ray is blocked by the ozone?
UVA, UVB;
UVC
What type of DNA mutation is often caused by UV rays?
Thymidine dimers
What is the underlying defect in xeroderma pigmentosum?
What is its inheiritance pattern?
A defect in nucleotide excision repair (to repair thymidine dimers, especially);
autosomal recessive
By what age have most individuals with xeroderma pigmentosum developed some sort of skin cancer (often squamous cell carcinoma)?
8
True/False.
Individuals with xeroderma pigmentosum typically live a normal lifespan.
False.
What is the most common cause of death among individuals with xeroderma pigmentosum?
Squamous cell carcinoma
In nucleotide excision repair, what enzyme typically removes the damaged section?
An endonuclease
In nucleotide excision repair, what enzyme typically refills the removed portion?
DNA polymerase
In nucleotide excision repair, what enzyme typically seals up the repaired DNA portion?
DNA ligase
Name three enzymes necessary to nucleotide excision repair.
Endonuclease, DNA polymerase, DNA ligase
True/False.
Squamous cell carcinoma is associated with mutations in the BRAF and RAS genes.
False (SCC is associated with P53 issues);
melanoma is associated with BRAF and RAS
Melanoma is associated with mutations in what two genes in particular?
BRAF and RAS
What two factors does HPV use to increase growth and potential neoplasia in cells?
What do these factors do?
E6, E7;
block tumor suppressors
What is the name for the disease where it appears that the patient’s skin is turning into tree bark or elephant skin?
What is the underlying issue?
Epidermodysplasia verruciformis;
excessive, keratinized, HPV wart-like growths
How does squamous cell carcinoma usually present?
An ulcerous, crusty, scaly lesion on the head, neck, or dorsum of the hand
What are some risk factors for squamous cell carcinoma?
Caucasian, immunosuppressed, high sun exposure
Squamous cell carcinoma has an association with what infectious agent?
HPV
Describe the histology of squamous cell carcinoma.
Neoplastic cells with keratin pearls
How does basal cell carcinoma typically present?
Smooth, pink, pearly mass on the head, neck, or dorsum of the hand
(especially the nose, upper lip, and cheek)
Mutations in what two genes are associated with basal cell carcinomas?
What drug helps block the pathway related to these mutations?
PTCH1, PTCH2;
vismodegib
How does basal cell carcinoma present on histology?
Circular blue-purple masses
Melanoma is positive for what marker?
S100
What type of genetic pathway inhibitor is used in melanoma treatment?
BRAF inhibitors
What is a squamous cell carcinoma precursor lesion (not necessary for its development though)?
Actinic keratosis
Cervical epithelial dysplasia is to cervical cancer
as
actinic keratosis is to _____________.
Squamous cell carcinoma
True/False.
All squamous cell carcinomas develop from actinic keratosis.
False.
What is Nikolsky’s sign?
What does it indicate?
Epidermal sloughing due to manual stroking;
a very severe blistering disease
A patient with severe blisters and associated skin lesions presents to the clinic. You note that the superficial layer of her diseased skin sloughs off when your hand passes gently over it.
What is this sign called and what does it indicate?
Nikolsky’s sign;
a severe blistering disease
What are the A and B of the ABCDEs of melanoma?
Asymmetry;
border irregularity
What are the C and D of the ABCDEs of melanoma?
Color;
diameter
What is the E of the ABCDEs of melanoma?
Evolution (change over time)
What is the most common type of melanoma?
Is it generally a better or worse prognosis than the others?
Superficial spreading melanoma;
better (relatively treatable)
Of the two more common subtypes of melanoma, which is the more aggressive and deadly?
Nodular melanoma
What is a slow-growing, in-situ melanoma most often found in the elderly?
Lentigo maligna
What very deadly form of melanoma is most often found in patients with darker skin tones?
Acral lentiginous
Epidermolysis bullosa simplex is caused by what underlying defect?
How does it typically present?
