Term
| A patient presents with an "end-product" deficiency of acetyl coA. When you take her blood glucose level you comment that she is ________? |
|
Definition
Hypoglycemic
(no substrate for gluconeogensis) |
|
|
Term
| While doing a research project focused on characterizing a novel genetic disease, you notice a large amount of locus and allelic heterogeneity in its presentation. You also note that there are multiple enviornmental-toxin-related mechanisms that can cause it to develop. Even though you can't rule out a number of other options, you suspect it is an example of a ___________ disease? |
|
Definition
| Inborn Error in Metabolism |
|
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Term
| A woman comes in to your clinic and explains that her mother had a mutation in the phenylalanine hydroxylase enzyme and is concerned because she recently got pregnant. You determine that the woman's mother did present with the disease, but controlled her symptoms quite well. What disease is the pregnant lady concerned that she might pass on to her child________? What are the chances of her passing the disease on if her husband is a carrier_________? |
|
Definition
1) PKU
2) 1/6 (2/3 chance that she is a carrier and 1/4 chance that she and her husband have a homozygous recessive child) |
|
|
Term
| Upon newborn screening, you discover that a child has hyperphenylalaninemia. Why is it important to also check tetrahydrabiopterin levels? |
|
Definition
You know that the child has a phenylalanine hydroxylase deficit, but if they also have a BH4 deficit, they could have issues with TTNA (see below)
Tryptophan hydroxylase (L-tryptophan to 5-HT)
Tyrosine hydroxylase (L-tyrosine to L-DOPA)
Nitric Oxide Synthase (L-arginine to NO)
Alkylglycerol monooxygenase (hydroxylating sn-glycerol) |
|
|
Term
|
Definition
-Allelic heterogeneity (mostly compound mutants) and variable expressivity
-Most frequent AA metabolism disorder (1-19,000)
- More common in Whites and Native Americans
- Mental retardation, seizures, social difficulties
- Restrict Phe and supplement with Kuvan (oral form of BH4) if PKU is BH4-responsive |
|
|
Term
| A mother with PKU (Phe >20) comes to you and explains that she wants to have a child. What advice do you give her? |
|
Definition
| BE CAREFUL- phenylalanine in maternal blood is actively transported across placental barrier resulting in 92% mental retardation. |
|
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Term
| A newborn baby presents with lethargy, vomiting, respiratory alkalosis and hepatomegaly. You suspect hyperammonemia and are worried that it might lead to encephalopathy and death. You order labs and they come back with elevated plasma ornithine and glutamate levels. What deficiency is it? |
|
Definition
OTC deficiency
X-linked (all males that have the gene deficit get it and half of females do because of X-inactivation).
2/3 of carriers have new mutation
1/8 of males are new mutations
Sperms mutate > oocytes
R148K carriers always have symptoms
R48K only seen during stressful conditions |
|
|
Term
| What are the chances that some who is a carrier for the R148Q mutations will exhibit hyperammonemia-like symptoms? |
|
Definition
| - They alway do, and kids die in newborn period unless treated |
|
|
Term
Understand
1) Sensitivity
2) Specificity
3) Positive Predictive Value
4) Negative Predictive Value |
|
Definition
1) how many people with target disease test positive?
2) How many people without disease test negative?
3) how many people with positive test result have the disease?
4) how many people with a negative test result are disease-free? |
|
|
Term
| True or False: Maternal age is a current indication for prenatal diagnosis? |
|
Definition
|
|
Term
| A pregnant woman comes in to your clinic (12 Weeks) and after doing some tests, you notice an abnormal maternal serum screen. What invasive prenatal diagnostic test should you run? |
|
Definition
|
|
Term
| A pregnant woman comes into your clinic who has had a previous child with a neural tube defect. She is 10 weeks pregnant. What diagnostic, prenatal test should you run? |
|
Definition
| WAIT FOR A FEW WEEKS. Amniocentisis (16-18 weeks)- CVS cannot detect AFD for Spinabifida. |
|
|
Term
| What are the four markers that you should use when running a prenatal screen for Trisomy 21 in the 2nd trimester? What other measure are these markers incorporated into? |
|
Definition
-0.75X AFP
-2X hCG
-0.7X UE3
-2X Inhibin-A
-Maternal Age |
|
|
Term
| What is the protocol for a patient with a positive Trisomy 21 screen in the 1st trimester (HcG and PAPP-A with nuchal translucency) |
|
Definition
| - Counseling and offer CVS |
|
|
Term
| What is the protocol for a patient with a positive Trisomy 21 screen in the 2nd trimester? |
|
Definition
1) Ultrasound for dating and determination of fetal viability
2) if dates are correct, offer amniocentesis |
|
|
Term
| A child is born with with a deletion causing premature activation of FGFR3 receptors (gain-of-function). What disease do they have? |
|
Definition
| Achondroplasia- arrest of cartilage proliferation |
|
|
Term
| When can you use pre-implantation diagnostic testing for Trisomy 21 and what are some issues with its use? |
|
Definition
- Have to be IVF patients.
- Take a cell biopsy at 8-cell stage and only keep viable cells
- PCR failure, allele dropout (recessive disorders), sperm contamination, cost, limited availability |
|
|
Term
| What was use has the FDA approved for FGF7? |
|
Definition
| Treatment of chemoradiation-induced oral mucosis |
|
|
Term
| Excess Cerberus released from the anterior visceral endoderm would inhibit which three molecules? |
|
Definition
|
|
Term
| Patients with Fibrodysplasia ossificans progressive (FOP) exhibit progressive endochondral ossification. A mutation in which gene is thought to be responsible for this? |
|
Definition
| BMP receptor (gain of function) |
|
|
Term
| Why might you prescribe your patient BMP-2? |
|
Definition
- Spine fusion
- Bone fractures
- Root Canal |
|
|
Term
| Wnt signaling usually controls the association between APC and beta-catenin. Why might mutations in the APC gene be a problem? |
|
Definition
| APC would dissociate from beta-catenin, causing to over-expression of beta-catenin-sensitive genes in the nucleus, stimulating cellular proliferation and leading to the development of colorectal tumors. |
|
|
Term
| If there is a mutation in the patched1 (PTCH1) gene, why might you also see basal cell nevus carcinoma (Gorlin syndrome?) |
|
Definition
| Shh usually de-represses PTCH1 and Smoothened, which in turn change the Gli family transcription factors. Gli factors are nuclear transcription factors that normally repress gene expression, and when they are altered, there is abnormal cell proliferation. |
|
|
Term
| A young, pregnant woman is taking Acutane for her acne, and is horrified when her baby comes out with severe birth defects. What happened? |
|
Definition
| Acutane is a retinoid (like retinal, which is activated to retinol in the liver and retinoic acid (RA) in the circulation by RALDH) that binds to RAR and RxR nuclear receptors, altering transcription. |
|
|
Term
What three structures arise from the node/cranial streak?
