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Unit 2 > Unit 2 - Week 2 - Loh 1 and 2, Stein 3, Amack 3 > Flashcards

Unit 2 - Week 2 - Loh 1 and 2, Stein 3, Amack 3 Flashcards

1
Q

Name some common categories of birth defects.

A
  1. Congenital malformation 2. Structural, functional or behavioral disorders 3% of births, 25% infant mortality
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2
Q

What is the most common structural birth defect?

A

Congenital heart defect

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3
Q

What are some sources of genetic birth defects?

A
  1. Single gene mutations 2. Chromosomal abnormalities 3. Sporadic 4. Inherited dominant, recessive or X-linked
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4
Q

What kind of genetic mutation is responsible for Axenfeld-Rieger syndrome?

A

Single gene mutation in either Pitx2 or FOXC1

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5
Q

What are some features of Axenfeld-Rieger syndrome?

A

Dental abnormalities Ocular defects Prominent forehead Redundant periumbilical cord

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6
Q

True or False: Multiple single nucleotide polymorphisms that alone are benign, together can cause disease.

A

True.

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7
Q

Holoprosencephaly (HPE) is due to:

A

Multiple causes (locus heterogeneity), many are in the SHH pathway (loss of fx)

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8
Q

What are the features of holoprosencephaly?

A

Forebrain malformation Facial defects

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9
Q

What are some features of congenital rubella syndrome?

A

Microcephaly PDA (patent ductus arteriosis)

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10
Q

Name some other microorganisms whose exposure in utero can cause birth defects.

A
  1. Coxsackie virus 2. Cytomegalovirus 3. Herpes simplex 4. Parvovirus 5. Rubella 6. Toxoplasma gondii 7. Treponema pallidum (syphilis)
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11
Q

What is the main defect of thalidomide poisoning?

A

Phocomelia, small limbs

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12
Q

What are the two prevalent hypotheses of birth defects caused by thalidomide?

A
  1. Disrupting angiogenesis 2. Inducing oxidative stress on the fetus
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13
Q

What is teratology?

A

The study of birth defects. A teratogen is an agent that causes birth defects

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14
Q

What is the most sensitive time period for a fetus to have teratogen exposure?

A

Weeks 3-8 during embryogenesis. But susceptibility depends on genotype of the mother and child, length of time of exposure etc.

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15
Q

FASD refers to:

A

all alcohol-related defects

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16
Q

What is the leading cause of congenital mental retardation?

A

Alcohol

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17
Q

What are the features of FAS?

A

Developmental delay Underdeveloped jaw Growth deficiency Facial features Defects in neuronal migration in the brain

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18
Q

Name some proposed mechanisms of action of alcohol damage to a fetus.

A

Cell migration and adhesion Cell proliferation and survival Cell signaling and gene expression

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19
Q

1% of all live births, and an estimated 10% of fetuses have:

A

malformation of the heart, usually multifactorial causes

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20
Q

Septal defects such as _____ result in a hole in the heart.

A

ASD, atrial septal defects VSD, ventricular septal defect

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21
Q

What is dextrocardia?

A

A condition where the heart is positioned on the right side of the thorax instead of the left. Reversal of the heart laterality is often caused by defects in establishing the L-R body axis during embryogenesis.

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22
Q

Heterotaxy can result in several congenital heart malformations including:

A
  1. Septal defects 2. Double outlet right ventricle (DORV) 3. Transposition of the great arteries (TGA)
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23
Q

Signs and symptoms of severe heart defects in newborns include:

A
  1. Rapid breathing 2. Cyanosis 3. Fatigue 4. Poor blood circulation
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24
Q

What is 22q11.2 deletion syndrome? What are the features?

A

22q11.2 deletion syndrome includes VCFS, or DeGeorge syndrome Tetralogy of Fallot Truncus arteriosis (outflow tract defects)

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25
Q

The outflow tract of the embryonic heart gives rise to the __1__. During heart development, the outflow tract remodels to form the __2__ and the __3__.

A
  1. the great arteries 2. aorta 3. pulmonary artery
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26
Q

Explain the defect truncus arteriosis that occurs in 22.q11.2 deletion syndrome?

A

A single common blood vessel comes out of the heart, instead of the usual 2. The developing vessel fails to separate completely, leaving a connection between the aorta and the pulmonary artery. There is also usually a ventricular septal defect.

