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350 Cards in this Set

  • Front
  • Back
What is genetic counseling?
communication process that deals with problems associated with occurence and recurrence of a genetic disorder in an individual and/or family
What is eugenics?
attempt to provide a biological solution for societal problems
What is genetics counseling concerned with?
the welfare of the individual, family, or both and only indirectly with the welfare of society
What is part one of the assessment?
overall discussion
What is part two of the assessment?
risk assessment
What is the critical age cutoff for a woman wanting to have kids?
> or equal to 35
What is the critical age cutoff for a man wanting to have kids?
> or equal to 45
What is part three of the assesssment?
review with patient
What is the baseline risk for a birth defect in all pregnancies?
What is the term risk for Down's Syndrome?
What is the difference between screening tests and diagnostic tests?
screening tests are non-invasive; diagnostic tests are only done when screening tests show an increased risk
What are the three screening tests?
FIRST, maternal serum screening, ultrasound
What are some examples of diagnostic tests?
CVS, amniocentesis, ultrasound, fetal blood sampling, fetoscopy/muscle biopsy
What does FIRST stand for?
first trimester integrated screening for trisomies
When is FIRST performed?
11-14 wks gestation
What tests are done with FIRST?
maternal blood sample and ultrasound
The nuchal measurement taken with ultrasound is important because?
a larger measurement means an increased risk for Down's Syndrome
What two things are tested for in the mother's blood sample with FIRST?
serum free hCG and pregnancy associated protein-A
If the mother or father have a balanced translocation, what does this mean for the child?
risk for an abnormality is high
Are all women offered the FIRST testing now regardless of their age?
yes, as of 2006
Because of age-based screening, the majority of Down Syndrome babies are born to mothers of what age?
teens and 20s
When is CVS performed?
11-14 wks gestation
What 2 things come from the fetus that are tested for in the mother's blood during the aneuploid screening?
Alpha-fetoprotein(AFP) and estriol(uE3)
What comes from the placenta that is tested for in the mother's blood during the aneuploid screening?
human chorionic gonadotrophin(hCG)
What is critical to know while doing these screening?
gestation time
What happens to AFP levels in a woman with a fetus that has an open neural tube defect?
AFP levels are high
What happens to AFP levels in a woman with a fetus that has Down's Syndrome?
AFP levels are reduced
What is the optimal time to perform a second trimester maternal serum screening?
17 wks
What is tested for in the triple screen?
AFP, hCG, uE3
What does the second trimester maternal serum screening traditionally detect?
open neural tube defects, DS, trisomy 18
What level is elevated in a Down's Syndrome pregnancy?
What ethnic group has a high incidence of sickle cell disease?
African Americans
What ethnic group has a high incidence of Tay Sachs, Canavan, and Gauchers?
What ethnic group has a high incidence of B-thalassemias?
What ethnic group has a high incidence of alpha-thalassemias?
Southeast Asians
What ethnic group has a high incidence of cystic fibrosis?
What ethnic groups have the highest carrier rates for CF? What are the rates?
Ashkenazi and Caucasian; 1/29
When is amniocentesis performed?
15-20 wks gestation
Southern blot analyzes? What type of probe is used?
Northern blot analyzes? What type of probe is used?
In situ hybridization analyzes? What type of probe is used?
Western blot analyzes? What type of probe?
proteins; antibody
Is a longer or shorter probe more specific?
What must be done to the target DNA strand in order for the probe to bind?
must be denatured
How is DNA denatured?
The Klenow subunit of DNA polymerase comes from?
What factors affect the stability of nucleic acid hybrids?
nature of the nucleic acid, length of the complimentary sequence, temperature, [Na+], and pH --- basically comes down to the number of H bonds
What is the order of stability for the following: RNA-RNA, DNA-DNA, RNA-DNA?
If more bonds are present is it more stable or less stable at higher temperatures?
more bonds means more stable
How does [Na+] affect stability of nucleic acid hybrids?
blocks the electrostatic force of phosphates so that DNA can interact with H
What does a gel tell you?
size of fragments in relation to the control lane
Why are Northern blots run on a denaturing gel?
keeps the RNA from annealing to itself
What does PCR do?
in vitro amplification of specific DNA sequences
Do you need a lot of genomic DNA to run PCR?
