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Flashcards in MCP Deck (103):
1

mutation

permanent, heritable change in the sequence of genomic DNA

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Inherited gene complement

mutations which are transmitted from one or both parents

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Acquired gene complement

subset of cells in an individual that arose by clonal propagation from a single mutation in one cell

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syndrome

characteristics which occur together and are assumed to have a common basis; variable presentation; ex: VCF syndrom

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Inborn errors of metabolism

genetically determined biochemical disorders in which a specific enzyme defect produces a metabolic block; all autosomal; usually recessive.

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Alcaptonuria

build-up of homogenistic acid in blood; black deposits

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albinism

mutation of tyrosine oxidase; no pigments made – can be complete or partial; complete are extremely sensitive to UV light

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salvage pathways

to avoid the over accumulation of a potentially toxic substance in cells

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Phenylalanine hydroxylase deficiency

a treatable inherited disease in which the body cannot properly process the amino acid phenylalanine

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Classiacal PKU

Autosomal recessive, 1/10,000; most common/severe; absence or near absence of phenylalanine hydroxylase. High levels of PHE are converted to a toxic phenylpyruvic acid.

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Variant PKU

intermediate form

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Tetrahydrobiopterin (BH4) deficiencies

BH4 helps process PHE, but is also important in the brain for NT synthesis. Worsens over time; Rx w/ L-Dopa or OH-Trp.

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X-linked Lysosomal storage disease(s)

Hunter and Fabry diseases

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Tay-Sachs

hexosaminidase A deficiency; rare autosomal recessive (common among Ashkenazi Jews); 6mo onset; dead by 4. clinical gem: cherry red spot

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mucopolysaccharidoses

Hurler, Hunter (x-linked) and Hurler-Scheie; . Rx ~bone marrow transplant, enzyme replacement therapy, gene therapy.

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Osteogenesis imperfecta

mutation in type 1 collagen; type II: perinatal lethal.
Class IV: mild to moderate bone deformity/fracturing,
Class III: intermediate.

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Ehler-Danlos Syndrome

post-translational modification of collagen (like COL5A/COL3A)

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Marfan syndrome

mutations I the fibrilin gene; tall, thin, long fingers. dislocated lens, joint laxity and dissection of the aorta

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Recombination/Crossover

exchange btwn homologous chromosomes; Meiosis I

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Reduction Division

Meiosis I; centromeres/ chromatids remain attached - homologs separate.
reduces the total number of chromosomes from 2N to N

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At the end of reduction division you have__________?

two haploid daughter cells (each chromosome has two chromatids).

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Heterodisomy

a cell w/ 2 different copies of a chromosome (both parents: A1/A2 instead of one or the other).
(Nondisjunction at anaphase I)

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Isodisomy

a cell with two chromosomes from same source (A1/A1) nondisjunction at Meiosis II

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Lyon Hypothesis

for determination of females, there must be two active Xs; inactivation occurs 3-7days after fertilization.

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To determine how many Barr bodies there are in a cell...

# of X chromosomes - 1

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metacentric centromere

p and q arms are roughly equal length

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submetacentric centromere

centromere displaced towards one side

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Acrocentric centromere

little rRNA p arm is called a Stalk and is capped by a modified telomere called a satellite. Chromosomes 13, 14, 15, 21, and 22 are acrocentric, and are the only chromosomes which are involved in Robertsonian translocations

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Triploidy

2N gamete that's fertilized into a 3N zygote; or dispermy.

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Tetraploidy

usually a post meiotic event

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Aneuploidy

numerical error
gain or loss of an individual chromosome; most are incompatible with life

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Patau syndrome

trisomy 13; Failure to thrive, bilalateral cleft palate/lip, rocker bottom feet, Polydactyly, “punched out scalp”

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Edwards Syndrome

trisomy 18; VSD, muscle hypoplasia, rocker bottom feet, crossed fingers, low set malformed ears. If survive - won't walk, talk, etc.

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Sex chromosome Aneuploidies all are a result of

nondisjunction errors in meiosis

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Klinefelter

47, XXY; infertile males, can develop breasts. Elevated FSH/LH, low Testosterone and higher pitched voice

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Turner Syndrome

45, X female, shorter, webbed neck, usually infertile unless mosaic. nonfunctioning eggs but a working uterus.