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27
Q

What is suggested by these characteristics? 1. Ventricular septal defect (VSD) 2. Pulmonary stenosis 3. Overriding aorta 4. Ventricular hypertrophy

A

Tetralogy of Fallot

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28
Q

___1___ contribute to the outflow tract. __1__ migrating from the dorsal __2__ into the arterial pole participate in separation of the outflow tract.

A
  1. Cardiac neural crest cells 2. neural tube
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29
Q

Cardiac neural crest cells contribute to the outflow tract. Genes located in the 22q11.2 deletion region, specifically TBX1, are thought to regulate:

A

cardiac neural crest cell (CNCC) development

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30
Q

Name the structure and single-letter.

A

Glycine, G

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31
Q

What kinds of proteins are the target of more than 50% of drugs being made?

A

GPCRs

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32
Q

Protein function is completely determined by 2 factors:

A
  1. Polymer length
  2. AA composition
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33
Q

Tipranivir functions by:

A

Inhibiting the aspartate resideues that carry out nucleophilic attack in HIV-protease-1, without being hydrolyzed.

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34
Q

What is APP?

A

Alzheimer Precursor Protein, normally cleaved into a 40-residue fragment. In AD, the peptide is cleaved in the wrong place, producing a 42-residue fragment with sticky ends, which is thought to contribute to the amyloid fiber aggregation.

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35
Q

Why are peptide bonds non-rotatable?

A

Because the peptide bond has partial double bond character, ESSENTIAL for protein folding by limiting the number of rotations of each aa.

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36
Q

Beta sheet (phi, psi) values are close to:

A

180 degrees, making the polypeptide almost fully extended.

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37
Q

Alpha helical (phi, psi) values are closest to:

A

0, resulting in a scrunched polypeptide

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38
Q

Glycine, due to its size, experiences fewer ___ than the other amino acids, as indicated by the large grey areas on the Ramachandran plot.

A

repulsions

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39
Q

Regions of a polypeptide containing glycine (1 or multiple) tend fo be more:

A

flexible

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40
Q

What is the pKa of aspartic acid?

A

4.0

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41
Q

What is the pKa of glutamic acid?

A

4.0

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42
Q

What is the pKa of histidine?

A

5.0

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43
Q

What is the pKa of cysteine?

A

8.5

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44
Q

What is the pKa of lysine?

A

10.0

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45
Q

What is the pKa of arginine?

A

12.0

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46
Q

What is the pKa of every carboxy terminus of a terminal aa?

A

4.0

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47
Q

What is the pKa of every amino terminus of a terminal aa?

A

8.0

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48
Q

Name the five MOST hydrophobic amino acids.

A

Alanine

Valine

Leucine

Isoleucine

Proline

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49
Q

Name the aromatic hydrophic amino acids:

A

Tryptophan

Phenylalanine

Tyrosine

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50
Q

Name the only Sulfur-containing hydrophobic amino acid:

A

Methionine

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51
Q

Define imino acid and give the 1 example.

A

An imino acid is one where the backbone nitrogen is not bonded to 2 hydrogens, but to its own side chain.

Proline

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52
Q

High pKa means:

A

Binds H+ tightly

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53
Q

Low pKa means:

A

binds H+ weakly

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54
Q

pKa is defined as the pH at which:

A

Half the ionizing groups are protonated, and half are deprotonated

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55
Q

pH < pKa means

A

lots of H+ in solution

forces H+ onto ionizing group

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56
Q

pH > pKa means:

A

low H+ in solution

pulls H+ off ionizing groups

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57
Q

Name the negatively charged amino acids:

A

Aspartic Acid

Glutamic Acid

Cysteine

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58
Q

Name the positively charged amino acids:

A

Lysine

Arginine

Histidine

*positivdly charged at physiologic pH

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59
Q

What is the only residue that can both accept and donate H+ readily at physiologic pH?

A

Histidine (pKa 6.5)

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60
Q

What is an imidazole ring?

A

5-membered histidine ring

61
Q

Histidine’s unique behavior at physiologic pH?

A

It is often used as a catalytic site in proteins (enzymes) engaging in acid-base catalysis

62
Q

Influenza hemagglutinin senses when the intracellular pH drops to ~5.0, at which point it:

A

changes conformation and initiates fusion of viral and cellular membranes

63
Q

Can pKa’s of amino acids change?

A

Yes, the chemical environment and surrounding amino acids and charged groups can influence and change a pKa of a particular amino acid (ie glutamic acid pKa 4 –> 8)

64
Q

If Aspartate is very near to another (-) charged amino acid, what happens?

