Flashcards in MCP Deck (103):
permanent, heritable change in the sequence of genomic DNA
Inherited gene complement
mutations which are transmitted from one or both parents
Acquired gene complement
subset of cells in an individual that arose by clonal propagation from a single mutation in one cell
characteristics which occur together and are assumed to have a common basis; variable presentation; ex: VCF syndrom
Inborn errors of metabolism
genetically determined biochemical disorders in which a specific enzyme defect produces a metabolic block; all autosomal; usually recessive.
build-up of homogenistic acid in blood; black deposits
mutation of tyrosine oxidase; no pigments made – can be complete or partial; complete are extremely sensitive to UV light
to avoid the over accumulation of a potentially toxic substance in cells
Phenylalanine hydroxylase deficiency
a treatable inherited disease in which the body cannot properly process the amino acid phenylalanine
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.
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.
X-linked Lysosomal storage disease(s)
Hunter and Fabry diseases
hexosaminidase A deficiency; rare autosomal recessive (common among Ashkenazi Jews); 6mo onset; dead by 4. clinical gem: cherry red spot
Hurler, Hunter (x-linked) and Hurler-Scheie; . Rx ~bone marrow transplant, enzyme replacement therapy, gene therapy.
mutation in type 1 collagen; type II: perinatal lethal.
Class IV: mild to moderate bone deformity/fracturing,
Class III: intermediate.
post-translational modification of collagen (like COL5A/COL3A)
mutations I the fibrilin gene; tall, thin, long fingers. dislocated lens, joint laxity and dissection of the aorta
exchange btwn homologous chromosomes; Meiosis I
Meiosis I; centromeres/ chromatids remain attached - homologs separate.
reduces the total number of chromosomes from 2N to N
At the end of reduction division you have__________?
two haploid daughter cells (each chromosome has two chromatids).
a cell w/ 2 different copies of a chromosome (both parents: A1/A2 instead of one or the other).
(Nondisjunction at anaphase I)
a cell with two chromosomes from same source (A1/A1) nondisjunction at Meiosis II
for determination of females, there must be two active Xs; inactivation occurs 3-7days after fertilization.
To determine how many Barr bodies there are in a cell...
# of X chromosomes - 1
p and q arms are roughly equal length
centromere displaced towards one side
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
2N gamete that's fertilized into a 3N zygote; or dispermy.
usually a post meiotic event
gain or loss of an individual chromosome; most are incompatible with life
trisomy 13; Failure to thrive, bilalateral cleft palate/lip, rocker bottom feet, Polydactyly, “punched out scalp”
trisomy 18; VSD, muscle hypoplasia, rocker bottom feet, crossed fingers, low set malformed ears. If survive - won't walk, talk, etc.
Sex chromosome Aneuploidies all are a result of
nondisjunction errors in meiosis
47, XXY; infertile males, can develop breasts. Elevated FSH/LH, low Testosterone and higher pitched voice
45, X female, shorter, webbed neck, usually infertile unless mosaic. nonfunctioning eggs but a working uterus.
phenotypic female (Turner, 45X) but 45X/46XY mosaicism . Y puts you at risk.
from congenital adrenal hyperplasia (21-hydroxylase def) or TDF translocation.
loss of distal end of short arm on chromosome 4;Greek warrior helmet syndrome
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
Pericentric v. paracentric inversion
Para: same arm
Peri: across the centromere. Larger inversion = smaller error.
uses molecular probes (DNA frags) labeled w/fluorescent dyes; these hybidize to chromosomes
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)
Four hallmarks of WAGR-11p
(W)ilm’s tumor, (A)niridia, (G)enitourinary, mental (R)etardation
1:3 with Aniridia, get Wilms tumor (nephroblastoma)
deletion of the elastin gene (ELN) on 7q; course hair/skin, stiff blood vessels. Can't live alone. good with music, suck at math.
interstitial micro-deletion on chromosome 22; also linked to SOX5 gene.
lack of parental contribution on chromosome 15 (paternal deletion, maternal uniparental disomy, or imprinting error: SNRPN/necdin inactivation)
Lack of maternal contribution in chromosome 15. maternal deletion, paternal uniparental disomy, or imprinting error (UBE3A inactivation)
Important genes on a maternal chromosome for imprinting consequences
SNRPN and necdin are methylated (inactive), and only transcribe the UBE3A.
