Diseases Flashcards
(84 cards)
1
Q
What is cholesterol involved in?
A
part of myelin, and participate in membrane raft. Cholesterol impairment is found in Alzheimer’s and Autism
2
Q
What clinical diseases are involved in malfunctions of clathrin coated pits?
A
- Familial hypercholesterolemia - many there’s inability to remove the bad LDLs and there are high levels in the blood. Clinical presentations: autosomal dominant (vertical transmission), early coronary disease, atherosclerosis (narrow arteries), and angina (chest pain)
- Huntington’s - nerve cells in brain waste away, with altered cell pathologies. Clinical presentations: uncontrolled movement, loss of balance. Later on, hard to swallow, talk, memory.
3
Q
Patient comes in with early onset hypotonia. Father had late onset of hypotonia. Patient also has impaired thinking, blindness, seizures, and deafness. What disease is this?
A
Tay Sachs, which is a mutation and lack of Hexsaminidase A, causing GM2 ganglioside build up in lysosomes.
4
Q
What kind of disease is this?
A
Cervical cancer caused by HPV which leads to squamous cell carcinoma, and cancer cells obliterate the epithelial structure. Causes ubiquination of p53. Clinical presentations: early there are no signs or symptoms, later on there is bloody discharge, and pelvic pain
5
Q
What is histopathy and clinical presentations of Sickle cell?
A
Caused by defected hemoglobin where a glutamate is switched for a valine. This causes the actin to lock, so RBCs are less squishy and obstruct microcirculation. Clinical presentations are: dizziness, shortness of breath, headaches, and fatigue.
6
Q
What is the histopathy and clinical presentations of Duschene’s muscular dystrophy?
A
Caused by disrupted dystrophin gene, so the dystrophin can’t anchor cytoskeleton to plasma membrane. This lack of support leads to permeable membrane, and exploding cells. Clinical presentations: muscle weakness, progressive crippling, loss mobility, loss coordination.
7
Q
What causes Nonsyndromic sensorineural autosomal recessive deafness?
A
A mutation in the GJB2 gene which encodes for connexin. In cochlear hair cells, this prevents passage of K+ ions
8
Q
What disease is caused by a mutation in helicase and what are the clinical presentations?
A
Bloom’s syndrome which clinically presents as short stature, photosensitivity, multiple health problems, increased risk of cancer, prominent ears, infertility, and genomic instability.
9
Q
What’s frequently mutated in leukemia?
A
TET2
10
Q
What are the two syndromes affected by abnormal levels of IGF2?
A
Beckwith Wiedmann = 2 big baby
Silver Russel = 0 small kid
11
Q
What are some diseases involved in hypermethylation?
A
Disruption of p16, APC/beta catenin, leads to mutations in BRCA1
12
Q
What are type 1 collagen disorders?
A
- Osteogenesis Imperfecta = inherited, characterized by fragile bones; blue sclerae
- Progressive Sclerosis = autoimmune disorder resulting in increased collagen production which leads to thickening of skin and arteries
- Scurvy = Vitamin C deficiency, so can’t add hydroxyls to proline/lysine
13
Q
What are type 2 collagen disorders?
A
Hypochondrogenesis ; affects cartilage, leads to short arms and legs, small chest with short ribs, and underdeveloped lungs
14
Q
What are the two types of Ehlers danlos collagen disorders?
A
Type 4 ehlers danlos is the vascular one so they bruise easy, in collagen type 3.
Type 1 is caused by mutation in collagen 5, which effects epidermal/dermal junctions leading to elastic skin; cigarette paper scars
15
Q
What are type 4 collagen disorders?
A
Alport’s which is thickening of basement membrane in kidney. Also affects hearing and eyes; usually X linked
16
Q
What are collagen type 7 disorders?
A
Epidermolysis bullosa which is fragile skin (junctional epidermolysis bullosa is type 4 collagen and leads to blistering, alopecia)
17
Q
What type of fibers are made from type 3 collagen?
