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Foundations 1 > 8/8/17 > Flashcards

8/8/17 Flashcards

1
Q

Osteogenesis Imperfecta

A

Type I: fractures of arm and leg bones, heal normally, have half of normal procollagen amount so Loss of Function mutation, blue sclera

Type II: bunch of bone fractures at birth, die soon, mutant collagen

Dominant negative LOF mutation

Substitute Gly in collagen

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2
Q

Achondroplasia

A

Autosomal dominant, fibroblast growth factor 3 (FGFR3)

Mutation so stabilize FGFR3 dimers, constitutively activate a negative regulator, increase with dad age

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3
Q

Anticipation

A

Occurrence of genetic disease at an earlier age of onset and with increasing severity in successive generations

Triplet repeats tend to expand, intron is FA

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4
Q

Huntington’s Disease

A

Autosomal dominant, high penetrance

Personality changes, motor probs, memory loss

Caused by polyglutamine mutation

Initial: impaired muscles, forgetful, personality change

Middle: involuntary and voluntary uncontrolled, slur speech, depress and crazy

End: immobile, mind is nonfunctional

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5
Q

Duchenne Muscular Dystrophy

A

1/3 are point mutations and insertions

Haldane Hypothesis

X-linked disorder

Myofibe degeneration and regeneration with adipose and connective tissue, calf pseudohypertrophy

Cardiomyopathy, retarded, die early

Dystrophin protects striated muscle membranes from damage by linking actin to ECM, is absent in DMD

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6
Q

Haldane Hypothesis

A

1/3 of mutant alleles are lost each gen in X-linked, if disease frequency is constant then 1/3 must be new mutations

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7
Q

Becker muscular dystrophy

A

Mutations in dystrophin gene but milder and onset

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8
Q

Spinal muscular atrophy

A

Autosomal recessive, LOF of SMN1

Muscle atrophy, SMN1 has a deletion that prevents it from making 90% of SMN transcript so SMN2 (with a single base change from SMN1) makes a small amount

Severity depends on SMN2 copy number

Type 1: Werdnig-Hoffman disease, floppy muscles and breathing probs, die before 2

Type 2: sit but not stand, die as a kid

Type 3/4: milder, adult survival

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9
Q

SMA treatments

A

Spinraza: exon skipping to include exon 7, intrathecal

Avexis: gene therapy, intravenous

Better motor milestones than SMA Type 1

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10
Q

Allelic heterogeneity

Locus heterogeneity

Clinical heterogeneity

A

Multiple Diff mutations in same allele

Mutations in more than one gene

Diseases have diff phenotype but caused by same phenotype

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11
Q

Mitochondrial diseases

A

Affect high aerobic tissues like eyes, nervous system, cardiac, and muscles

Leber hereditary optic neuropathy, MERRF, and MELAS

Affected males don’t transmit to kids

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12
Q

Satellite DNA

A

Alpha-satellite: kinetochores of all chromosomes

Beta-satellites: variable regions of 1,9,Y, and acrocentrics

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13
Q

SNP

A

A change in DNA that occurs in at least 1% of the population

Responsible for most variation in gene expression

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14
Q

UV Radiation Effect

A

Thymine dimers that need nucleotide excision repair

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15
Q

Alkylation and cross linking agents

A

Cytoxan and tobacco

Add methyl to G and may cross link DNA strands

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16
Q

Demaminatin of C

A

Converts to U so one strand binds with A instead of G

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17
Q

ROS

A

Makes 8-oxoguanine

Now pairs with A or C

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18
Q

Fragile X Syndrome

A

Retarded, big ears and jaw, big balls

Triplet repeat mutation, RNA binding protein (FMRP) for translation regulation and synaptic plasticity plasticity

5’CGG repeat gets enlarged during maternal meiosis which causes miRNAs to methylated the 5’CpG island, only occurs after a certain CGG repeat size threshold

Example of anticipation

GOF: trigger miRNA release
LOF: transcription shuts down for the neuroplastic gene