No, requires only ng
What are the ingredients for PCR?
template DNA, primers, dNTPs, buffer, Mg+2, thermostable DNA polymerase (Taq)
What is the thermostable DNA polymerase used in PCR?
How does PCR work?
DNA is denatured, primers attach to each strand, a new DNA strand is synthesized behind primers on each template strand; continued rounds of amplification produce large numbers of identical fragements which contain the DNA region of interest
What does linkage analysis do?
identifies which gene on which chromosome
Mapping a gene determines what two things? What does it require?
where it is and what chromosome it is on; analysis of variation between affected and unaffected individuals
What is "cloning" a gene?
physically separating a gene or a cDNA from the rest of the genome
What is genetic mapping?
looking for a gene; uses recombination between polymorphic markers and the phenotype to narrow the interval
What are polymorphic markers?
markers located throughout the genome that everyone has; we know where these are located
What do recombinants define in genetic mapping?
define the boundaries of the genetic interval
Why are first degree relatives so important in genetic mapping?
they can yield crucial information because they may have recombination in genome section that you are looking at, but not the condition; this helps to narrow the interval
A recombination event is more likely to occur if there is _____ space between the 2 points
Greatest possible distance between 2 chromosomes is?
Recombination is?
non-random and sex-specific
How is recombination sex specific?
will occur at different points along the chromosome in male vs female miosis
What three chromosomes see sex-specific recombination?
13, 18, 21
What are hot-spots?
areas where recombination likely to occur
What is the LOD score?
logarithm of odds that 2 loci are physically linked and not associated by chance
What LOD score would be accepted as evidence of linkage?
>3.0 (1000:1)
What LOD score would be evidence against linkage?
<-2.0 (100:1)
What is synteny?
genes that are close together on one chromosome in one species may be close together on a chromosome in another species
What is FISH?
technique which can be used to detect and localize the presence or absence of specific DNA sequences on chromosomes; uses fluorescent probes which bind only to those parts of the chromosome with which they show a high degree of sequence similarity; fluorescence microscopy can be used to find out where the fluorescent probe bound to the chromosome
How many chromosomes should normally light up with FISH?
If >2 chromosomes light up with FISH what happened?
recombination occurred
What color top tubes and type tube are used for a blood draw that is going to be DNA tested?
purple top; EDTA
What tissue is the best sample for DNA?
What are the 5 steps in DNA extraction from a blood sample?
lyse RBC, pellet WBCs, lyse WBCs, degrade protein, precipitate DNA
What test must be used if repeat lengths are >60?
southern blot
What test must be used if repeat lengths are <60?
What is a restriction site?
area that can be cleaved by a restriction endonuclease
What are oligonucleotides?
synthetic DNA used as primers, probes, or linkers; usually a 5'OH instead of a 5'phosphate
What is another name for polynucleotide kinase? What does it do?
T4 kinase; puts radioactive phosphate on piece of DNA
Why is a longer probe better? When can't you use a longer probe?
more likely to bond to a region that doesn't match; if you are trying to detect a subtle mutation
When do you use an oligonucleotide probe? Why?
when you are trying to detect a subtle mutation; shorter and unstable if adjust pH or temperature slightly
How do you measure specificity of ASOs?
% of matched H bonds
What are ASOs?
short sequences of single stranded DNA that are complimentary to DNA sequences of specific alleles; can be radioactively labeled and used as probes to test for the presence of specific alleles in an individual's genome, namely diseased alleles; in an autoradiogram for an ASO test, a positive result signifies that the ASO probe was able to bind to the target DNA and that the allele of interest is present on one or both of the individual's chromosomes
What are 3 important things about ASOs?
mutation must be known, can be automated, suitable for screening for frequent mutations
Can ASOs be used to detect large deletions?
What are some diseases that you can test for with ASOs?
achondroplasia, sickle cell, alpha and beta thalassemias, CF, tay sachs, charcot marie tooth, 21-hydroxylase deficiency
What two things are used to track variation in DNA?
Distance between the lengths cut by restriction enzymes varies due to? This causes what to happen to the lengths of the fragments?
transversions, insertions, or deletions; lengths of fragments vary; this is what tells us apart from someone else
What is variable number of tandem repeats?
short nucleotide sequence ranging from 14 to 100 nucleotides long that are organized into clusters of tandem repeats, usually repeated in the range of between 4 and 40 times per occurrence; clusters of such repeats are scattered on many chromosomes; each variant is an allele and they are inherited codominantly
What two things are important about RFLPs and VNTR?
precise mutation may not be known, and tracking occurs via linkage to a polymorphic marker
RFLPs are a subset of what?