Important genes on a paternal chromosome for imprinting consequences
UBE3A is methylated (inactive), and SNRPN and necdin are transcribed.
varied in severities based upon patterns of X-inactivation; linked to mutations in the MECP2 TF, which leads to lack of proper neuronal development
Lack of adenosine deaminase (ADA) leads to...
an accumulation of dATP in cells; toxic. B and T cells die, and you get severe immunodeficiency.
XYY males and XXX females are similar in that they:
are usually fertile and phenotypically "normal"
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
a gamete without any chromosomal rearrangements can occur with ______
Uniparental heterodisomy maintains the...
heterozygosity for the pair of chromosomes involved.
Uniparental isodisomy occurs when a child inherits copies of...
same chromosome from one parent and no copy of that chromosome from the other parent
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%).
Microarrays cannot detect...
balanced gene translocations
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)
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
iron accumulation/deposits in organs-->dysfunction/shut down. Ultimately lethal. Iron circulates in blood, so pt get regular phlebotomies
Rx for Hemophilia A
give factor VII
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.
Treating intracellular protein issues:
modify the given protein so it can get into the cell, or enhance it's gene expression.
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.
Bone marrow Transplantation
collect bone marrow stem cells for hematologic or lysosomal storage diseases.
Problems with Allogenic Stem cell use
risk for graft vs host disease and will require immunosuppressive drugs throughout the remainder of their lives
Gene Therapy is defined as
the deliberate introduction of genetic material into human somatic cells for therapeutic, prophylactic or diagnostic purposes
in vivo gene therapy
genes are incorporated into vectors and targeted to specific cells in the body
ex vivo gene therapy
cells are extracted from pt and genetically modified; then returned to pt
Mitochondrial disorders (like MERRF) often are
progressive with late onset
Ultrasound: usually performed around
18 weeks gestation
thicker than 3mm is usually indicative of an abnormality. 6mm is associated with Down’s syndrome.
a non-invasive test; btwn 15-20 weeks. produced by fetal liver/crosses placenta.
Low MSAFP is associated with
Down Syndrome (false positives if mother is really fat)
High MSAFP is associated with
NTDs; teratoma, renal agenesis/obstruction, uropathy, upper GI obstruction, bladder/cloacal extrophy...
AFP, hCG, uE3 and dimeric inhibin-A
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
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
Amniotic fluid is withdrawn for testing usually performed at 16-18 weeks gestation (earlier may impose mobility of fetus)
If AFAFP levels are elevated, it must be confirmed with
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)
Low AFP is associated with _______, confirm with a __________.
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)
Chorionic villus sampling (CVS):
collection of placental cells, done usually between 10 and 12 weeks gestation
single sperm is injected into an egg, helpful for males with a low sperm count
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
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
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
The normal CYP2C19*1 allele is responsible for?
converting clopidogrel to active metabolite (blood thinner)
CYP2D6's 4 genotypes
Extensive: 2 functional alleles
poor: no functional alleles, accumulation
Ultra: duplicate copies; degrades drug rapidly.
Warfarin inhibits the enzyme
epoxide reductase resulting in inhibition of vitamin K metabolism
mesenchymal tissue (bone, cartilage, muscle, fat)
are gain of function/dominant mutations, meaning only one mutation is required to activate
Tumorigenesis requires mutation of both alleles (recessive). Mutations are often expressed as solid tumors
Two categories of Tumor suppressor cells are?
Gate keepers - cell cycle
Caretakers - stability
genes which directly suppress tumors by regulating cell cycle/inhibiting overgrowth
loss of function eliminates checkpoint into S phase
the most ubiquitous tumor supressor (also a gatekeeper)
familial cancer syndrome from inherited p53 mutation
maintain cell integrity, often by repairing DNA damage. Mutation can lead to an inc in genomic instability/accumulation of mutations.