A

Its pKa increases because it would rather keep its H+ (to reduce repulsion)

65
Q

Name the amino acids which contain amide bonds.

A

Asparagine

Glutamine

66
Q

Name the amino acids with a terminal hydroxyl group:

A

Serine

Threonine

(Tyrosine)

67
Q

What is the primary way that cross-links between domains/amino acids are fashioned?

A

S-S

Cysteines bonding; disulfide bridge

68
Q

Why does proline tend to form kinks?

A

Because the peptide bond it forms with its neighbors is cis, not trans, in 1/4 of the X-Pro peptide bonds

69
Q

The strongest electrostatic forces are found:

A

in salt bridges (ion pairs)

70
Q

Where are electrostatic interactions found on proteins?

A

Typically on its surface

71
Q

How are electrostatic interactions affected in aqueous solution?

A

They are weakened (D, dielectric constant = 80), whereas in a vacuum, D=1, where electrostatic interactions are strongest.

72
Q

Give some examples of buried charged amino acids in proteins:

A

Glutamic acid buried in the F0 proton channel of the F0F1 ATP synthase (binds a H+);

Lysine buried in rhodopsin GPCR (binds 11-cis-retinal chromophore);

73
Q

H bonds have a directional component: they are strongest when:

A

the atoms lie in a straight line

74
Q

Physiological pH =

A

7.4

75
Q

Since rotations do not occur around the peptide bond, it considered to be:

A

planar

76
Q

The two rotatable bonds per amino acid residue are called:

A

Phi and Psi angles

77
Q

What is the only difference between a folded protein and an unfolded one?

A

Bond rotations. Folded proteins have a single, rigid structure and have frozen out most of the rotational degrees of freedom.

78
Q

Why do only 10-20% of phi,psi combinations actually work in nature?

A

Various backbone and side chain atoms approach each other too closely and begin to repel one another/occupy the same space.

79
Q

Phi and psi values of 180 indicate:

A

The chain is in a fully extended conformation. (0 indicates compaction.)

80
Q

What are the indications for prenatal diagnostic tools?

A

Familial chromosome anomaly

Consanguinity

Family hx of a genetic disorder for which testing is available

Familial X-linked recessive disorder without testing available

Increased risk of ONTD (open neural tube defect)

Carrier of genetic disorder, ethnic risk

Ultrasound anomaly

Repeated miscarriages

Anxiety

Environmental exposures

81
Q

What is MSAFP?

A

Maternal Serum Alphaprotein - high and low levels have been associated with fetal abnormalities

This is a non-invasive blood test, and its values can be skewed by the mother’s weight, race and diabetic status

82
Q

Name the noninvasive prenatal tests.

A

Ultrasound

Examination (basic physical)

83
Q

Name the invasive prenatal tests.

A

Molecular Studies

Cytogenetics

Biochemical

84
Q

Ultrasounds tells you:

A

Gestational age, sex

Verify viability

Identify possible abnormalities

Determine a multiple pregnancies

85
Q

When during pregnancy is ultrasound usually performed?

A

Week 18

86
Q

What is a nuchal translucency? What does it indicate?

A

It is a finding on an ultrasound, a fluid-filled space between the skin and vertebrae. When it is too big (6.0mm), it can be an indicator of Down syndrome.

87
Q

Ultrasound can determine what kinds of defects?

A

Neural tube defects, ie meningomyoceles

Cleft palate/cleft lip

Nuchal translucency

88
Q

What is the worst outcome of a neural tube defect?

A

Anencephaly, absence of the brain

Encephalocele, when the brain is extruded from the skull

89
Q

Low levels of AFP are found in __1__. High levels of AFP are found in __2__.

A
  1. Down Syndrome
  2. Open spina bifida
90
Q

MSAFP is a screening test for risk assessment. What does this mean?

A

This means that alone, AFP is not a diagnostic end, but with certain levels, can indicate the need for further testing.

91
Q

What is the maternal serum quad test?

A
  1. AFP (alpha fetoprotein)
  2. hCG
  3. unconjugated estriol (uE3)
  4. dimeric inhibin-A (glycoprotein hormone secreted by the ovary)

**80% combined detection for Down syndrome

92
Q

What is PAPP-A?

A

It is another lab test to determine risk for Down Syndrome, and is thought to be more informative than the quad test alone.

Pregnancy-associated plasma protein-A (when down, suggests DS)

93
Q

What is NIPS/NIPT?