What do SNPs tell you?
whether you can cut there or not
CA repeat lengths are examples of?
Multiple markers around a gene allow you to construct?
Are markers genes?
When do you use single-strand conformational polymorphism (SSCP)?
when the mutation in the gene to be analyzed is unknown
What does the analysis of ssDNA depend on?
the tendency of the ssDNA to form intramolecular H bonding (hairpin loops)
If mutated, ssDNA will fold?
differently from normal ssDNA
What gel is used with SSCP?
a denaturing gel which allows the ssDNA to bind back on itself
Each ssDNA migrates at a different speed because of?
intramolecular H bonding which confers a different shape of folding
What are the advantages of SSCP?
can screen multiple samples at once, moderately sensitive, cheaper than some other methods
What are the disadvantages of SSCP?
not all point mutations affect secondary structure, preferential identification of small insertion/deletion, still have to sequence aberrant products
What can be used to identify mutations in CF?
What type of sequencing can be used to identify mutations in AD condition?
DNA sequencing
If order for the next base to be added to a sequence, what must be present?
3'OH group
What can you adjust to get a wide range of fragment sizes?
What do two bands in the same position on a gel signify?
that person is heterozygous for the mutation (2 alleles)
What is fluorescent sequencing? What would 2 peaks with different color in the same spot mean?
different colored dyes are attached to each ddNTP and sequence is read by the computer; mutation in that position because there are 2 different alleles
Southern blots can detect deletions of?
10s kbs
Larger deletions must be detected by? What are some examples of these conditions?
FISH; Williams syndrome, DiGeorge Syndrome, Prader-Willi, Angelman
Is FISH a small probe or a large probe?
very large probe
By looking at a pedigree how can you tell if the condition is AD? AR?
AD if all generations are affected; AR if some generations are skipped
What is meant by "establishing phase?"
determining which 2 chromosomes carry mutation
What type of chip is used to identify an individual mutation? How does it work?
"re-sequencing" chip; take pt's DNA and see where it hybridizes with chip
What can comparative genomic hybridization (CGH) detect? What can't it detect?
CGH will detect only unbalanced chromosome changes; structural chromosome aberrations such as balanced reciprocal translocations or inversions can not be detected because they do not change the copy number
What can affect the metabolic pathways of certain drugs?
specific mutations in DNA that differ from person to person
What are pluripotent stem cells?
cells that can give rise to any fetal or adult cell type
What are multipotent stem cells?
cells capable of differentiating only into a few certain cell types
Why is reproductive cloning so difficult?
hard to understand and match the stage of the cell cycle
Why are most pharmaceutical products obtained by expression cloning in tissue culture cells and not bacteria?
bacteria don't modify proteins post-translationally
What 3 things in the mammalian expression vector are used for binding to get purified protein?
myc epitope, 6xHis, Term
What is Pcmv?
promoter that directs expression of coded genes
What is needed for expression in mammalian cells?
poly A tail
What is the selection marker for bacterial cells?
What is the selection marker for eukaryotic cells?
What is the bacterial ORI?
What are the poly A tails?
SV40 pA and BGH pA
What is the eukaryotic ORI?
f1 ORI
What type of mice are used to study how gene expression is controlled?
What is the concept behind transgenic mice?
you add in a gene and see how the mice change
What is the concept behind knockout mice?
knockout mice contain an artificially induced mutation in their cells which abolishes the activity of a preselected gene
The absence of what gene affects the development of dorsal limb structures?
What is the concept behind gene augmentation therapy? What can be treated this way?
you are not making something that you need; try and add the gene to fix problem; sometimes vector can be lost if not integrated into the DNA; CF
What is the concept behind targeted gene mutation correction? What can be treated this way?
try to correct the mutant gene being produced; GOF mutations and possibly cancer
What could be treated by targeted inhibition of gene expression?
infections and activated oncogenes
What could be treated by direct killing of disease cells?
In vivo vs ex vivo gene therapy can be used to treat?
metabolic disorders
What is the retrovirus a good vector to use? When using this vector what do you replace the replicating virus genes with?
integrates into the host genome automatically; therapeutic gene
What is used to get DNA past a membrane?