Defective keratins 5 and 14;
pediatric friction-induced blisters on hands and feet
Epidermolysis bullosa simplex affects what cellular junction?
It mostly affects what cell layer?
Hemidesmosomes;
the (epidermal) stratum basale
What autoimmune disorder affects hemidesmosomes of the stratum basale?
What congenital disorder affects hemidesmosomes of the stratum basale?
Bullous pemphigoid;
epidermolysis bullosa simplex
What autoimmune disorder affects desmosomes of the stratum spinosum?
What congenital disorder affects type VII collagen of the basement membrane?
Pemphigus vulgaris;
dystrophic epidermolysis bullosa
A three-year-old girl is brought to the clinic for examination of frequent blisters on her hands and feet.
What is the likely diagnosis and what causes this disorder?
Epidermolysis bullosa simplex;
congenital defect in keratins 5 and 14 (of the hemidesmosomes of the stratum basale)
Epidermolysis bullosa simplex affects what layer of the epidermis?
The stratum basale
A 55-year-old patient presents with widespread, pruritic ulcers and skin erosions that affect the oral cavity, scalp, chest, and other portions of the body.
Immunofluorescene of a skin biopsy shows a net-like pattern in the stratum spinosum.
What is the diagnosis?
Pemphigus vulgaris
Pemphigus vulgaris affects what layer of the epidermis?
The stratum spinosum
Which typically presents with blisters, pemphigus vulgaris or bullous pemphigoid?
What antibody type causes both disorders?
Bullous pemphigoid;
IgG
Which epidermal layer is typically affected by bullous pemphigoid?
The stratum basale
How is pemphigus vulgaris treated?
This is to prevent suppression of autoantibodies against what structure(s)?
Steroids (e.g. prednisone);
desmoglein I and III
How does pemphigus vulgaris present on immunofluoresence?
How does bullous pemphigoid present on immunofluoresence?
Net-like pattern in the stratum spinosum;
linear pattern at dermoepidermal junction
Bullous pemphigoid is caused by autoantibodies against what two proteins?
This affects what type of cellular junction?
BPAG1, BPAG2;
hemidesmosomes
What is a congenital disorder resulting from defects in keratin 5 and 14?
What is an autoimmune disorder resulting from autoantibodies against desmoglein 1 and 3?
What is a congenital disorder resulting from defects in collagen VII?
What is an autoimmune disorder resulting from autoantibodies against BPAG1 and BPAG2?
Epidermolysis bullosa simplex;
pemphigus vulgaris;
dystrophic epidermolysis bullosa;
bullous pemphigoid
What is a congenital disorder of the epidermis resulting in hemidesmosomal dysfunction?
What is an autoimmune disorder of the epidermis resulting in desmosomal dysfunction?
What is a congenital disorder of the epidermis of the epidermis resulting in basement membrane dysfunction?
What is an autoimmune disorder of the epidermis resulting in hemidesmosomal dysfunction?
Epidermolysis bullosa simplex;
pemphigus vulgaris;
dystrophic epidermolysis bullosa;
bullous pemphigoid
What age range is typically affected by pemphigus vulgaris or bullous pemphigoid?
50s to 60s
What protein is affected in dystrophic epidermolysis bullosa?
This leads to what problem?
Collagen VII;
separation of the basal lamina and reticular lamina
True/False.
Dystrophic epidermolysis bullosa typically results in widespread ulceration, dehydration, infection, and even finger resoprtion. This constellation of issues typically results in early death.
True.
Epidermolysis bullosa simplex typically affects what layer of the skin?
Pemphigus vulgaris typically affects what layer of the skin?
Dystrophic epidermolysis bullosa typically affects what layer of the skin?
Bullous pemphigoid typically affects what layer of the skin?
The stratum basale (hemidesmosomes);
the stratum spinosum (desmosomes);
the basement membrane (type VII collagen);
the stratum basale (hemidesmosomes)
An 8-year-old girl is brought to see you in the clinic. Her parents show you a small lesion (1 cm diameter) with an ulcerous, scaly center. Upon skin examination, another such lesion is noticed on the back of the hand.