A
reticular
18
Q
Patient comes in with skeletal abnormalities, cognitive impairment, heart disease, respiratory problems, enlarged liver and spleen. What lysosomal disease is this?
A
Hurler’s syndrome which is caused by build up of GaGs in lysosomes
19
Q
What can you use to describe melanomas?
A
The ABCDE rule: asymmetry, border, color, diameter, evolution
20
Q
Which disorders are caused by defects in carboxylation?
A
Bleeding disorders. Carboxylation is important for vascular calcification and bone metabolism.
21
Q
What disease are caused by prenylation?
A
cancer , inflammation, and premature aging
22
Q
What is UPS/ERAD and what diseases can it cause?
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UPS/ERAD is ubiquitin proteasome system/ER associated degradation pathway. It can lead to diseases like cystic fibrosis, alpha 1 antitrypsin defiency, cancer, osteogenesis imperfecta, Marfans.
23
Q
What causes Alzheimer’s Disease?
A
Beta amyloid has abnormal proteolysis of precursor. This leads to amyloid plaques. Tau is hyperphosphorylated and cleaved to make inappropriate forms of tau leading to neurofibrillary tangles. Causes neuronal death, dementia
24
Q
What is abnormal about prions?
A
they have fewer alpha helices and more beta sheets
25
What are two keratin disorders
Epidermolysis bullosa and monilethrix
26
What are 3 elastin disorders?
1. alpha 1 antitrypsin = it's a protease inhibitor made by the liver and protects lungs, but a lack of would cause infections.
Marfans = mutation in fibrillin 1, and increase in TGFB signaling; presents as tall, long extremities (autosomal dominant)
Cutis Laxa = rare, inelastic hangy skin due to serile to proline substitution in in fibrillin 5
27
What does mutation of Wnt/beta pathway cause?
If the APC in this pathway is mutated, it can cause forms of colon cancer. This pathway is usually important in embryonic development, but too much beta catenin activation can lead to tumor
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Patient comes in with multiple tumors: sarcomas, breast cancer, leukemia, and adrenal tumors, all tumors are malignant. What disease does she have?
Li Fraumeni Syndrome, a rare autosomal dominant disorder caused by a mutation in p53.
29
What disease is associated with over active c-myc?
Cancer. c-Myc is TF for increased cyclin D, SCF ubiquitin ligase subunit (breaks down p27), and TF for E2F. This is regulated by Mad because Mad Max=no proliferation, and p53 because if there's too much mitogen, p53 is saved from degradation by Arf which removes mdm2
30
What drugs are used to stabilize/destabilize microtubules? Side effects?
Colchicine - prevents assembly by insertion into the plus end
Vinblastine and vincristine - antitumor therapy that inhibit tubulin by wedging between tubulin
Mayatansine = tumor inhibitor that inhibits protofilament elongation
Taxol - binds along microtubules to stabilize against depolymerization.
Too much destabilizing drugs can lead to neuropathy due to no axonal transport.
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Which adaptor protein can be dysregulated in cancer?
Beta catenin which links caderins to actin
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Pemphigus
autoimmune skin disease in which antibodies are produced against desmosomal cadherin proteins
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What causes leukocyte adhesion deficiency?
Mutation in beta2 integrin.
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What diseases do dysregulated metalloproteinases cause?
Cardiovascular disease, cancer, neurodegenerative, gynecological, and diabetes.
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Integrin mutation disorders
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What is Goodpasture's syndrome?
Autoimmune disorder that affects lungs and kidneys. Antibodies against collagen cause pulmonary hemorrhage, glomerulonephritis
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What are the 5 types of DNA damage?
1. Depurination = spontaneous loss of adenine or guanine base; can lead to deletion
2. Deamination = spontaneous loss of NH
3. Oxidative = varies, but can cause guanine to pair with A instead of C
4. Pyrimidine dimers = linkage between pyrimidines, UV
5. Dstrand break = radiation, chemicals, mechanical stress
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When do you use MMR repair, and what is associated disorder?