What about the caudal streak? |
|
Definition
Node/Cranial (notochord, prechordal mesoderm, foregut mesoderm)
Caudal (Cardiac mesoderm, Somites, Lateral mesoderm) |
|
|
Term
| The epiblast cells of the developing embryo are expressing extremely low levels of Nodal? What might you be concerned? |
|
Definition
| Nodal is required for the generation of endoderm and mesoderm (prechordal and notochord) |
|
|
Term
| A 2.5 week old embryo has a primitive streak that runs from the anterior visceral endoderm all the way to the node. How is this possible? |
|
Definition
| the AVE (region of hypoblast) is not secreting Cerberus effectively, and thus Nodal activity is not innactivated in the rostral regions of the embryo. |
|
|
Term
| A 3 week old embryo has failed to initiate neural induction within overlying epiblast cells. There is an abundance of epidermal cells and lateral mesodermal tissue can be seen where somites should have developed. What happened? |
|
Definition
| The epiblast and non-axial mesoderm are not secreting Noggin and Chordin into the dorsal midline (BMP antagonists). Epidermal fate is not being suppressed so neural induction cannot take place, and Noggin is not inducing somite formation. |
|
|
Term
| What would happen to an embryo that was not producing Dickopf in the anterior visceral endoderm? |
|
Definition
| Dickopf is critical for Wnt and BMP repression , which promotes the development of anterior neural character. The embryo would not develop a brain! |
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Term
| If the somitic mesoderm and the regressing node were not producing RA, FGFs and Wnts, what would happen to the embryo. |
|
Definition
| Caudal (posterior) identity would be disrupted |
|
|
Term
| A recent drug given to mothers to relieve birthing stress has a side result of lowering embryonic levels of RALDH2. Why should you be concerned? |
|
Definition
| RALDH2 is critical for synthesizing RA, which is partly responsible for posterior identity formation. RA is also required for the separation of the trachea and esophagus during budding. |
|
|
Term
| Where might the protein product of the 3' end of the Hox1a be localized? |
|
Definition
3' end is more antior (5' is posterior)
Smaller numbers are more cranial (larger are caudal)
This gene would be in the anterior portion of the midbrain, most likely. |
|
|
Term
| In a neural tube stage embryo, excess RA results in the 2nd segment of the neural plate (CN V) acting like the 4th segment (CN V11). How might this happen? |
|
Definition
Remember that Hox gene expression patterns can be set by signaling molecules such as RA. RA is expressed highly in the somatic mesoderm, adjacent to the future hindbrain and cranial spinal chord. Thus, excess RA caused an abnormal cranial of Hoxb1 expression, which caused more cranial regions to look more caudal!
This can be seen for FGF8 as well, which is expressed in caudal embryonic regions, in the regressing node. |
|
|
Term
| You observe excess amnionic fluid (polyhydramnios) in a developing embryo. What congenital defect might you worry about? |
|
Definition
| Esophageal atresia- the proximal and distal esophageal portions fail to join. This is often seen along with Tracheo-esophageal fistula (trachea opens into distal esophagus). |
|
|
Term
What molecules regulate early lung budding>
What molecules regulation endodermal proliferation and lung branching? |
|
Definition
The lungs and trachea bud off from the cranial part of the embryonic foregut, where visceral mesoderm wraps around endoderm.
RA originating from caudal regions is responsible for FGF10 induction in the visceral mesoderm that leads to direct outgrowth
Shh down regulated GFG10 expression as buds grow, via Gli 1 nuclear activity. |
|
|
Term
| How might low levels of retinol in patients with congentital diaphragmatic hernias relate the hernia to pulmonary hypoplasia? |
|
Definition
| RA is needed for lung budding, which means the hernia may not only be a result of intestinal pressure alone. |
|
|
Term
| Why do you see tracheal and respiratory abnormalities in some children with Pfeiffer an Apert syndromes? |
|
Definition
| These are syndromes resulting from mutations in FGFR genes. We know FGFs are responsible for lung budding and branching, as well as lunch and trachea separation |
|
|
Term
| How is Shh signaling related to EA and TEF? |
|
Definition
| Mutations in Gli2 and Gli3 genes (downstream effectors of Shh signaling expressed in embryonic foregut mesoderm), as well as FoxF1 (lung and gut mesoderm) are associated with the development of EA and TEF |
|
|
Term
| If a pregnant patient visits your practice and complains of insomnia, what might you refrain from prescribing Thalidomide (give examples of a few results)? |
|
Definition
It causes proximal limb defects in the fetus by altering regulation of FGFs, leading to cell death in the limb bud and the AER (decreases FGF and FGFR expression). It also acts as an antiangiogenic factor.
Phocemelia- abbreviated proximal limb elements (rare genetic condition) |
|
|
Term
| What structure is primarily responsible for proximodistal (PD) limb fate? |
|
Definition
The formation of the apical ectodermal ridge (AER), which is a thickening of ectrodermal tissue surrounding the parietal layer of lateral mesoderm during development, is necessary for PD determination.
Limb forming zones are specified very early, even before evidence of bud formation
The effects of its removal are time-dependent (earlier removal results in the loss of a greater portion of structures) |
|
|
Term
| What group of cells is responsible for setting the pattern of digits along the anteroposterior (AP) axis? What molecules are involved in its action? |
|
Definition
The zone of polarizing activity (ZPA) is located in the posterior margin cells of the anterior margin of the limb bud.
These cells express Shh, and its diffusion pattern establishes a gradient along the AP axis. The caudal localization of Shh is maintained by Gli3, which determines the distribution of Hox genes, and in doing so regulates the regions where Shh is expressed.