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gonadoblastoma

phenotypic female (Turner, 45X) but 45X/46XY mosaicism . Y puts you at risk.

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XX “male”

from congenital adrenal hyperplasia (21-hydroxylase def) or TDF translocation.

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Wolf-Hirschhorn Syndrome

loss of distal end of short arm on chromosome 4;Greek warrior helmet syndrome

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Karyotype for Robersonian Down syndrome; ie: 15;21 translocation

46, not 47 due to fused chromosome; The recurrence risk is much higher for offspring of Robertsonian translocation carrier parents than trisomy 21 due to a nondisjunction during meiosis

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Pericentric v. paracentric inversion

Para: same arm
Peri: across the centromere. Larger inversion = smaller error.

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FISH

uses molecular probes (DNA frags) labeled w/fluorescent dyes; these hybidize to chromosomes

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Three types of FISH

1. Repeat sequences: gain/loss
2. Single copy DNA: particular gene associated locus
3. Chromosome painting: along a whole chromosome (ID source of extra DNA)

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Four hallmarks of WAGR-11p

(W)ilm’s tumor, (A)niridia, (G)enitourinary, mental (R)etardation

1:3 with Aniridia, get Wilms tumor (nephroblastoma)

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Williams Syndrome

deletion of the elastin gene (ELN) on 7q; course hair/skin, stiff blood vessels. Can't live alone. good with music, suck at math.

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VCFS

interstitial micro-deletion on chromosome 22; also linked to SOX5 gene.

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Prader-Willi Syndrome

lack of parental contribution on chromosome 15 (paternal deletion, maternal uniparental disomy, or imprinting error: SNRPN/necdin inactivation)

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Angelman Syndrome

Lack of maternal contribution in chromosome 15. maternal deletion, paternal uniparental disomy, or imprinting error (UBE3A inactivation)

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Important genes on a maternal chromosome for imprinting consequences

SNRPN and necdin are methylated (inactive), and only transcribe the UBE3A.

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Important genes on a paternal chromosome for imprinting consequences

UBE3A is methylated (inactive), and SNRPN and necdin are transcribed.

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Rhett Syndrome

varied in severities based upon patterns of X-inactivation; linked to mutations in the MECP2 TF, which leads to lack of proper neuronal development

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Lack of adenosine deaminase (ADA) leads to...

an accumulation of dATP in cells; toxic. B and T cells die, and you get severe immunodeficiency.

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XYY males and XXX females are similar in that they:

are usually fertile and phenotypically "normal"

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androgen receptor gene defect

Mutation of the androgen receptor gene on the X chromosome resulting in complete lack of protein product. no internal female genitalia, testes in the abdominal cavity

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a gamete without any chromosomal rearrangements can occur with ______

Alternate segregation

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Uniparental heterodisomy maintains the...

heterozygosity for the pair of chromosomes involved.

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Uniparental isodisomy occurs when a child inherits copies of...

same chromosome from one parent and no copy of that chromosome from the other parent

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Heteroplasmy

maternal mitochondria are a mix of mutant and normal; thus, inheritance is variable in severities (there must be a high proportion of mutant mitochondria present in that cell (~85%).

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Microarrays cannot detect...

balanced gene translocations

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Contiguous gene syndromes

spots on chromosomes that are rich with genes; these syndromes have weird combos of unrelated things. ex: WAGR (11p), Miller-Dieker (17p) and Angelmann/Prader (15)

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In a defect in the urea pathway preventing degradation of NH3 to urea can be treated by diet and ______.

administering sodium benzoate. Pushes excess ammonia to combine with glycine --> hippurate which can be excreted

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Hereditary homochromatosis

iron accumulation/deposits in organs-->dysfunction/shut down. Ultimately lethal. Iron circulates in blood, so pt get regular phlebotomies

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Rx for Hemophilia A

give factor VII

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Pros and cons for extracellular treatment at the protein level

Usually you can just administer the missing protein. But these can be costly or antigenic.

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Treating intracellular protein issues:

modify the given protein so it can get into the cell, or enhance it's gene expression.

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One method to treat Sickle Cell on the protein level

Cecitabine: increases levels of y-globin (by inhibiting methytransferases methylation). this inhibits dHb from polymerizing.

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Bone marrow Transplantation

collect bone marrow stem cells for hematologic or lysosomal storage diseases.