Repairs in polymerase errors or insertions/deletions. Important in S phase, and stability of microsatellites (short repeats). A mutation in MMR enzymes leads to inherited colorectal cancer (Lynch Syndrome). MMR has MutS that recognizes DNA mismatch on nicked strand, and MutL is nuclease that removes strand. Involved in diseases of anticipation expansion which increase per generation.
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When do you use base excision repair?
When there's deaminated C's, A's, depurination, Alkylated bases, oxidized bases, bases with open rings, or reduced double bonds. Repairs by removing base via hydrolysis N glycosidic bond (glycosylase), and AP endonuclease clease backbone
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When do you use Nucleotide excision repair, and what is associated disease?
When damage involved entire nucleotide via large hydrocarbon or pyrimidine dimers from UV light. Has TF2H helicase that has two pathways: Transcription coupled = removes lesions from template via XP proteins that come off stalled RNA pol 2. Global genome repair = removes lesions all over genome, reduced in differentiated cells. Associated disease is Zeroderma pigmentosum, which is autosomal recessive and caused by defective NER. Clincally: locus heterogenity, increased risk cancer
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How is double strand break repaired?
If S phase replication forks aren't repaired or there ionizing radiation/ oxidation, it can lead to translocations or cell death. DsB can be repaired by NHEJ or HR. NHEJ is in G1, and PO-Ku is helicase, nuclease trims. This is error prone. HR is in S, G2, and meiosis and allows for genetic exchange between homologous DNA, essential and precise; sister strand gap repair
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What does HR repair require, and what mutation is HR involved in?
Homologous sequences, strand invasion, strand elongation, cleavage. BRCA1 BRCA2 is mutated in breast/ovarian cancer due to HR
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Why are frameshifts and silent mutations bad?
Frameshift can lead to early appearance of stop codon, and silent is synonymous because it can affect splice sites, make mRNA unstable, and interact with other rna
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What diseases are caused by expansion nucleotide repeats?
Fragile X in promoter region (methylation), Friederich ataxia in intron, Huntington and cerebellar ataxia in exon, and myotonic dystophy I (RNA toxic gain of function) in 3' UTR. Usually associated with maternal transmission
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What is Fragile X syndrome?
X dominant, most common repeat disorder, there's hypermethylation of FMR1causes intellectual disability. Clinically presents: large ears, prominent forehead, tremor/ ataxia, and phenotype is variable and corresponds with # of repeats.
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What's myotonic Dystrophy 1?
Autosomal dominant, progressive muscle deterioration, myotonia, cardiac arrythmia, testicular atrophy, insulin resistance. There's RNA gain of function, and number of repeats increases severity.
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What
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What's Huntington's Disease?
Autosomal Dominant, caused by exonic repeats of polyglutamine in huntingtin protein, leading to aggregation (toxic gain function) Clinically: Causes progressive movement disorder, intellectual impairment, psychiatric disturbance, dementia, delayed penetrance (between age 30-50)
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What causes trinucleotide expansion?
Failure of MMR repair to fix hairpins, which causes "slippage", and recombination/ polymerase slippage.
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What is microsatellite instability (MSI) and what does it cause?
insertions or deletions in microsatellite due. High MSI in colorectal cancer, ovarian which is lynch syndrome. Lynch syndrome is caused by hypermethylation of promoters of MMR proteins. Different than Huntington's because Huntington's due to secondary struction of gene , not MMR proteins.
51
What are two polyploid examples?
Triploidy = (69,XXX) usually death via miscarriage. Caused by fertilization of one egg by two sperm
Tetraploidy = (92, XXXX)
52
What are properties of down syndrome?
Trisomy 21, usually caused by nondysjunction (primary), or robertsonian translocation (familial) Clincally presents: decreased intellectual ability, hypotonia, cardiac abnormalities, increased leukemia, epicanthic folds, palmar crease, thyroid autoimmunity, and alzheimers.
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What are properties of edwards syndrome?
Trisomy 18, most die within first year. Caused by nondisjunction, and mosaicism makes it milder. Clincally presents: rocker bottom feet, small head, clenched fists, more severe cardiac problems.