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19
Q

Red-green color blindness

A

Red and green located on X chromosome

Unequal crossing over

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20
Q

Hemoglobin Lenore

A

Fusion of beta globin genes due to unequal crossing over

Delta beta fusion

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21
Q

Dominant Negative Mutation (LOF)

A

Heterozygous alleles

Mutant polypeptide loses own function AND interferes with function of the normal allele

More than 50% reduction in function

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22
Q

RET GOF mutation

A

Transmembrane receptor with tyrosine kinase domains that activate MAPK pathway for transcription

Can cause Multiple Endocrine Neolasia 2, a thyroid cancer

Missense mutations that that cause excess reaction to ligand, constitutively active receptors, overproduction of neuroendocrine cells

Changes to Cys a big thing

GOF mutation

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23
Q

Friedrich Ataxia

A

GAA repeats in intron

GOF: heterochromatin formation
LOF: transcription shit down

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24
Q

Myotonic dystrophy

A

CTG in 3’ UTR

GOF: attract RNA binding proteins from extra RNA, abnormal splicing of other gene transcripts like insulin receptor and muscle chloride channel

LOF: other transcripts

Open, triangular shaped mouth in baby
Weird face

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25
Q

Base excision repair

A

Fix most common DNA damage, purine loss and 8-oxoguanine

MUTYH involved in 8-oxoguanine repair

LOF muatins lead to colorectal cancer

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26
Q

Xeroderma pigmentosum

A

Nucleotide excision repair prob

Skin and eyes sensitive to UV, get skin cancer

Autosomal recessive

27
Q

Complementation

A

Single allele mutations in two diff loci don’t produce disease

28
Q

Mismatch repair

A

Replication errors like mismatch nucleotides, microsatellites

MLH1/PMS2 and MSH2/MSH6 recognize mismatch and recruit other repair machinery like EXO1

29
Q

Lynch Syndrome

Hereditary nonpolyposis colorectal cancer

A

Defective base mismatch repair leads to cancers like colorectal and ovarian

Mutations in 4 mismatch repair genes plus EPCAM, which prevents transcription of MSH2

30
Q

DsDNA damage signal and repair syndromes

A

Maintenance of structure and integrity of DNA (helicase): Bloom syndrome

Signal the repair process: ataxia telangiectasia

Locate damage and trigger repair: Fanconi anemia

Repair of DNA: BRCA 1 and 2

End-joining of dsDNA: Nijmegen breakage syndrome

31
Q

Bloom syndrome

A

Maintenance: suppression of recombination
DNA RecQ helicase

Predisposed to most cancers, excess sister chromatid exchanges that can lead to unbalanced exchanges

Short stature

32
Q

Ataxia telangiectasia

A

Signals BRCA of chromatin changes like by ionizing radiation

Difficulty with movements and chromosomal instability, cancer

33
Q

Franconia anemia

A

LOF recessive

Sensitive to DNA damage like cross links

Short stature,skin hyperpigmentation, malformed kidneY and limb, bone marrow failure

Locate and trigger

34
Q

Nijmegen breakage syndrome

A

Super rare

Short, progressive small head, immunodeficiency, and increased non-Hodgkin lymphoma

End joining of dsDNA

35
Q

HereditRy breast/ovarian cancer syndrome

A

Single LOF mutation, autosomal dominant phenotype (only non biallelic LOF recessive)

Higher breast and ovarian cancer plus prostrate in dudes

36
Q

SsDNA break repair

A

PARP1: poly[ADP-ribose]polymerase 1

PARP1 inhibitor for chemo for BRCA mutation: eliminating one DNA repair pathway leads to genome instability like cancer, eliminating both repair pathways leads to cell death

37
Q

Nuclear transport

A

Prospective protein has a positive nuclear localization signal that binds to nuclear import receptor, nuclear import receptor moves down cytosolic fibrils and releases protein

38
Q

Mitochondrial transport

A

Precursor protein with positive N terminal signal sequence binds to the import receptor protein, protein unfolded to be threaded through intermembrsne space and past protein translocator in inn

39
Q

Ribosome location

A

Proteins destined to be translated on ER-bound ribosomes have ER import sequence, located on N terminus