Shh also promotes the maintenance of FGFs, thereby promoting mesenchymal proliferation in limb expansion. |
|
|
Term
| A number of important signaling molecules are located within the AER and are important for limb bud formation . What phenotype might you expect to see if Tbx4 was missing? What about Tbx5? |
|
Definition
Tbx4- hindlimb absence
Tbx5- forelimb absense |
|
|
Term
| What signaling molecule can mimic the activity of the AER? |
|
Definition
|
|
Term
| A limb bud is developing correctly proximally, but appears abnormal distally development. Which signaling factor is active, and which is deficient? |
|
Definition
Retinoic acid is functioning properly (remember that ectopic RA signaling proximalizes marker expression in the limb bud).
FGFs are probably not functioning properly (remember that FGFs are important for distal limb development). |
|
|
Term
| If a developing limb exhibits polydactaly or abnormal definition of upper arm, lower arm and digit regions, what gene family might be implicated? |
|
Definition
Hox genes.
Recall that in addition to their early role in defining the position of limbs, Hox proteins specify PD limb regions (regulated by RA and FGF). Ectopic Hox11 expression has also been shown to lead to the formation of extra digits, implicating it is AD patterning in the digits |
|
|
Term
| A developing limb exhibits a deficit in interdigit cell death (webbed fingers). What signaling molecule would you expect to have been disrupted? |
|
Definition
BMPs.
In addition to being important for interdigit cell death, early in development, BMPs are important for AER formation. |
|
|
Term
| A newborn with Pallister-Hall Syndrome presents with polydactaly. You perform PCR analysis to detect a mutation in which gene? |
|
Definition
Gli3.
Gli3 normally restricts Shh to caudal mesenchyme, but without this retriction, Shh can cause the growth of additional digits |
|
|
Term
| A newborn presents with Syndactaly. You perform PCR analysis to detect a mutation in which two gene families? |
|
Definition
Hox and FGF
Hox11 mutations effect proximal limb parts (radioulnar stenosis)
Hox13 mutations lead to hand and foot abnormalities.
In Pfeiffer and Apert syndromes, constituive activation of the FGF8 receptor, FGFR2, can inhibit interdigit cell death (remember, BMPs also influence AER formation by decreasing FGF expression, thus indirectly limiting syndactyly) |
|
|
Term
| What deficit might cause radial defects (Hold-Oram Syndrome)? What about small patella syndrome? |
|
Definition
radial- Tbx5 (forelimb)
patella- Tbx4 (hindlimb) |
|
|
Term
| What types of defects are associated with VACTERL and what signalling molecule is most associated with these. |
|
Definition
Vertebral (spina bifida, abnormal vertebra)
Anorectal (fistula with urinary and intestinal tracts- poop goes out with pee)
Cardiovascular (abnormal septa and outflow tract)
TEF and EA
Renal Dysplasia
Limb Defects (radial deficiencies and polydactyly
Shh signaling!!! |
|
|
Term
| Which VACTERL association cosegregate (i.e. associate)? |
|
Definition
Gut (ATE)
Limb and foregut (LTE)
Vertebral and gut (VA and VTE) |
|
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Term
| A patient presents with both polydactaly and TE (deficits associated with VACTERL). Knowing which signaling molecule is usually involved in this condition, which effector genes should you design primers for in your mutational analysis? |
|
Definition
Gli3 and Fox genes.
Remember, Shh is linked to VACTERL.
Gli3 is associated with polydactyly
Fox genes are associated with both TEF and EA |
|
|
Term
| A patient presents with vertebral deficits associated with VACTERL. What gene would you analyze and why? |
|
Definition
Shh!!
Shh is expressed in the notochord. Remember, the notochord is located adjacent to the schlerotome cells, which enable vertebral cartilage differentiation.
Shh also induces myogenic differentiation in the myogenic somite, as well as patterning of cells within the ventral neural tube such as motor neurons. |
|
|
Term
| A patient presents with anal-urogenital fistula . What gene would you analyze and why? |
|
Definition
This is VACTERL, so think Shh!!
Shh is expressed in the cranial and caudal ends of the primitive gut tube, where it influences Hox distribution in the visceral mesoderm. Importantly, Shh enables the loss of the cloacal membrane, therebye ensuring that the anoretal and urogenital canals separate properly. |
|
|
Term
| A newborn presents with hand-foot-genital syndrome. What gene would you analyze and why? |
|
Definition
| Hox genes are important for limb and genital development. They are expressed in a restricted fashion in the developing uterus and oviduct (intermediate mesoderm), and are critical for cell patterning. |
|
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Term
| A pregnant patient comes into your office and you discover that she has been exposed to the enviornmental estrogen, DES. After running some tests, you notice that the boundary b/w the uterus and oviduct has been lost and she has a malformed cervix. How might DES be responsible for this? |
|
Definition
| DES represses Wnt7a expression, which normally maintains Hox expression in the developing reproductive tract. Thus, a change in Hox expression caused these changes. |
|
|
Term
| If aborted on the 10th day post-fertilization, which layers of tissue will be prsent in the embryo? |
|
Definition
| epiblast and hypoblast, sandwhiched b/w the amnion and the yolk sac, within the chorion. Gastrulation starts at week 3. |
|
|
Term
| At which two membranes does the ecterm directly contact the endoderm? What is the significance of these junctions? |
|
Definition
| Oropharyngeal membrane (future oral cavity) and Cloacal membrane (future anal canal) |
|
|
Term
| Why would adisruption of internalization and fusion of the midline ectoderm at 3 weeks post-fertilization be so drastic? |
|
Definition
| This is the initial formation of the neural plate, which will utimately becomet he neural tube and then the brain/spinal chord. |
|
|
Term
| Which three structures emerge from the somites int the trunk mesoderm? |
|
Definition
| Vertebra (schlerotome), Skeletal muscle (myotome), dermal connective tissue of back (dermatome). |
|
|
Term
| Upon examination of a three-week-old embryo, you notice that the parietal and visceral layers of lateral mesoderm are in direct contact. What is wrong and what consequence might this have? |
|
Definition
| The coelomic cavity is missing! This is the precursor for the body cavities (it open into the chorion in development). This embryo would not be viable. |
|
|
Term
| The coelomic cavity is horseshoe-shaped, and makes contact with which two structures? |
|
Definition
Cardiogenic mesoderm (cranially)
Septum transversum- future diaphragm and liver (caudally) |
|
|
Term
| The embryonic endoderm is "tucked" in the interior embryo as a result of ______? |
|
Definition
lateral folding
The embryo bulges up off of the yolk sack, and its sides fold in. |
|
|
Term
| You notice in a 3-week-old embryo that the coelomic cavity, cardiogenic mesoderm and septum transversum are not beneath the neural tube, and you are worried that the primary heart tube will not be able to form. What might be happening |
|
Definition
| Cranial folding is disrupted, and even though lateral folding could, in theory, bring the two cardiogenic tubes together to form the primary heart tube, the tubes are incorrectly located for this to occur! |
|
|
Term
| How is the alantosis brough geneath the embryo during early development? |
|
Definition
| Caudal embryonic folding. |
|
|
Term
| True or False: The heart outflow tract develops from the trunk neural crest cells arising from the dorsal aspect of the neural tube. |
|
Definition
False!