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What are properties of Patau syndrome?
trisomy 13, least survival rate out of trisomies. Caused by maternal nondisjunction, and some due to translocation. Clinically presents: normal birth weight, small head, sloping forehead, large nose, small eyes, cleft lop, malformations of CNS, epilepsy, and heart defects
55
What are properties of Klinefelter's syndrome?
(XXY) Caused by sexual nondisjuction. Presents as hypogonadism, gynecomastia (increased breast cancer, sparse body hair, usually infertile. Intellectual abiity increases with number of Xs
56
What are properties of Turner Syndrome?
Monosomy X, very few survive. Caused by full absence of X caused by nondisjunction paternally, structural abnormalities of X (no pseudoautosomal portion), and mosaics so has variable expressivity. Clinically presents as short stature, webbed neck, congenital heart disease, amenorrhea, hypothyroidism.
57
What are types of structural chromosomal abnormalities?
Inversion - broken parts of chromosomes rejoin; can be pericentric (opposite sides cetromere) or paracentric (same side), leads to reduced gametes, Translocation - Non homologous exchange, Deletion - causes rings to form when deletion at both ends (however if you only lose telomeres no phenotype), and Duplication - loss of one arm leads to addition of the other (usually fatal, some cause Turner's syndrome)
58
What are two types of Translocations?
Balanced Reciprocal - no loss genetic material, but can produce abnormal gametes.
Robertsonian - fusion of acrocentrics (13, 14, 15, 21, 22), also increased production of abnormal gametes. In case of trisomy 14-21, 2/3 of live births are phenotypically normal, and 1/3 of their gametes are phenotypically normal.
59
What are two deletion syndromes?
Wolf Hirschhorn (-4p) = variable intellectual disability, greek warrior helmet, broad nose, high forhead, wide eyes, seizures and delyaed growth are common.
Cri du chat = (5p-) = caused be new mutations, parental translocation, or pericentric inversion. Has characteristic cry, low birth weight, and small head. Severe learning disabilities and failure to thrive.
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What are the microdeletion syndromes?
1. prader willi of 15q11-13 = mental retardation, short stature, obesity, hypotonia, small feet
2. Angelman 15q11-13 = mental retardation, ataxia, laughter, seizures.
3. Digeorge 22q11 = cleft palate, heart defects
4. Rubenstein 16q13.3 = mental retardation, broad thumbs, great toes
5. williams sydrome 7q11-23 = growth delay, short stature, varying illectual ability, elf features, friendly, cardiac defects, hypercalcemia, elastin deleted
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Which diseases are associated with heterozygote advantage?
Cystic fibrosis, hemoglobinpathes, PKU, and tay sachs
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What are some diseases that can be detected prenatally (either ultrasound, xray, tissue, etc.)?
dwarfism, cystic fibrosis, hemophilia, neural tube, osteogenesis imperfecta, tay sachs, sickle cell, PKU, cleft lip
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pleiotropy
more than one observable effect caused by same gene
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What are properties of Tay Sachs?
Autosomal recessive, popular in jewish community, lysosomal storage disease caused by deficiency of lysosomal enzyme. Leads to damage to neurons, blindness, seizures, hypotonia, and death by 5 years, and can be prevented by carrier screening
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what factors affect expression?
1. New mutations - increases with paternal age, common autosomal dominant
2. Germline mosaicism - mutation in embryonic development of one parent affects germline
3. Reduced penetrance - individual with a disease causing genotype but doesn't have phenotype
4. Age dependent penetrance - disease phenotype but not apparent until later in life
5. Variable expression - degree of severity where penetrance is all or none; can be influenced by environment mutations of same gene (allelic heterogeneity)
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Locus heterogenity
Xeroderma pigmentosum
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incomplete dominance
autosomal dominant conditions are more severe in homozygotes
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Manifesting heterozygote
heterozygotes for recessive disorders somtimes have mild abnormalities
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sex influnced dominance
some traits are dominant in one gender but recessive in other (baldness)
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Pseudodominant inheritance
matings of homozygotes can produce pedigrees that look like dominant transmission
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What are properties of autosomal dominant?
matings between two affected are rare, so usually one parent affected, recurrent risk is 50%, vertical transmission, males and females equally, common arise for new mutations
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What are examples of autosomal dominant disorders?