You notice that the patient’s face is nearly covered in freckles.
What is the diagnosis of the lesions?
What is the larger diagnosis to be made?
Squamous cell carcinoma;
xeroderma pigmentosum (autosomal recessive)
Name the drug that is a thymine analog that blocks reverse transcriptase.
How does it accomplish this?
Zidovudine (AZT);
the 3’-hydroxyl is replaced with a nitrogenous compound
Name the drug that is a purine analog that blocks reverse transcriptase.
How does it accomplish this?
2’,3’-dideoxyinosine;
the 3’-hydroxyl is replaced with hydrogen groups
Zidovudine (AZT) is an analog of what compound?
What enzyme does it block?
What types of disease is it used to treat?
Thymine;
reverse transcriptase;
retroviruses
2’,3’-dideoxyinosine is an analog of what compound?
What enzyme does it block?
What types of disease is it used to treat?
Purines;
reverse transcriptase;
retroviruses
What specific portion of a nucleotide can be modified in order to halt DNA synthesis?
The 3’-hydroxyl
What drug is used to treat HSV?
What drug is used to treat CMV?
Acyclovir;
gancyclovir
What are acyclovir and gancyclovir?
What are they used to treat, respectively?
Guanosine analogs;
HSV, CMV
Will acyclovir and gancyclovir be phosphorylated in all human cells?
Why or why not?
No;
just infected cells (where viral kinase is present)
What drug is used to treat HSV?
What forms of HSV?
Acyclovir;
cold sores, varicella zoster, herpes zoster
What drug is used to treat CMV retinitis?
Gancyclovir
What disease is characterized by a mutation in the MLH1 or MLH2 genes that begin mismatch excision repair by identifying mispairing?
Hereditary nonpolypoisis colorectal cancer
Hereditary nonpolypoisis colorectal cancer is commonly associated with a mutation in one of which two genes?
These genes are related to what normal cellular function?
MLH1, MLH2;
mismatch excision repair
What type of cancer is commonly linked to a defect in mismatch excision repair?
Hereditary nonpolypoisis colorectal cancer
Xeroderma pigmentosum is related to a defect in what normal cellular function?
This normal cellular function is responsible for what process?
Nucleotide excision repair;
fixing thymidine dimers
How can one remember that xeroderma pigmentosum is related to defects in nucleotide excision repair?
The proteins are named after xeroderma pigmentosum
(e.g. XP-C, XP-F, XP-G)
Besides squamous cell carcinoma and other skin malignancies, what may be some symptoms of xeroderma pigmentosum?
Progressive neurological complications, including loss of sight or hearing.
The lifespan of an individual with xeroderma pigmentosum is shortened by how long?
~30 years
Besides xeroderma pigmentosum, what is another disease related to defects in nucleotide excision repair?
What are the two main manifestations of this disorder?
Cockayne syndrome;
neurological defects and premature aging
Cockayne syndrome is associated with defects in what cellular system?
Cockayne syndrome is associated with mutations of what genes?
Nucleotide excision repair;
ERCC6; ERCC8
Name the enzyme responsible for each of the following in nucleotide excision repair:
- scanning and recognition of errors -
- helicase activity -
- endonucleases (2) -
XP-C
TFIIH
XP-F, XP-G
What form of Cockayne syndrome is associated with a mutation in ERCC8?
What form of Cockayne syndrome is associated with a mutation in ERCC6?
CS A
CS B
What does the WT1 (mutations associated with Wilm’s tumor) gene do?
Repress oncogenic function
(at the proximal promoter)
Where on the gene does the WT1 gene repress oncogenic activity?
The proximal promoter
Besides phalloidin, what other toxin is found in death cap mushrooms?
How does it exert its toxic effects?
Alpha-amanitin;
prevents RNA polymerase II binding
What effect does alpha-amanitin have on normal cellular processes?