Signal recognition particle binds to ER signal sequence and then binds to SRP receptor on ER

Stay in cytosol if have no ER import signal sequence

40
Q

ER embedded proteins

A

Protein threaded through protein translocator until hit hydrophobic stop transfer sequence, spit out, signal peptidase cleaves N terminal signal sequence

41
Q

Swyer Syndrome

XY gonadal dysgenesis

A

Mutation in SRY

Normal guy karyotype but external female genitalia without ovaries

SRY is a TR that initiates sex determination in embryogenesis

Can be from mutations in nuclear localization signal of SRY

42
Q

Alpha thalassemia

A

Deletions of 1-4 alpha globin genes

3 deleted copies gets kinda serious, Hemoglobin H disease

4 deleted is Hemoglobin Bart’s with 4 gamma subunits, neonatal death

43
Q

Beta Thalassemia

A

Many different types of mutations cause this

Thalassemia major is Cooley’s anemia, with enlarged organs and bones deformed

44
Q

Heinz body hemolytic anemias

A

Point mutation in Beta subunit

Denature Hb molecule

Coagulation in the erythrocyte

45
Q

Better to have increased or decreased oxygen affinity?

A

Decreased since increased is more severe

46
Q

Sickle Cell anemia

A

Single point mutation (Hb S) changes Glu to Val (BGlu6 to Val)

Hydrophobic patch makes sticky in T state and polymerize

47
Q

Hemoglobin C

A

Glu6Lys

West Africa

Milder anemia due to reduction in RBC lifespan

48
Q

Not bad Hb variants

A

Hb E and Hb I

Involve point mutations that have AA with opposite charge

Both variants arose independently

49
Q

Hb glycosylation

A

Not enzymatic, proportional to glucose conc.

Used for HbA1c levels

Little effect on function

50
Q

Levinthal’s Paradox

A

10 possible conformations for each AA

Proteins can’t fold randomly because it would take ridiculously long, so a predetermined path must exist

51
Q

Foldon

A

Units that fold in a single cooperative step

Secondary structure elements

52
Q

Anfinsen Conclusions

A

Info for folding is in primary structure

Folding is thermodynamically controlled, no need for energy

53
Q

Consequences of Excluded Volume Effect

A

Increase: effective conc., asosociation rate constants of large molecules, Rate of aggregation

Decrease apparent solubility

54
Q

Proteins at risk for aggregating

A

Names can’t chains synthesized from polysomes: growing chains close together not fold but aggregate

Nuclear proteins: crowded and charged macromolecules

Mutant proteins:

Unfolded proteins under environmental stress like heat

55
Q

Foldases

A

Catalyze rate-limiting step in folding

56
Q

Peptidyl-prolyl CIA trans isomerase

PPI

A

Accelerates folding cuz catalyze CIA and trans isomer conversions of Pro peptide bonds

57
Q

Protein disulfide isomerase

A

Catalyze disulfide interchange reactions, which is rate limiting in ER lumen

Localized to ER

58
Q

Anfinsen Cage

A

Sequester polypeptide to prevent aggregation and provides appropriate folding environment

Found in chaperonin

59
Q

Systemic amyloidosis

A

Extra cellular deposition and accumulation of insoluble protein

Amyloid have beta sheet structures that cross link

Transthyretin binds and transports thyroid hormone and vitamin A through the body

60
Q

Alpha-1-antitrypsin deficiency

AATD

A

Alpha-1-antitrypsin is stuck in liver and can’t go to lungs, helps protect lungs from neutrophil elastase

Caused by incomplete folding or aggregation

61
Q

Alzheimer’s disease

A

Beta amyloid plaques

Example of localized amyloidosis

Secretase cuts APP (a large precursor protein) to form beta amyloid

Abnormal postranslational modifications of precursor proteins

62
Q

Molecular chaperones

A

Decrease rate of aggregation

Can work in tandem

Some require ATP

Prevent inappropriate interactions among proteins

63
Q

Prions

A

Infectious agents composed of misfiled proteins

Spongiform encephalopathy

Foundations 1 (19 decks)

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