The heart outflow tract and cartilage/bone of the face and jaw arise from the cranial neural crest cells.
The chromaffin cells of the adrenal glands arise from the trunk crest cells.
Pigment cells and peripheral nerve ganglia arise frmo both. |
|
|
Term
| The pleural and peritoneal cavities are separated in development the the development of which structures? |
|
Definition
The pleuroperitoneal folds.
These mesodermal folds are also responsible for closing the pericardioperitoneal canals, which lie above the septum transversum and developing heart and connect the cranial and caudal coelomic cavities |
|
|
Term
| The cranial coelomic cavity is a precursor to which cavities |
|
Definition
| the pericardial and pleural |
|
|
Term
| The diaphram develops from the cranial coelomic cavity, arising from the _________ folds and __________. |
|
Definition
| pleuroperitoneal folds and septum transversum |
|
|
Term
| Folding leads to the internalization of endoderm tissue as a gut tube. Abnormal development of the region that lies beneath the brain and above the heart might cause the following issue. |
|
Definition
| This where the oropharyngeal membrane is! This issue might lead to a deformed oral cavity, since the membrane might break down incorrectly. |
|
|
Term
Which organs originate via budding off the primitive gut tube?
Which organ develop as expanded regions of the original gut tube? |
|
Definition
trachea, lungs and liver are budding
stomach and intestines are expanded regions of the foregut and midgut, respectively. Bladder is hindgut expansion |
|
|
Term
| You might have an issue with the development of visceral organs if the development of either of which two types of tissue was disrupted? |
|
Definition
Endoderm (inner epithelial lining)
Visceral Mesoderm (smooth muscle and connective tissue)
REMEMBER, ectodermal neural crest cells are responsible for innervation of visceral organs, so you really get contribution from all three |
|
|
Term
| True or False: Muscle innervation patterns often reflect adult muscle position, rather then embryonic muscle position. |
|
Definition
FALSE!
as muscle cell precursors leave the somite, they bring motor axons from each axial level of the spinal cord with them. Example is innervation of the diaphragm by the phrenic nerve (this is established when diaphram is in cervical position). |
|
|
Term
| A failure of cranial neuropore closure is associated with which condition? How common is it? |
|
Definition
| Anencephaly- degeneration of brain and lack of top of skull (1:1000- common) |
|
|
Term
| Failure of vertebral spine formation +/- neural tube issues are associated with which condition? How common is it? How can you test for it? |
|
Definition
Spina bifida- 1/1000-common
Can test for neural tube defects with amniocentisis after 16 weeks. |
|
|
Term
| A deficiency in ventral body wall tissue and failure of closure of the ventral body wall is associated with which developmental condition? How common is it? |
|
Definition
| Gastroschisis- Viscera and heart may be exposed, depending upon where deficiency is. 1/10,000- rare! |
|
|
Term
| You notice upon birth, that a newborn child's viscera have herniated into the thoracic cavity and they are impinging upon proper lung development. What condition is this and how common is it? |
|
Definition
| Diaphragmatic hernia- pericardioperitoneal canal remains open do to defect in pleuroperitoneal membranes. 1/2000, common) |
|
|
Term
| What were the primary goals of the human genome project? |
|
Definition
1) Sequence the entire human genome
2) Identify every gene (25,000)
3) Private sector and ethical issues
4) Comparative genomics |
|
|
Term
| What did the human genome project tell us? |
|
Definition
1) 3000 bases per gene
2) about 30,000 genes
3) much variation in human proteins comes from alternate splicing
4) 90 of human variation (0.09%) results from SNPs |
|
|
Term
| What is the HAPMap and what does it describe? |
|
Definition
Maps haplotypes in different racial groups and attempts to connect them to disease patterns ("tagged SNPs" are 1 every 6-7 SNPs)
It describes the variation that occurs, where it occurs, and its distribution among populations |
|
|
Term
| What is Mende's 1st Law of Segregation? |
|
Definition
Posits random combination of gametes at fertilization in a monohybrid cross (half gametes have 1 allele, half have the other).
Predicts 3:1, dominant to recessive relationship |
|
|
Term
| What is Mendel's second law of Independent Assortment? |
|
Definition
Genes for different traits assort independently in the formation of gametes- predicts 9:3:3:1 ratio.
Violated by linked genes or genes on the same chromosome. |
|
|
Term
| If the affected gene in a genetic disorder is a structural protein, what type of disorder would you predict it to be? |
|
Definition
Autosomal Dominant- Unaffected people have normal children
Examples include Marfan Syndrome (Fibrullin 1), Achondroplasia (gain of function), retinitis pigmentosa |
|
|
Term
| If the affected protein in a genetic disorder is an enzyme, what type of disorder would you predict it to be. |
|
Definition
Autosomal recessive, most likely.
Examples include Sickle-Cell Anemia (glycine to valine in Hb), Cystic Fibrosis (CFTR) and PKU (Phe hydroxylase) |
|
|
Term
| What kind of genetic disease presents with severely affected males and mildly-symptomatic females? |
|
Definition
| X-linked recessive- since female carriers may be mildly symptomatic due to unequal x-innactivation (lyonism) |
|
|
Term
| In a disorder where males pass on the abnormal trait to all of their daughters, what percentage of male children will have the disease? |
|
Definition
| 0%! This is an x-linked dominant disorder, in which fathers cannot pass on the disease gene to their sons. |
|
|
Term
| What type of disorder is passed on from an affected mother to all of her children? |
|
Definition
Mitochondrial. Men cannot pass it on
Ex) Leber's Hereditary Optic Neuropathy. |
|
|
Term
| Cis-acting elements and activator or repressor proteins are examples of which type of genetic control? |
|
Definition
transcriptional!