1. Familial hypercholesterolemia- caused by LDL receptor deficiency, decreased clearance from blood, xanthomas, acrus cornealis. and atherosclerosis. Displays allelic heterogeneity and incomplete dominance
2. Retinoblastoma - eye tumor, usually somatic mutation or new mutations paternally. Displays reduced penetrance because 10% who have mutation don't develop disease (two hit model)
3. Li Fraumeni
4. Neurofibromatosis type 1 = caused by NFT gene which is important for GTPase that regulated Ras MAPK variable expression; usually caused by new mutation, either have cafe aur lait spots or the neurofibromas; also have hypertension, learning disabilities, scoliosis
5. Achondroplasia - heterozygotes have reduced stature, but cognitively normal. Homozygotes die in infancy. 100% penetrance; mostly due to new mutations
6. Marfan's = fibrillin mutation, allelic heterogeneity, dominant negative effects, variable expressivity; pleiotropy because affects eyes, skeleton, and cardiovascular
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What are properties of autosomal recessive?
males and females equally affected, consaguinity, pseudodominant
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What are some autosomal recessive disorders?
1. Cystic fibrosis - usually white people (population stratfication), mutation in CFTR gene which codes for chloride channel, allelic heterogeneity, compound heterozygote. Clinically: pancreatic insufficiency, meconium ileus, lots of chloride in sweat, males are sterile
2. PKU - defect in metabolism of phenyalanine
3. lysosomal storage diseases
4. Alkapotunria - black urine
5. Glycogen storage diseases
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What are characteristics of X-linked recessive?
Males are hemizygous so more affected, manifesting heterozygotes, no father son transmission
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What are some X linked disorders?
1. Hemophilia - mutation in coagulation factor 7, sometimes new mutation, variable expressivity, and allelic heterogeneity
2. Duschenne's Muscular Dystrophy - muscle weakness before age 5, pseudohypertrophy of calves, wheel chair by 11, reproductive fitness of 0. Female heterozygotes have higher creatine levels
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What are properties of X linked dominant?
usually females more affected, no father son transmission, but all daughters have; sometimes hard to tell difference between x recessive because incomplete penetrance in heterozygotes
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What are examples of X linked dominant disorders?
1. rett syndrome = autistic behavior, mental disability, seizures, severity is variable, mutation in MECPs
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Y linked
Chromosome infertility
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What is codominance and an example?
when both allelic traits are expressed in heterozygote, ex. AB blood, also epistasis involved in this because h/h overrules AB making O
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What are characteristics of mitochondrial disorders and examples?
variability in expression and reduced penetrance, found in tissues that require a lot of ATP like CNS. Disorders:
1. MELAS - encephalopathy, lactic acidosis, stroke like episodes, mutations in tRNA, progressive neurological deterioration
2. Leber hereditary optic neuropathy - begins around age 30, homoplasmic (all mtdna is mutated), and incomplete penetrance
3. Kearns Sayre - progressive muscle weakness, cerebellar damage, heart failure
4. MERRF - myoclonic epilepsy, ragged, red fibers in muscle ataxia, sensorineural deafness
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Multifactorial disorders
things like diabetes, obesity, cancer, or things that cluster in families like cleft lip, spina bifida. These disorders are not like quantitative traits that only depend on genes not environment (polygenic).
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threshold model
predisposition to a discrete trait, thought to come from genetics and environmental liability factors, trait expressed when threshold passed
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What makes recurrence higher?
More than one family member has, expression in proband is more severe, the proband is the sex less commonly affected, and increases with relatives. So if prevalence = x and risk of offspring of proband is y = xy
ex. Pyloric stenosis = hyperplasia of pyloris muscles can cause obstruction, infants have recoccuring vomit, dehydration; the reocurrence risk is high for males BUT if proband is female the recurrence risk is higher than if proband were male