A

The newest non-invasive prenatal diagnostic assay

94
Q

What is cfpDNA?

A

Cell free placental DNA (free floating DNA), sometimes innacurately called cffDNA (cell free fetal DNA)

95
Q

What is the major driving force for protein folding?

A

Hydrophobic effect

96
Q

The hydrophibic effect is not the fear or repulsion of water, but rather:

A

The affinity of water for ITSELF. Exposure to hydrophobic molecules induces in water an energetically unfavorable state called a clathrate.

97
Q

True or False: Hydrophobic groups and water repel each other.

A

False.

98
Q

True or False: Hydrophobic groups have a unique mutual attraction.

A

False. Hydrophobic clustering tendency is due to te attempt to reduce the nonpolar SA exposed to water to increase entropy, due to the water formations it creates in the presence of hydrophobic compounds.

99
Q

What accounts for 60% of protein structure?

A

Secondary structure

100
Q

What are the 3 types of secondary protein structures?

A
  1. Alpha helix
  2. Beta sheet
  3. Beta turn
101
Q

The most commonly observed secondary protein structure, the alpha helix, has a periodicity of:

A

3.6 residues

102
Q

In alpha helix protein structure, the NH of i hydrogen bonds with the CO peptide of:

A

i + 4

103
Q

Examples of alpha-helix stabilizing side chain interactions include:

A

All of them:

Lys-Glu (ie electrostatic);

Val-Leu (ie hydrophobic);

Asn-Asp (ie H-bonding); and

van der Waals

104
Q

A polypeptide of multiple alanines results in:

A

An alpha helix

105
Q

What are the amino acids most likely to break an alpha helical conformation?

A

Proline;

Glycine (small, flexible)

106
Q

Like helices, beta sheets are _______ structures.

A

fully hydrogen-bonded

107
Q

True or False: Beta sheets exist only in the anti-paralel conformation.

A

False! It is less common, but still possible, to have a parallel beta-pleated sheet. However hydrogen bonding in parallel sheets is at an angle, kind fo slanted, whereas antiparallel hydrogen bonds are straight, and therefore more favorable.

108
Q

The periodicity of a beta sheet is 2. What does this mean?

A

This means that the side chains of every other amino acid are in close contact with one another.

109
Q

There are many examples where the structures of two functionally different proteins are similar except for the length, positions and/or sequences of their __1__. In these cases, the __1__ define the business end of the protein.

A

Loops/random coils, anything that is not formal secondary structure.

110
Q

Motifs are often used for:

A

molecular recognition–to bind to other molecules tightly and specifically

111
Q

The _____ motif is one of the most common elements by which proteins recognize specific sequences of DNA.

A

HTH, helix-turn-helix

112
Q

Give 3 characteristics of the zinc finger motif:

A
  1. The Zn2+ is intended to reduce the need for an extensive hydrophobic core for stability;
  2. It binds DNA weakly; many repeats of this sequence are needed to bind DNA;
  3. The spacing of the histidines is (i, i+4);
  4. It binds the major groove of DNA
  5. It is found in transcription factors, ie Zif268.
113
Q

What is a heptad repeat?

A

a-b-c-d-e-f-g

where a and d are nonpolar, and

e and g are charged, usually of the opposite charge

The signature of coiled-coil domains

114
Q

Name some proteins that are known to contain coiled-coil domains, which contribute to their fibrous stability.

A

Myosin

TF;s, ie GCN4

115
Q

A classical repeat of the coiled coil heptad is:

A

leucine zipper, where leucine or valine occupy positions a and d in the repeat.

116
Q

An intrinsically disordered protein domain, such as GCN-4, is one that:

A

Only adopts the correct conformation iwhen it binds to its ligand.

117
Q

Give an example of a coiled-coil interaction that does not involve a DNA ligand.

A

Myosin tails are very long coiled-coils;

Viral penetration, ie the haemagglutinin in H1N1 influenza.

118
Q

When is a cfpDNA sample taken during pregnancy?

A

10-22 weeks

119
Q

How is cfpDNA analyzed?

A

Next gen sequencing, or other DNA sequencing technology, compared the amount of expected DNA from mother and baby and amount of DNA present

120
Q

If cfpDNA sequencing is a screening test, what is the corresponding diagnostic test for aneusomy?

A

FISH and/or karyotpe analysis

121
Q

When is an amniocentesis usually performed?