Other examples include alternate promotors for alternate isoforms and histone modifications. |
|
|
Term
| A patient comes into your office with a deficit in HSP 90. Why might you be concerned (i.e. what signaling cascade would be altered and how?)? |
|
Definition
Transcriptional control by glucocorticoids would be altered.
Usually, upon glucocorticoid entry into the cell, HSP90 releases glucocorticoid receptors, which then dimerize, enter the nucleus and effect target transcriptional genes. |
|
|
Term
| How might a mutation in the gene that encodes the IkB kinase influence transcriptional control? |
|
Definition
It could muck of NFkB-senstive genes!
Remember, TNF binds to its membrane receptor leading to IKKK phosphorylation, which in turns phosphorylates IkB-kinase. This marks IkB for ubiquitinylation, and releases NFkB to enter the nucleus. |
|
|
Term
| What type of transcriptional control is the dystrophin gene an example of? |
|
Definition
| Alternate promotors giving rise to tissue and cell-specific gene expression. |
|
|
Term
| How is it determined whether antibodies become membrane-bound molecules or secreted signaling molecules? |
|
Definition
Post-translational poly-A addition.
To product the long-transcript, which encodes the membrane-bound antibody, RNA is cleaved near its 3' end.
Alternatively, in stimulated B-cells, to produce the short-transcript, which encodes the secreted antibody form, RNA is cleaved upstream of the splice site, leaving an additional portion of intron that encodes the hydrophilic C-terminal tail needed for secretion. |
|
|
Term
| What type of control is alpha-tropomyosin variation an example of? |
|
Definition
| Post-transcriptional control by alternate splicing. Different isoforms are targeted for fibroblasts, brain cels, smooth muscle cells, ect. |
|
|
Term
| How and why is Ferretin production limited in the presence of IRE-BP? |
|
Definition
| The binding of IRE-BP to the 5' UTS of the Ferritin H-Chain mRNA signals an absence of iron and prevents mRNA entry at the ribosome. This makes sense since Ferretin is an iron transport protein. |
|
|
Term
| How and why is Transferrin production upregulated in the presence of IRE-BP? |
|
Definition
| Control of mRNA stability! IRE-BP signals the absence of iron and binds to the mRNA to protect it from degradation. This makes sense, since Transferrin is responsible for getting more iron into the cell. |
|
|
Term
| What type of molecules are required for RNA editing and provide an example of the process. |
|
Definition
RNA-dependent deaminases.
In ApoB, cytosine deaminase replaces a C with a U, generating a stop codon, and producing a smaller product. |
|
|
Term
| How might a mutation in a noncoding region of DNA or a mutation in the introns of protein coding genes lead to abnormal gene expression? |
|
Definition
Regulatory RNAs such as miRNAs are produced in these regions.
Remember, miRNAs are synthesized in the nucleus and cleaved by RNAase Drosha into pre-RNAs, which enter the cytoplasm and are processed into small duplexes of 22nt by RNAse III Dicer. One strand of miRNA is incorporated in the RISC complex, and guide the complex to their complementary regions in the 3' UTR of target mRNAs. In this way, miRNAs regulate gene expression. |
|
|
Term
| What are three cellular processes regulated by RNAi? |
|
Definition
1) The degradation of RNA virus mRNAs
2) Post-translational control of protein synthesis
3) Research for targeted gene-knockdowns.
Remember, miRNAs block translation at the ribosome and degrade mRNA transcripts (only for best antisense-sense matching) |
|
|
Term
| True or False: methylating a cytosine residue in a CpG island of a maternal gene would lead to maternal imprinting? |
|
Definition
True!
In maternal imprinting, the paternal allele is expressed. Methylation at CpG islands inhibits the expression of those alleles, so in this case, the maternal gene would be repressed. |
|
|
Term
| True or False: When methylated DNA replicates, the newly synthesized strands must be re-methylated? |
|
Definition
True!
The new strand will use the methylated strand as a template and DNA methytransferases will methylate it. |
|
|
Term
| What is the connection b/w Prader-Willi and Angelman Syndromes, and genomic imprinting? |
|
Definition
These syndromes involve male- and female-specific imprinting at imprinting centers. Remember, this type of imprinting is achieved in the germ line, where imprinting patterns from fathers and mothers are erased and re-established in the following generation.
Both PWS and AS involve obesity, small hand and small feet. PWS is caused by a lack of paternal genes or maternal dissomy. AS is caused by a lack of maternal genes or paternal dissomy. |
|
|
Term
| Would a mutation in a histone de-acetylase enzyme lead to gene repression or activation? |
|
Definition
| Deacetylation leads to chromatin condensation and gene repression. Alternatively, acetylation opens up the chromatin and enables gene expression |
|
|
Term
| How is it that in limb girdle muscular distrophy, there is a disease phenotype despite an amino acid position being changed from G to another codon for G? |
|
Definition
| Activation of a cryptic slice donor sequence, resulting in aberrant splicing with loss of coding sequence and the introduction of a frame-shift. |
|
|
Term
| Thymine dimers can be induced by UV-radiation. What type of DNA repair fixes this and how does it work? |
|
Definition
Nucleotide excision repair (NER)
Proteins recognize and remove small region containing damage (nuclease-helicase-Poli-ligase)
Poli delta and epsilon repair the region and ligase seals it.
For pyrimidine dimers not removed in this pathway, Poli eta and zeta can do the job, but zeta is error-prone! |
|
|
Term
| Sometimes methylated cytosines in CpG islands can spontaneously deaminate to form T, causing a base-pair mismatch. What DNA repair pathway deals with this and how does it do it? |
|
Definition
Base excision repair
DNA glycosylase removes deaminated cytosine
Sugar-P with missing base is cut out with AP endonuclease and phosphodiesterase
Poli and ligase fill in and seal gap. |
|
|
Term
| A mutation in either the mutS or mutL genes would disrupt which DNA repair pathway? |
|
Definition
Methy-directed mismatch
mutS (mismatch recognition)
mutL (complex formation)
These deficits could give rise to sporadic colon tumors |
|
|
Term
| What is common about Huntington's Disease, Fragile X and Myotonic dystrophy? How do these diseases most likely arise? |
|
Definition
They are all Trinucleotide expansion conditions.