How does this manifest?
Blocks RNA polymerase II;
liver damage –> flu-like symptoms –> coma –> death
What two toxins do death cap mushrooms contain that stabilize F-actin and block RNA polymerase II, respectively?
Phalloidin;
alpha-amanitin
In HIV, viral cyclin T binds host CDK9. What is the effect?
Hyperphosphorylation of RNA polymerase II
What effect does HIV have on RNA polymerase II via hyperphosphorylation?
Overactivation
Where does the beta-thalassemia mutation occur?
The beta-globulin locus
Lupus tends to affect what part of the spliceosome?
This has what immediate effect?
snRNPs;
splicing does not occur, and hnRNA is not turned into mRNA
(hnRNA thus builds up in the nucleus)
What is leukoencephalopathy with CNS hypomyelination and vanishing white matter (VWM)?
Loss of cerebral white matter / oligodendrocytes following an acute fever
What defect causes leukoencephalopathy with CNS hypomyelination and vanishing white matter (VWM)?
Why do the neurological symptoms often appear following a fever?
A defect in eukaryotic intiation factor 2 (eIF2);
eIF2 plays a role in responding to cellular stress
(if it is defective, the response is dimished)
Besides assisting in formation of the preinitiation complex (PIC) for translation, what else does eukaryotic initiation factor 2 do?
How?
Responds to cellular stress (e.g. heat);
stalls translation during times of heat so that denatured proteins don’t build up and accumulate
What is a eukaryotic initation factor (eIF) that is involved in translation and also cellular responses to high temperatures?
(Note: this protein stalls translation during times of high heat in order to prevent accumulation/aggregation of denatured proteins)
eIF2
What is it called when amyloid (not always amyloid though!) protein misfolds and aggregates/accumulates within cells?
What shape are the proteins in when aggregated?
Amyloidosis (not always amyloid!);
beta-sheets
Misfolding of what protein is associated with type II diabetes?
What is the effect?
Amylin;
beta-cell apoptosis
What is an infectious amyloidosis involving misfolded proteins?
What protein is involved?
Prion disease
PrPc
Alzheimer’s disease is associated with beta-amyloid plaques that are accumulations of what protein?
Amyloid precursor protein
Misfolding of what protein is associated with Huntington’s disease?
What are the repeats in the involved gene?
HTT protein;
CAG
Misfolding of what protein is associated with Parkinson’s disease?
What are the associated aggregates called?
Alpha-synuclein;
Lewy bodies
Misfolding of what protein is associated with ALS?
Superoxide dismutase (SOD1)
Misfolding of what protein is associated with spinal cerebellar ataxia?
What are the repeats in the involved gene?
Ataxin;
CAG
Misfolding of amylin and associated amyloidosis is associated with what disease?
Type II diabetes
Misfolding of amyloid precursor protein and associated amyloidosis is associated with what disease?
Alzheimer’s disease
The PrPc protein and associated amyloidosis is associated with what disease?
Prion diseases (e.g. CJD)
Misfolding of the HTT protein and associated amyloidosis is associated with what disease?
Huntington’s disease
Misfolding of alpha-synuclein and associated amyloidosis is associated with what disease?
Parkinson’s disease
(I think, also Lewy body dementia)
Misfolding of the superoxidase dismutase (SOD1) protein and associated amyloidosis is associated with what disease?
Amyotrophic lateral sclerosis
Misfolding of ataxin and associated amyloidosis is associated with what disease?
Spinal cerebellar ataxia
What effect does phalloidin (found in death cap mushrooms) have on cells?
What effect does alpha-amanitin (found in death cap mushrooms) have on cells?
F-actin stabilization;
RNA polymerase II inhibition
How does ricin (of the castor bean) inhibit translation?
By depurinating 28s rRNA
(and thus targeting it for ubiquination)
Ricin (of the castor bean) halts cellular function at what part of the central dogma?
Translation
What enzyme normally cleaves APP extracellularly?