What can be used to treat X-SCID?
gene therapy
10% of patients treated with retroviral gene therapy have developed leukemia...why?
due to insertion of the vector and its replication
What virus vector doesn't integrate into host genome?
What are the steps for Western blotting?
proteins extracted from tissue and separated in gel, electroblotted onto membrane, first treat with Ab specific for protein of interest, then use labeled Ab to target first Ab
What are the two types of human characters?
dichotomous; continuous or quantitative
What is a dichotomous character?
either have it or you don't have it; example would be diseases or malformations
What is a continuous character?
character that everyone has but to different degrees; example would be height, weight, or BP
What are the 3 types of human genetic diseases?
mendelian diseases, chromosomal diseases, multifactorial diseases
What does fully penetrant mean?
you are seeing the complete effect of the gene; other genes and environmental factors have no effect
What does low penetrance mean?
specific gene plays a small part along with other genetic and environmental factors
What is the frequent, chronic, lifetime risk of a multifactorial disorder in Western populations?
about 60%
What does polygenic mean?
caused by the presence of disease allele at MULTIPLE gene loci
Do mulitfactorial disorders have Mendelian segregation?
NO, but do aggregate in families
What is the most frequent congenital malformation which shows mulitfactorial inheritance?
congenital heart defects
Polygenic inheritance is aka?
quantitative inheritance
What is polygenic inheritance determined by?
many genes each having a small additive effect; NO dominance or recessiveness
Many affected loci give what type of distribution?
normal distribution
What is regression to the mean?
both population variation and random variation occur; when random mating occurs, you will see population variation because of these two factors
What does regression to the mean say about a certain character?
the distribution of a certain character is the same in each generation
What is variance of a phenotype?
genetic variation + environmental variation
What is heritability?
proportion of phenotypic variation in a population that is attributable to genetic variation among individuals
What is H2 if condition if only genetically determined?
What is H2 if condition is determined by only environmental factors?
Many multifactorial disorders have H2 in the range of?
Heritability is a property of?
a population
What does the threshold theory postulate?
postulates that susceptiblity to the disease is a continuous character
The more affected family members you have, the more your risk? What happens to the distribution of susceptibilities curve?
increases; shifts right
Which has a higher susceptiblity...a sibling of an affected girl or the sibling of an affected boy?
sibling of an affected girl
How do you identify genes for a common disease?
perform family, twin, or adoption studies
What are you looking for with familial aggregation?
testing whether the disease prevalence in genetically related family members of affected individuals is increased over the prevalence of the disease in the general population
What is a proband?
first patient in a family
First degree relatives have what % of gene sharing?
50%; parents, siblings, children
Second degree relatives have what % of gene sharing?
25%; uncles, aunts, nieces, nephews, grandparents, grandchildren, and half siblings
Third degree relatives have what % of gene sharing?
12.5%; first cousins, great-grandchildren
Sib-sib correlation for height is?
about 0.5
RR or lambda is?
familial relative risk
What does familial relative risk measure? What should the number be?
degree of risk to relatives; should be >1
What is lambda R?
risk to relative of an affected proband compared to the population risk
Is relative risk a theoretical calculation?
no, empirical; derived from surveys of families
What do twin studies test?
compare disease concordance rates among identical twins with those of fraternal twins
MZ (identical) twins share what % of their DNA?
DZ (fraternal) twins share what % of their DNA?
If genetic factors play a significant role, which twins will have a higher concordance rate?
identical twins
What would an ideal twin study look at?
MZ twins separated at birth and brought up in two entirely separate environments
Which studies are the most powerful to disentagle genetic and environmental factors? What are you testing?
adoption studies; determining if individuals are more concordant with their adoptive parents or with their biologic parents for a disease
If an adopted child is more concordant with their adoptive parents, what is responsible? If more concordant with birth parents, what is responsible?
environment; genes
What is ascertainment bias?
occurs when false results are produced by non-random sampling and conclusions made about an entire group are based on a distorted or nontypical sample
Are monogenic disorders seen in large or small families? Do they deal with high or low penetrance genes?
large; high
Are multifactorial disorders seen in large or small families? Do they deal with high or low penetrance?
small; low
What 5 things does parametric linkage analysis require?
mode of inheritance of gene, disease gene frequency, penetrance of disease gene, affection status of all family members, relationship between family members
What type of linkage analysis is commonly used for multifactorial genetic models?
non-parametric linkage analysis
What is the most common non-parametric method of linkage analysis?
affected sibpair methods
What is the concept for affected sibpair methods?
at a single gene locus an offspring can receive any 2/4 parental alleles; pairs of siblings can share 0, 1, or 2 alleles transmitted from their parents; LINKAGE will cause a shift in this distribution
For a dominant condition, how many alleles must affected sibs share?