They often arise from replication slippage leading to tandem-repeat expansion.
Remember, these repeats are located in noncoding regions and introns as well as coding regions of exons! |
|
|
Term
| Which type of dsDNA break-repair do you see in S-phase of the cell cycle and why? |
|
Definition
HEJ. In S-phase, chromosomes are close together physically, making it easier to copy the second, normal chromosome.
Remember, BRCA1 and BRCA2 are involved in dsDNA repair and are implicated in breast cancer! |
|
|
Term
| True or False: Proteins begin folding once they are fully translated in the ribosome. |
|
Definition
FALSE!
They start folding as they begin to be synthesized, making use of ATP-dependent chaperones such as hsp70 |
|
|
Term
| True:False ADP-bound hsp70 has a high affinity for molten globule proteins. |
|
Definition
True.
Remember, hsp70 action is regulated by the ATP cycle. When ADP is made into ATP, hsp70 releases folded proteins |
|
|
Term
| A deletion in the 19s cap of the cytoplasmic proteosome would cause the following issue? |
|
Definition
19s cap controls entry of proteins tagged for degredation and utilizes ATP energy to unfold proteins delivered to the 20s core.
Remember, the 20s core actually proteolizes the proteins |
|
|
Term
| Why would a defect in the ubiquitin-conjugating enzyme (E2) cause issues? |
|
Definition
In addition to the U-activating (E1) and U-ligase (E3), this enzyme is responsible for ubiquitinylation of proteins for degredation.
Remember, polyubiquitinylation is critical for delivery to the proteosome. E3 recognizes the "degradation signal" in the target protein, and transfers Ubiquitin to the target protein via a covalent bond to a specific lysine residue.
There are many E3s, a few E2s, and few E1s |
|
|
Term
| Mutations in short tandem repeats of 1-3 nucleotides encompassing approximately 10-100 nucleotides would likely have what physiological consequence? |
|
Definition
These are microsatellite regions.
Expansions of these regions can cause replication slippage and lead to errors in production production. |
|
|
Term
| Mutations in tandem repeats of approximately 9-36 bases, encompassing several hundred nucleotides could have what physiological consequence? |
|
Definition
There are minisatellite poymorphisms.
Located primarily in telomeres, these mutations can effect the protection of DNA ends during replication. |
|
|
Term
| How might CNVs alter disease susceptibility? |
|
Definition
| Remember, 3000 genes contain CNVs. If these genes are dose-sensitive, then too many or too few copies could cause cancer or disease. |
|
|
Term
| What is the only type of structural chromosomal variation that cannot be detected by CGH? |
|
Definition
Inversions!
These don't alter the structure of the chromosomes directly, like insertions/deletions/translocations |
|
|
Term
| A mutation of over 5-170 nucleotides over an array >100kb would most likely cause what physiological consequence? |
|
Definition
There are satellite repeats.
They are in centromeres, and therefore might alter cell-cycle regulation. |
|
|
Term
| True or False: LINES move autonomously within the genome using a reverse transcriptase and endonuclease, mediating exon shuffling |
|
Definition
True
SINES (such as Alu) also jump around, but require neighboring LINES for mobilization |
|
|
Term
| True:False In Sickle-Cell Anemia, a missense mutation in Globin-B leads to decreased production of beta globin. |
|
Definition
False!
Remember, reduced production is beta-thalasemia. In Sickle cell, the G6V missense mutation decreases the solubility of the deoxygenated hemoglobin molecule, and under stressful conditions leads to crystallization and accumulation of these sickled red blood cells in vessels causing
Ischemia
reduced elasticity
cell membrane damage
pain |
|
|
Term
| How is the HbS variant from sickle-cell protective against falciporn malaria? |
|
Definition
| The life cycle of Sickle cells is only 10-20 days. This is what causes anemia (so much loss of iron). However, they are also more susceptible to falciporm infection, where they loss potassium, sequester and kill the parasites. |
|
|
Term
| Which organ systems are most susceptible to injury in sickle-cell? |
|
Definition
| Brain, Spleen, Lungs, Kidneys- All because of vascular occlusion |
|
|
Term
| What is the term for a transient disappearance of erythroblasts from the bone marrow of affected sick-cell patients? |
|
Definition
acute aplastic crisis.
Remember, an acute anemic crisis is marked by increases in RBC lysis. |
|
|
Term
| How does hydroxy urea work as a treatment for Sickle-Cell? |
|
Definition
| It keeps fetal Hb levels (gamma) up by acting on the locus control center on chromosome 11. Fetal Hb does not polymerize! |
|
|
Term
| How is NO used as a treatment for sickle-cell disease? |
|
Definition
| Its a vasodilator and it seems to be especially low in sickle-cell. There are promising options for supplementation with L-arginine (its synthetic precursor) |
|
|
Term
| How is Marfan syndrome an example of allelic heterogeneity, variable expressivity and new mutations? |
|
Definition
| The mutation in the FBN1 gene can be at various locations in the gene (AH), can cause different symptoms (VE) and can arise from new mutations in the gene that were previously unseen (NM). |
|
|
Term
| What type of issues can mutations in the Fibrillin 1 gene cause |
|
Definition
Marfans!
It is a glycoprotein that is deposited in the ECM, where it makes microfibrils that can sequester certain growth factors, preventing them from become activated prematurely. |
|
|
Term
| How is Marfan syndrome diagnosis determined? |
|
Definition
If no mutation or familial contribution, need at least 2 major organ system contributions and a third involved.
If there is a mutation or family history, you need one major organ system criterion and a second involved. |
|
|
Term
| Explain how Huntington's disease is an example of a autosomal dominant disease with "anticipation." |
|
Definition
The CAG trinucleotide repeat expansion in exon 1 of the HD gene encodes a polyglutamine tract (these tracts are unstable during meiosis and are most frequency expanded through paternal transmission).
27-35 repeats: individual unaffected, but can pass on
36-39: reduced penetrance
40-55: adult onset
>55: juvenile onset |
|
|
Term
| What physical manifestations of Huntington's disease might you notice, even before running lab tests? |
|
Definition
Cognitive Disturbances
Psychiatric Disturbances
Motor function issues |
|
|
Term
| What genetic principle is exhibited by the black and orange spots on certain cats? |
|
Definition
Mosaic X Inactivation.