What enzyme normally cleaves APP intracellularly?
What enzyme is pathological in its extracellular cleavage of APP?
Alpha-secretase;
gamma-secretase (PSEN1);
beta-secretase
What ApoE genotype is protective against Alzheimer’s disease?
What ApoE genotype is increases one’s likelihood of developing Alzheimer’s disease?
What genotypes are associated with familial Alzheimer’s disease?
ApoE2;
ApoE4;
PSEN1, PSEN2
Cholera toxin is produced by Vibrio cholerae.
How does it cause prolonged activity of adenylyl cyclase enzymes in the small intestinal epithelium?
What channel does this effect?
What is the clinical effect?
It binds the Gαs subunit of a GPCR;
cAMP increases and CFTR channels are overactivated;
Cl- movement and subsequent diarrhea
Cholera toxin binds GPCRs in the small intestine and overactivates what effector enzyme?
What effect does this have on cellular channels?
Adenylyl cyclase (increases cAMP);
CFTR channels are overactivated
What are the two mechanisms by which cholera toxin causes fluid and electrolyte leakage into the GI tract?
By causing overactivation of adenylyl cyclase and CFTR;
by causing weakening of the zona occludens
Both cholera toxin (in the small bowel) and bortadella pertussis (in the lungs) cause overactivation of CFTR channels and subsequent movement of intracellular fluid to the extracellular space.
Cholera toxin does it by modifying/stimulating what protein?
Bortadella pertussis does it by modifying/inhibiting what protein?
Gαs (cholera activates stimulatory pathways);
Gαi (pertussis inactivates inhibitory pathways)
(Note: the end effect on CFTR channels is the same)
How does propranolol decrease heart rate and strength of contraction?
(molecular mechanism)
By blocking GPCR adenylyl cyclase activation
(and thus decreasing Ca2+ release from the SR)
B-adrenergic / GPCR / adenylyl cyclase / cAMP / PKA signaling causes what change in cardiac muscle?
Increased intracellular Ca2+ –> increased HR and force of contraction
What trinucleotide repeat causes Huntington’s disease?
CAG
What trinucleotide repeat causes myotonic dystrophy?
CTG
What trinucleotide repeat causes Friedrich’s ataxia?
GAA
What trinucleotide repeat causes Fragile X syndrome?
CGG
What trinucleotide repeat causes myotonic dystrophy?
What trinucleotide repeat causes Fragile X syndrome?
What trinucleotide repeat causes Huntington’s disease?
What trinucleotide repeat causes Friedrich’s ataxia?
CTG;
CGG;
CAG;
GAA
Name the four diseases discussed in class that are associated with trinucleotide repeating of the following:
CAG
CTG
CGG
GAA
Huntington’s disease
Myotonic dystrophy
Fragile X syndrome
Friedrich’s ataxia
In diseases of trinucleotide repeats, what change is associated with manifestation and then increasing severity of S/Sy?
Increasing number of repeat copies
In Tay-Sachs disease, the defect in the enzyme _____________ leads to a buildup of what substance within lysosomes?
Hexosaminidase A;
GM2 ganglioside
A child is born with a clinical presentation that looks a lot like Down syndrome.
What genetic analysis test do you chose to confirm your diagnosis?
Karyotyping
A child is born with a clinical presentation that looks a lot like Cri-du-Chat syndrome.
What genetic analysis test do you chose to confirm your diagnosis?
FISH
(checking a single genetic sequence deletion)
A child is born with a clinical presentation that looks a lot like DiGeorge (velocardiofacial) syndrome.
What genetic analysis test do you chose to confirm your diagnosis?
FISH
(checking a single genetic sequence deletion)
A child is born with some sort of connective tissue disorder, but you aren’t sure which it is.
What test can be used to fish around in multiple genes at once?
Microarray
What are some treatment options for multiple sclerosis?