1 or 2
For a recessive condition, affected sibs must share?
both parental alleles
What does identical by descent (IBD) mean?
same identical allele inherited from the same parent
What does identical by state (IBS) mean?
same allele but not necessarily identical
IBS can occur under what 2 conditions?
when one of the parents is homozygous for a marker allele or when parents are heterozygous for the same marker allele
Can different mutations in the same gene cause the same genetic disease?
The same mutation is seen over and over again in what two mutational classes?
hot-spot mutations and founder mutations
What are the 5 important founder mutations?
HFE, CFTR, HbS, FV Leiden, LCT
What is the condition with the HFE gene affected?
iron overload; heterozygotes have protection from anemia
What is the condition with the CFTR gene affected?
CF; heterozygotes have protection from diarrhea
What is the condition with the HbS gene affected?
sickle cell disease; heterozygotes have protection from malaria
What is the condition with the FV Leiden gene affected?
thrombosis; heterozygotes have protection from sepsis
What is the condition with the LCT gene affected?
lactose tolerance; heterozygotes can consume milk
What is linkage disequilibrium?
non-random association of alleles at two or more loci, not necessarily on the same chromosome; not the same as linkage, which describes the association of two or more loci on a chromosome with limited recombination between them; linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies; non-random associations between genes at different loci are measured by the degree of linkage disequilibrium (LD)
Linkage diseqilibrium between the C282Y mutation causes?
hemochromatosis and HLA-A3
What is a haplotype?
genetic make-up of an individual chromosome
The smaller the region, the _____ ago the mutation occurred
Size of fragment correlates to?
age of mutation
What are you testing in principle genetic association studies?
test for differences in genetic marker frequency between affected cases and unaffected controls
If you see excess of certain marker alleles in affected cases, what does this indicate?
indicates association between DNA marker and disease
What are the 3 possibilities for a + association?
allele is actually the cause of the disease, association is an artifact of population mixture, allele is in linkage disequilibrium with actual disease causing gene
What are markers for association analysis?
SNPs-single nucleotide polymorphisms
Why are SNPs good markers?
mutationally stable, frequent, equally spaced both inside and outside genes
What are the major source of functional polymorphisms? How?
SNPs; influence gene splicing, promoter fx, protein structure, and RNA stability
What is the major source of disease susceptibility in common genetic diseases?
Haplotype sharing can lead to?
allelic association
Linkage studies deal with families or population? Do you have to know the pedigree?
families; yes
Association studies deal with families or populations? Do you have to know the pedigree?
populations; no
With linkage studies is the number of recombination events between pts low or high?
Do linkage studies need large numbers of genetic markers?
In association studies, strength and association depends on?
age and number of mutations
What is the transmission disequilibrium test?
family-based association test to test for the presence of genetic linkage between a genetic marker and a trait; specificity of the test is that it will detect genetic linkage only in the presence of genetic association
What is the most common food intolerance in Western populations?
celiac disease (0.5%-1%)
What is celiac disease?
abnormal immune response to gluten proteins that leads to inflammation and damage in the SI of GENETICALLY susceptible individuals
>95% of all CD pts carry?
HLA-DQ2 or HLA-DQ8 gene
How much of the normal population expresses the HLA-DQ2/8 gene?
How many APs are fired per second with the combined firing for the purkinje cells?
What will parallel fiber synapses display following a paired firing of the synapse with a climbing fiber?
depressed (smaller) EPSP for up to one hr
Strong depolarization of the purkinje cell causes?
VG calcium channels to open
The rise in intracelluar ionic calcium in the purkinje cell causes an increase in? Now what?
protein kinase C; further release of stored calcium for the SR
What does the presynaptic terminal of the parallel fiber release?
The release of glutamate causes what channels to open?