In certain cells, the black genes are epigentically silenced, while in others, the orange ones are. |
|
|
Term
| How does an X Inactivation center work ? |
|
Definition
An X inactivation specific transcript is silent on the active X chromosome, but is transcribes into a nuclear, noncoding RNA within the Barr body of the silent X-chromosome.
Remember, some genes can escape, and balanced translocations can cause some male traits to be found in females |
|
|
Term
| Why are pseudoautosomal regions important for X chromosomes |
|
Definition
| It needs to pair with the Y chromosome even though they are not homologous. It has one on the p arm and on the q arm |
|
|
Term
| What important gene is on the Yp chromosome. What about Yq? |
|
Definition
Yp= Testis determining factor (SRY) (DNA-binding transcription factor) located near the pseudoautosomal boundary. It is normally deleted in females.
Yq- Spermatogenesis gene. You can check for azospermia in this gene with FISH. |
|
|
Term
| How can you have 46, XX males? 46, XY females? |
|
Definition
46, XX males can arise because the SRY gene from the Y chromosomes is translocated on the X Chromosome (problem in meiotic recombination). These individuals are sterille, with pseudohermaphrodites.
46, XY females occur because of Yp deletion in SRY. Increased rate of gonadoblastoma and need HRT to induce 2ndary sex characteristics. |
|
|
Term
| A patient presents with a chromosomal abnormality. You determine it to be 45, X. What abnormality is this, how can it arise, and what features are associated? |
|
Definition
Turner Syndrome
Non disjunction
98% abort, Xp- short, Xq- sterile
Can be mosaic (i.e. 45, X/46, XY) |
|
|
Term
| A patient presents with a chromosomal abnormality. You determine it to be 47,XXX. What abnormality is this, how can it arise, and what features are associated? |
|
Definition
Arise from NDJ
Phenotypically normal females
Tall with mild development disabilities
Fertile |
|
|
Term
| A patient presents with a chromosomal abnormality. You determine it to be 47,XYY. What abnormality is this, how can it arise, and what features are associated? |
|
Definition
Arise from NDJ
Tall Males
Only issue is behavioral problems |
|
|
Term
| A patient presents with a chromosomal abnormality. You determine it to be 47, XXY. What abnormality is this, how can it arise, and what features are associated? |
|
Definition
Klinefelter
NJD
Tall with small testes
Infertile and 15% mosaic |
|
|
Term
| How is Down Syndrome an example of a "gene dosage" effect? |
|
Definition
| Trisomy 21 (1:700 individuals) involves 3 copies of genes, and thus has 50% more effect of the genes. |
|
|
Term
| What are the three ways by which Down syndrome can occur? |
|
Definition
1) Nondisjunction (most common)- newly formed egg or sperm has 24 chromosomes instead of 23
2) Translocation (3-4% of cases)- All or part of chrom 21 is attached to another chromosome! Can be diagnosed with a karyotype. Can have an Inherited risk (as opposed to NDJ)
3) Mosaicism (1-2% of the time. Extra copy in some cells but not others. This can arise because a one germ line drops off the extra copy of chromosome 21, or if one half of cells have a duplication event. Difficult to diagnose, but you can try by taking biopsies from skin and then bone marrow. These individuals generally have less severe phenotypes |
|
|
Term
| What are the healthcare guidelines for GI, Respiratory, Eyes, Neurological, Dental, Endocrine, Hematologic, Musculoskeletal and Immunological interventions in Down Syndrome? |
|
Definition
GI- Consider obstructures
Respiratory- RSV immunization, car seat, hearing screen every 6m to 4 yeras
Eyes- check red reflex, nystagmus, myopia
Neurological- Infantile spasms can indicate regression
Dental- Tooth brush ALOT
Endocrine- Thyroid screen and GH deficiency screen
Hematologic- Anual blood draws
Musculoskeletal- Spinal chord compression, hypotonia, plagiocephaly
Immunological- Diminished response or autoimmune (celiac) |
|
|
Term
| What are the 4 epidemiologic features of complex genetic disorders? |
|
Definition
Heritability
Non-Mendelian Inheritance
Chronic and of later onset, appearing to be acquired
Monogenic or syndromic forms have earlier onset. |
|
|
Term
| What are two drawbacks of using the candidate-gene approach to screening for complex genetic conditions? |
|
Definition
1) may not know the pathophysiology well enough to be aware of plausable options
2) Function of much of genome is not well characterized |
|
|
Term
| Why can mutations in the Nkx2.5 gene cause congenital heart disease? |
|
Definition
Nkx2.5 (in addition to Gata proteins) is a transcription factor expressed in the primary heart tube that is critical for cardiac development. In combination with Tbx5, these factors lead to chamber-specific features.
Its expression is initiated by BMPs from the endogermal layer and restricted to the lateral mesoderm by Chordin and Noggin from the notochord and by Wnts from the neural plate. |
|
|
Term
| If there is excess RA in the primary heart tube , what malformation might you be worried about? |
|
Definition
| RA defines AP heart regions. Excess RA creates malformations in the outflow tract (truncus arteriosis-aortic sac) and expansions in the inflow tract (two-horned sino-atrium) |
|
|
Term
| True: False During primary heart tube development, heart tube looping causes the outflow tract (Aortic Sac) to lie behind and above the inflow tract (sinoatrium). |
|
Definition
FALSE!
the inflow tract comes to lie behind and above the inflow tract |
|
|
Term
| In the developing heart tube, blood flows in via which three veins? |
|
Definition
1) Paired cardinal veins from the embryonic body
2) Paired vittelline veins from the yolk sac
3) Paired Umbillical veins from the chorion |
|
|
Term
| In the developing heart tube, blood flows out via which three vessels? |
|
Definition
1) Paired aortic arches curving around foregut
2) Paired dorsal aorta to different embryonic regions
3) Paired vitelline and umbilical arteries to the yolk sac and chorion. |
|
|
Term
| The dorsal mesocardium serves as an avenue of entry for pharyngeal mesoderm cells that secondarily contribute cardiac progenitors. Which cardiac aspects use these cells? |
|
Definition
1) Base of aorta and pulmonary trunks (outflow tract)- defects lead to conotruncal defects
2) Right atrial (inflow) and ventrical regions |
|
|
Term
| What issues would an embryo have if it were lacking Isl1? |
|
Definition
| Isl1 (along with Tbx1 and Fgf10) are critical for second heart field cell differentiation. Isl1, in particular, is also a marker fro cardiac stem cell populations in later developmental stages. |
|
|
Term
| How is Tbx1 related to Shh? |
|
Definition
Tbx1 is a transcription factor important for second heart field stem cell differentiation. It regulates Fgfs, and is regualted by Shh and RA.