Beta-interferon and steroids
A patient suffers from leukoencephalopathy with vanishing white matter due to a mutation in what?
eIF2
(eukaryotic initiation factor 2)
(responsible for slowing down / halting translation during heat stress)
In a mutation of WT1, this loss of function mutation leads to a decrease in transcriptional ___________.
This results in the most common abdominal solid tumor among pediatric patients:
Repression;
Wilms’ tumor (nephroblastoma)
Can Turner’s syndrome be described as 45,X aneuploidy?
Yes.
The improper folding of which protein is associated with Parkinson’s Disease?
The improper folding of which protein is associated with type II diabetes?
The improper folding of which protein is associated with ALS?
Alpha-synuclein;
amylin;
superoxide dismutase I
The improper folding of which protein is associated with prion diseases?
The improper folding of which protein is associated with Alzheimer’s disease?
PrPc;
amyloid precursor protein (or β-amyloid)
The improper folding of which protein is associated with spinal cerebellar ataxia? Due to what trinucleotide repeat?
The improper folding of which protein is associated with Huntington’s disease? Due to what trinucleotide repeat?
Ataxin, CAG;
HTT (Huntington’s protein) CAG
One of your patients comes into your office complaining of weakness and dizziness. You find that he is anemic and send for a mutation analysis for JAK2. You find that he has the mutation V617F found in Polycythemia Vera. You remember that JAK signaling is primarily in the cytokine family of receptors.
Name a difference between kinases of the receptor tyrosine kinase family and the cytokine family of receptors.
Cytokine receptors have an extrinsic kinase
(it is not built into the intracellular receptor structure)
Cholera toxin induces the secretion of Cl- and rapid dehydration in the small intestine by permanently activating:
The G-alpha stimulatory (Gαs) subunit
A 3 month old infant presents to the ER after turning red then purple from a coughing spell. The mother states the child initially had common cold symptoms—runny nose, sneezing, cough and low-grade fever for approximately 2 weeks, but has not improved. The mother states the child’s cough has become progressively worse and is now characterized as dry, coughing spells that can last up to a minute or more and this last spell caused the child to turn purple. As a first year resident you take a mucous swab, which comes back positive for Bortedella pertussis.
Modification of what G-protein causes this illness?
What substance does the modification prevent the release of from this G-protein?
Gα inhibitory (Gαi) subunit;
GDP
A patient presents with polycythemia vera. This is a mutation in the ______ gene and subsequent mutation to the ________ of a cytokine receptor.
JAK2;
kinase
What is an example of a type of receptor expressed in some breast cancers that utilizes the Ras-MAPK pathway?
What percentage of breast cancers express this receptor?
HER-2;
25%
Of in-patient pediatric disease, what percentage have a major genetic component?
What percentage of chronic disorders of childhood are genetically determined?
71%
97%
What is the leading cause of death among infants?
Congenital and/or chromosomal malformation
What is the leading cause of death among infants?
What is the second leading cause of death among infants?
Congenital and/or chromosomal malformation;
Prematurity / low birth weight
What is the leading cause of death among infants?
What is the second leading cause of death among infants?
What is the third leading cause of death among infants?
Congenital and/or chromosomal malformation;
Prematurity / low birth weight;
SIDS
What is the leading cause of death among infants?
What is the second leading cause of death among infants?
What is the third leading cause of death among infants?
What is the fourth leading cause of death among infants?
Congenital and/or chromosomal malformation;
Prematurity / low birth weight;
SIDS;
maternal complications
What is the leading cause of death among infants?
What is the second leading cause of death among infants?
What is the third leading cause of death among infants?
What is the fourth leading cause of death among infants?
What is the fifth leading cause of death among infants?
Congenital and/or chromosomal malformation;
Prematurity / low birth weight;
SIDS;
maternal complications;
accidents
A chronic leukemia is defined by what characteristic?
An acute leukemia is defined by what characteristic?
< 10% blasts;
≥ 20% blasts
(the accelerated stage is between these two)
CML is caused by chromosomal translocation of involving which two chromosomes?