With the parallel fiber firing, what receptors are stimulated?
direct and indirect glutamate receptors
The direct (AMPA) channel allows?
a rise in intracellular Na+ in the purkinje cell which causes further depolarization
THe indirect (mGluR1) receptor allows?
a rise in intracellular second messengers IP3 and DAG in the purkinje cell which also causes a rise in calcium and PKC
During the motor learning process what happens to the number of complex spikes?
What happens to the number of complex spikes when the task is learned?
returns to normal
What happens to the number of simple spikes during the learning process?
gradually decreases and remains depressed after the task is learned
Before learning, how many APs does the purkinje cell fire per second?
Which fiber fires more frequently during learning?
After learning a task, what happens to the post-synaptic membrane under the parallel fibers?
What causes long-term depression?
AP on parallel fiber and AP on climbing fiber occurring simultaneously
What is the main second messenger that causes LTD?
What happens to the deep cerebellar nuclei with motor learning?
A decrease in APs from the purkinje cells causes _____ of the deep cerebellar nuclei
Experience causes cerebellar circuits to be?
modified; this is learning
Cerebellar lesions cause ataxia on what side of the lesion?
Midline lesions of the cerebellum would be in?
vermis (spinocerebellar) or flocculonodular lobes
Midline lesions of the cerebellum cause?
truncal ataxia - unsteady gait, and eye movements abnormalities accompanied by intense vertigo, nausea, and vomiting
How do you test for truncal ataxia?
Romberg test - Ask pt to close their eyes and stand still; if they wobble or move, there is a problem
Lateral lesions of the cerebellum occur in?
paramedian or cerebrocerebellum
Lateral lesions of the cerebellum cause?
appendicular ataxia - unsteady limb movement
What do you test for in lateral lesions of the cerebellum?
action or intention tremor, asynergia, dysmetria, dysrhythmia, dysdiadochokinesia
What is dysmetria?
pt can't approximate areas of body
What is asynergia?
unregulated movements that are non-functional
What is dysdiadochokinesia?
pt unable to perform rapid alternating movements
What is the thalamus part of?
forebrain - diencephalon
Mamillary bodies are important for?
What are the 4 major components of the midbrain?
epithalamus, thalamus, hypothalamus, subthalamus
What is found in the epithalamus?
parts of pretectum and the pineal body
What is found in the the thalamus?
relay nuclei
The thalamus is bounded by?
anterior and posterior commissures
What are the major regulatory functions of the hypothalamus?
autonomic fx, endocrine fx, homeostasis, and limbic system
What is found in the subthalamus?
parts of the midbrain tegmentum and the subthalamic nuclei of the basal ganglia
Relay nuclei in the thalamus receive inputs from ______ and project to?
numerous pathways; cerebral cortex
What receives massive reciprocal connections back from the cortex?
relay nuclei in the thalamus
All sensory modalities except ______ have relays in the thalamus?
VPL receives sensory from?
VPM receives sensory input from?
LGN receives sensory input from?
eyes through the optic tract
MGN receives sensory input from?
Taste sensory input travels to what relay nuclei?
Sensory from middle ear for balance travels to what relay nuclei?
How do you calculate RR?
sibling risk/general pop. risk
What is a protective relative risk?
Does parametric linkage analysis require you to make an assumption?
Does non-parametric linkage analysis require you to make an assumption?
To perform a transmission disequilibrium test what is needed?
affected individual plus the parents
During the CD linkage analysis no obvious functional candidate was found in region 19p. What were the follow-up strategies? Which one was used?
gene-based and haplotype based; haplotype based
Association to the 19kb haplotype encompassed what gene?
MYO9B gene
Heterozygotes for the MYO9B gene had what increased risk for developing CD? What was the increased risk for homozygotes?
1.66; 2.27
What does the myosin IXB variant encode?
encodes for a myosin molecule that has a role in the remodeling of enterocytes
What would happen in the SI if tight junction assembly was impaired?
could be enhanced epithelial paracellular permeability
What would happen to the immunogenic gluten peptides if the SI had enhanced permeability?
gluten peptides could enter the deeper mucosal layer more easily and initiate the inflammatory response
What is the frequency for Hirschsprung disease?
What is Hirschsprung disease? Caused by?
absence of nerve cells in the LI which leads to no BM and therefore abnormal abdominal distention; defect in the migration of neural crest cells during development
What is the recurrence risk for Hirschsprung disease? What is the RR? Sex ratio?