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Problems with Allogenic Stem cell use

risk for graft vs host disease and will require immunosuppressive drugs throughout the remainder of their lives

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Gene Therapy is defined as

the deliberate introduction of genetic material into human somatic cells for therapeutic, prophylactic or diagnostic purposes

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in vivo gene therapy

genes are incorporated into vectors and targeted to specific cells in the body

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ex vivo gene therapy

cells are extracted from pt and genetically modified; then returned to pt

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Mitochondrial disorders (like MERRF) often are

progressive with late onset

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Ultrasound: usually performed around

18 weeks gestation

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Nuchal translucency

thicker than 3mm is usually indicative of an abnormality. 6mm is associated with Down’s syndrome.

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MSAFP

a non-invasive test; btwn 15-20 weeks. produced by fetal liver/crosses placenta.

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Low MSAFP is associated with

Down Syndrome (false positives if mother is really fat)

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High MSAFP is associated with

NTDs; teratoma, renal agenesis/obstruction, uropathy, upper GI obstruction, bladder/cloacal extrophy...

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Quad screening

AFP, hCG, uE3 and dimeric inhibin-A

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Quad screening that would indicate Down Syndrome?

High levels of hCG and dimeric inhibin A, paired with low levels of AFP and uE3 have an ~80% predictive value for Down Syndrome

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Non-Invasive Prenatal Screening (NIPS) - when and what is it.

sample of the mother’s blood is taken at 10-22 weeks gestation. cell free DNA is isolated; comprised of both mother and fetal DNA. a screening test that gives a risk for a chromosomal abnormality

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Amniocentesis (when/what)

Amniotic fluid is withdrawn for testing usually performed at 16-18 weeks gestation (earlier may impose mobility of fetus)

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If AFAFP levels are elevated, it must be confirmed with

AChE test
The only source of Ach in a normal individual is the neural tube – if detected, then it must have escaped from a body opening (like an open NTD)

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Low AFP is associated with _______, confirm with a __________.

Down syndrome
karyotype analysis

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Multiple (non-identical) pregnancy will cause an elevation in what prenatal test?

MSAFP (AFAFP will be the same b/c you are only sampling from one amniotic sac).
(identical twins share a sac, MSAFP=AFAFP)

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Chorionic villus sampling (CVS):

collection of placental cells, done usually between 10 and 12 weeks gestation

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ICSI

single sperm is injected into an egg, helpful for males with a low sperm count

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Next generation sequencing

a whole genome screen. This is the same technology which powers NIPS, and can flag inappropriate embryos. While very costly, it can greatly help those who have major difficulties conceiving

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If the 1st polar body tests positive for the CF mutation known to be carried by the mom, then the corresponding egg

would not be expected to have a CF mutation

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if the 1st polar body has no CF mutation (in a known maternal carrier)

the mutation must be in the oocyte that will develop into the egg. This oocyte would be eliminated from the pool and would not be selected to take part in IVF

90

The normal CYP2C19*1 allele is responsible for?

converting clopidogrel to active metabolite (blood thinner)

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CYP2D6's 4 genotypes

Extensive: 2 functional alleles
poor: no functional alleles, accumulation
intermediate: heterozygotes
Ultra: duplicate copies; degrades drug rapidly.

92

Warfarin inhibits the enzyme

epoxide reductase resulting in inhibition of vitamin K metabolism

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Sarcoma

mesenchymal tissue (bone, cartilage, muscle, fat)

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Carcinoma

epitheloid tissues

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Oncogenes

are gain of function/dominant mutations, meaning only one mutation is required to activate

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Tumor suppressor

Tumorigenesis requires mutation of both alleles (recessive). Mutations are often expressed as solid tumors

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Two categories of Tumor suppressor cells are?

Gate keepers - cell cycle
Caretakers - stability

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gatekeepers

genes which directly suppress tumors by regulating cell cycle/inhibiting overgrowth

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RB1

loss of function eliminates checkpoint into S phase
(Gatekeeper/tumor suppressor)

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p53

the most ubiquitous tumor supressor (also a gatekeeper)

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Li Fraumeni

familial cancer syndrome from inherited p53 mutation

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Caretakers

maintain cell integrity, often by repairing DNA damage. Mutation can lead to an inc in genomic instability/accumulation of mutations.

103

HNPCC is caused by

mutation of a DNA Mismatch Repair Gene; The accumulation of errors eventually results in system dysfunction