9 and 22
What karyotypic finding is pathognomic for CML?
A Philadelphia chromosome t(9;22)
(the tip of chromosome 9’s q arm and all of 22’s tiny q arm)
What genetic sequence is produced in the creation of a Philadelphia chromosome?
This results in what disorder?
BCR-ABL
(and the BCR-ABL fusion protein which activates JAK/STAT signalling);
CML
What drug is used to treat CML?
How does it work?
Imatinib (Gleevec);
binds the ABL kinase domain of the BCR-ABL fusion protein
CML will become the more aggressive _____ if the percentage of blast cells rises.
AML
What is a blast crisis in regards to CML?
The CML has accelerated into AML and symptom severity has increased
(e.g. increasing tiredness, fever, splenomegaly)
How does Burkitt’s lymphoma typically present?
Nontender lymph node swellings in the neck, groin, below the jaw, under the arms or abdomen (amongst other locations)
The majority of Burkitt’s lymphoma cases are seen in which sex?
Males
Burkitt’s lymphoma is a type of __-cell lymphoma.
It is caused most often by a translocation between chromosomes __ and __ (but it can also be caused by __ and __ or __ and __).
What gene is inappropriately expressed in this malignancy?
B;
t(8; 14) [t(8;22); t(8;2)];
c-Myc
Translocations of chromosomes 8 and 14 are most associated with what malignancy?
What gene is overexpressed?
Burkitt’s lymphoma;
c-Myc
c-Myc is overexpressed in what malignancy involving chromosomes 8 and 14?
Burkitt’s lymphoma
A tumor cell shows a t(8;14). What gene is likely overexpressed?
c-Myc
What is the notation for normal amyloid protein?
What is the notation for the abnormal amyloid protein seen in Alzheimer’s disease? This is after what enzyme’s improper cleavage?
Aβ;
Aβ42, β-secretase
What gene is associated with late-onset AD?
What genes are associated with early-onset, familial AD?
APOE4;
APP, PSEN1, PSEN2
Which protein in this image is targeted by antibodies in bullous pemphigoid?
Which protein in this image is congenitally defective in epidermolysis bullosa simplex?
Which protein in this image is congenitally defective in dystrophic epidermolysis bullosa?
BPAG1, BPAG2;
keratin 5, keratin 14;
type VII collagen
Which protein in this image is targeted by antibodies in Goodpasture’s syndrome?
Which protein in this image is targeted by antibodies in bullous pemphigoid?
Which protein in this image is congenitally defective in Alport’s syndrome?
Type IV collagen;
BPAG1, BPAG2;
type IV collagen
Name the antibiotic:
prevents the binding of aminoacyl tRNA to the A-site of bacterial ribosomes.
Tetracycline
Name the antibiotic:
- inhibits elongation phase in translation;*
- also causes miscoding*
Streptomycin
Name the antibiotic:
inhibits peptidyl transferase
Chloramphenicol
Name the antibiotic:
blocks translocation reaction of translation
Erythromycin
Name the antibiotic:
prevents transcription by binding bacterial RNA polymerase
Rifamycin
Describe the type of drug and mechanism of action: chloramphenicol.
This stops what phase of the central dogma?
Antibiotic;
inhibits peptidyl transferase;
translation
Describe the type of drug and mechanism of action: streptomycin.
This stops what phase of the central dogma?
Antibiotic;
inhibits initiation complex movement to the elongation phase;
translation
Describe the type of drug and mechanism of action:
Rifamycin
This stops what phase of the central dogma?
Antibiotic;
binds RNA polymerase;
transcription
Describe the type of drug and mechanism of action: Tetracycline
This stops what phase of the central dogma?
Antibiotic;
blocks aminoacyl-tRNA binding to the ribosomal A-site;
translation
Describe the type of drug and mechanism of action: Erythromycin
This stops what phase of the central dogma?
Antibiotic;
blocks translocation reaction;
translation