3-4%; 200; 4 males to 1 female
For Hirschsprung disease, the proportion of affected sibs is higher when the index patient is?
What is RET? Function?
receptor tyrosine kinase; promotes neural crest stem cell migration to the intestines
Effect of RET is dominant or recessive? Is there complete penetrance?
dominant; no
What are the 2 RET ligands?
What is GDNF? What does it do?
glial cell line derived neurotrophin factor; has a role in neural crest cell migration
What is NRTN? What does it do?
neurturin; promotes survival of neural crest cells
Are RET ligands capable of causing disease alone?
What is EDNRB? What is it associated with?
endothelin receptor kinase type B; sensineural deafness and white forelock
Gene effects of EDNRB are dominant or recessive?
Is the EDNRB gene capable of causing disease alone?
Waardenburg syndrome is?
white forelock
EDNRB is involved with what 2 things?
spread of neural precursors from small bowel to large bowel and also of melanocytes
What is EDN3? What is its function?
endothelin 3; ligand for EDNRB
What is ECE1 function?
enzyme involved in proteolytic maturation of EDN3
What is SOX10? What is its function?
transcription factor z; required for differentiation of enteric glial cells
Is SOX10 found in dominant or recessive Hirschsprung syndromes?
RET, EDNRB, EDN3,GDNF, and SOX10 account for what % of familial cases of Hirschsprung disease? What % of sporadic cases?
60-70%; 10-30%
What is the recurrence risk for CD?
What is risk for DM1 in the 10-19 yr old age group?
What is DM1?
autoimmune disorder; destruction of pancreatic beta cells and therefore no insulin production
What HLA marker is present in 30% of DM1 pts?
What HLA marker is absent in DM1 pts and therefore confers protection?
What is the population risk for DM1 with HLA-DQ2/8?
What is the sibling risk for DM1 with HLA-DQ2/8 shared?
Do offspring from an DM1 male or female have a greater risk?
male (5% compared to 2%)
What % of adults in the US have DM2?
What % of affected's first degree relatives have DM2?
What is MODY? AR or AD?
maturity onset diabetes of the young; AD
Which type of diabetes has NO association with lifestyle or obesity?
What is MODY 2?
glucokinase deficiency; mostly asymptomatic
What % of MODY 2 heterozygous women develop gestational DM?
What is MODY 1 and MODY 3?
single gene type 2 DM; affects hepatocyte nuclear factor
What is HNF1A?
activator of HNF4A
What is HNF4A?
activates liver-specific genes in glucose, cholesterol, and FA metabolism
Deficiency of peroxisome proliferator activated receptor gamma causes? Common or rare?
DM and severe obesity; rare
What is peroxisome proliferator activated receptor gamma?
ligand dependent transcription factor regulating genes involved in lipid and glucose metabolism and adipocyte differentiation
What was found in whole genome association studies?
transcription factor 7-like 2 and zinc transporter SLC30A8
What is most common form of dementia? What is the strongest risk factor?
Alzheimer's Disease; age
What % of individuals over the age of 65 have AD? Over the age of 80?
5%; 20%
What is the brain pathology in AD?
abundant extracellular senile plaques and intracellular neurofibrillary tangles
What are the 3 genes associated with early onset AD?
amyloid precursor protein, presenilin 1, and presenilin 2
What is seen in about 50% of early onset AD pts?
presenilin 1
How does amyloid precursor protein correlate to Down's syndrome?
located on chromosome 21; 50% of Down's syndrome pts develop AD
What is the function of amyloid precursor protein (APP)?
cell surface protein; highly conserved evolutionarily
What are the functions of presenilin 1 and 2?
both involved in proteolytic cleavage of APP
Abnormal clevage of APP results in?
beta amyloid which aggregates with other proteins in senile plaques
Some mutations of APP and PS1 have been shown to cause overproduction of?
abeta42 peptide aka beta amyloid
Which ApoE is thought to be protective?
Which ApoE is thought to confer 30-50% genetic risk?
What is elevated in E4 homozygotes vs E3?
total plasma cholesterol and LDL cholesterol
Which ApoE is the ancestral allele?
ApoE4 allele is associated with?
earlier age of onset and increased risk for AD
Presence of one ApoE4 allele increases lifetime risk from _____ to _____
9%; 29%
Does having ApoE4 mean you are going to get disease?
What is useful for investigating dyslipidemias but not for prediciton of AD?