A

14-20 weeks gestation, most commonly between 16 and 18 weeks.

122
Q

What are the kinds of studies that can be performed on amniotic fluid?

A

AFAFP

Cytogenetics

Metabolic Assays

Molecular Diagnostics

123
Q

Low AFP levels are associated with:

A

Triploidy

Trisomies 13, 18 and 21

Mosaic Turner Syndrome

Unbalanced Translocations

124
Q

Ideally, Amniotic Alpha fetal protein, AFAFP, should confirm the results of:

A

MSAFP

125
Q

What is the only benign indication for high AFP in both MSAFP and AFAFP tests?

A

Monozygotic twin pregnancy

126
Q

If the AFAFP appears to be high, it must be confirmed with:

A

an acetylcholinesterase test, AChE, which is ONLY present in the amniotic fluid is there is an ONTD

127
Q

True or False: AFP is a diagnostic test for ONTD and other fetal abnormalities.

A

False. It is a screening test. If AFP is high –> AChe. If AFP is low –> karyotype analysis

128
Q

Which invasive prenatal screening test carries more risk to the fetus, chorionic vilus sampling (CVS) or amniocentesis?

A

CVS - 1/100 risk of fetal loss

Amniocentesis - 1/200 risk of developmental issues due to taking too much fluid or hurting the fetus

129
Q

CVS has a particular risk for:

A

Removing cells necessary for circulation in the extremeties, affecting limb development

130
Q

What kinds of analysis is CVS used for:

A

NOT AFP, because no fluid

Molecular diagnostics

Metabolic assays on cells

Cytogenetics

131
Q

Where does CVS get its tissue from?

A

The placenta

132
Q

If the findings from a CVS test are abnormal, __1__ is done to confirm that the results are fetal in origin, and not a problem with the __2__.

A
  1. Amniocentesis
  2. Placenta
133
Q

What is one reason why placental and fetal cells might differ?

A

Mosaicism

Placental mutation - fetus ok

Fetal mutation - CVS fails to pick up (confined fetal mosaicism)

134
Q

If a woman is concerned about her baby inheriting Fragile X Syndrome, what is the best way of tesing this?

A

Test HER for the Fragile X premutation. If positive, see if fetus is male. Then consider additional testing.

135
Q

Genetic counseling decisions come from the parents. In this way, the process is:

A

Non-directive

136
Q

What does ART stand for (in the context of prenatal testing)?

A

Assisted Reproductive Technologies

137
Q

Name some majoe ART’s:

A

IVF

ICSI - intracytoplasmic sperm insertion

Donog egg

ZIFT - zygote intrafallopian transfer

138
Q

IVF is followed by:

A

ZIFT

139
Q

What is ISCI?

A

A single sperm is injected into an egg, good for males who have low sperm count

140
Q

In polar body analysis, what happens?

A

Oocytes are collected from mom, and the polar bod is tested for the genetic anomaly or interest (ie CF mutation). If that polar body is positive, and mom is a carrier (not full mutation), the egg would be expected to be normal.

141
Q

What occurs in PGD, preimplantation genetic diagnosis?

A

IVF, and at 8 cell stage, 1 cell is removed and tested with FISH (NOT karyotype bc no metaphase cell).

142
Q

PGD testing is beginning to be replaced by:

A

Next gen sequencing (as in NIPS), because it can do a whole genome screen

143
Q

Why would a Turner individual use a donor egg?

A

Because she has a functional uterus, but does not usualy produce her own eggs

144
Q

If a woman has a mitochondrial mutation, how can she have children without that mutation?

A

Use a donor egg, remove the donor nuclei, replace with mom’s nuclei (with donor mitochondria), IVF and ZIFT.

145
Q

What is a major disadvantage of peptide-based medications?

A

They are rapidly digested by proteases in the body, ie. Fuzeon for HIV, intended to inhibit gp41 (viral protein) to prevent HIV entry into the cell.

146
Q

How did scientists improve the goal of inhibiting gp41?

A

Using a D-gp41 chemically synthesized. D-gp41 and L-gp41 bind together and the D protein is longer lived in the body than is Fuzeon.

147
Q

What viruses use harpooning mechanisms to get into cells?

A

HIV

SARS

Ebola

148
Q

What is Fuzeon?

A

A peptide drug that interacts with cellular N-trimer. It is based on the viral C-peptide region (gp41), but is not very effective because it is rapidly degrade din the body, being a peptide drug.

Unit 2 (11 decks)

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