Remember, Tbx1 also influences cranial neural crest development, which in turn promotes second heart field cell proliferation by regulating FGFs. |
|
|
Term
| Why (developmentally) does blood from the placenta and body only flow in to the right atrium. |
|
Definition
Venous blood initially enters through both the right and left sinus horns, but the right horn expands and becomes the SVC an IVC as it is incorporated into the wall of the right atrium. It becomes the sinus venarium (separated from rough part by crista terminalis)
The left horn ultimately becomes the coronary sinus |
|
|
Term
| When in development does heart septation take place? |
|
Definition
| In the second month of development |
|
|
Term
| What step in the septation of the primitive atrium and AV canal is Shh-dependent? |
|
Definition
The formation of the Septum Primum cap from dorsal mesocardium (spina vestibuli)
Remember, septation involves:
Operation Space Ostrich Ssends FOxes Many Times
1) ostium primum
2) septum primum
3) ostium secundum (new openings in septum primum)
4) Septum secondum (overlaps with primum)
5) Foramen ovale (bypass pulm circulation)
6) Tricuspid and Mitral Valve formation |
|
|
Term
| What is a concern if the septum primum and septum secundum don't fuse after birth? |
|
Definition
|
|
Term
| What is it referred to when there is a large hole in the center of the heart because the endocardial cushions fail to grow or fuse? |
|
Definition
| Common or Persistent AV canal |
|
|
Term
| What do the conal cushions become in the developing heart at approximately 5-6 weeks? |
|
Definition
Right: Conus arteriosus
Left: Aortic vestibule |
|
|
Term
| What do the tuncal cushions become in the developing heart 5-6 weeks into development? |
|
Definition
Divide outflow tract into aortic and pulmonary trunks
Aside- aorticopulmonary septum gives rise to cranial neural rest cells that form the truncal cushions |
|
|
Term
| What happens in a persistent truncus arteriosus? |
|
Definition
| The aortic and pulmonary trunks dont separate because of failed cushion formation or neural crest abnormalities. |
|
|
Term
| What are the four components of tetralogy of fallot? How does it arise? |
|
Definition
1) pumlonary stenois
2) overriding aorta
3) VSD
4) Hypertropy of right ventricle
Misalignment of aorticopulmonary septum (pulm outflow is too small, aortic outflow is too bigl) |
|
|
Term
| How does oxygenated blood from the placenta bypass the liver and pass directly into the right atrium of the embryonic heart via the IVC? How does it bypass the pulmonary system? |
|
Definition
1) Umbilical vein
2) Foramen ovale and ductus arteriosus shunt. |
|
|
Term
| Why might a patient present with coincident atrial-septal defects, conduction defects and limb abnormalities? |
|
Definition
| Hold-Oram Syndrome with TBX5 mutation (primary heart field, craniofacial and limb) |
|
|
Term
| Why might a patient present with heart outflow tract abnormalities as well as craniofacial defects? |
|
Definition
DiGeorge Syndrome with TBX1 mutations (important for cranial neural crest contributions to heart and craniofacial structures).
Important for second heart field, while TBX5 is primary heart tube! |
|
|
Term
| What factor is responsible for TBX5 expression. What other roles does it play? |
|
Definition
| RA induces TBX5 expression and limb bud induction, as well as heart looping and forebrain neuron development. Also, RA is important for neural crest development. |
|
|
Term
| What is the role of Shh in the development of the heart. What about the limb? Neural development? |
|
Definition
Critical for pharyngeal mesoderm and cranial neural crest population development that contribute to the heart.
Also, mesenchymal cell proliferation and AP patterning in the limb, and neural tube patterning. |
|
|
Term
| Which branchial arch does the maxillary prominence and mandibular prominence arise from? |
|
Definition
1st branchial arch. The largest!
Remember, above it is the frontonasal prominence, which which is the tissue that covers the forebrain (ultimately innervated by the opthalmic division of CN V) |
|
|
Term
| What condition can arise if superficial portions of the medial nasal and maxillary prominences do not fuse appropriately? |
|
Definition
|
|
Term
| What gross anatomical regions are likely to be most affected by something that affects neural crest development? |
|
Definition
Head and Neck
ex) Neural crest cells that populate 1st branchial arch give rise to middle ear bones, maxillary and mandibular bones and cartilages of the external ear.
ex2) Neural crest cells that populate the frontonasal region contribute to nasal orbit and frontal bones. |
|
|
Term
| What 4 components is the skull derived from? |
|
Definition
1) Skull Base- cartilages anterior to notochord ultimately replaced by bone (endochondral ossification)
2) Skull roof- flattened plates of bones that form via intramembranous ossification
3) Viscerocranian- feeding structures/ bones from intramembranously and endochonrallly ossified bones from neural crest mesenchyme
4) Occipital regin- schlerotome cells of occipital somites |
|
|
Term
| The stylopharyngeus muscle is innervated by the fascial nerve. Which branchial arch does this muscle arise from and what skeletal derivative arises from neural crest cells? |
|
Definition
|
|
Term
| If you had a congenital malformation of structures arising from the 1st pharyngeal pouch, which structures would be affected? 2nd? 3rd? 4th? |
|
Definition
1st- tympanic membrane and auditory tubes
2nd- palatine tonsils
3rd- thymus and inferior parathyroid glands
4th- superior parathyroid glands
Remember, the pharyngeal pouches are endodermal outpocketings of the foregut that are surrounded cranially and caudally by branchial arch tissue at 4-5 weeks of development (see syllabus pg 285) |
|
|
Term
| Provide an embryonic explanation for why the taste bunds of the anterior 2/3 of the tounge are innervated by the facial nerve, while the posterior 1/3 taste buds are innervated by the glossopharyngeal nerve. |
|
Definition
They arise from different precursor tissues!
Anterior 2/3 is derived from stomodeum ectoderm (mouth and anterior oral cavity), while the posterior 1/3 arises from the pharyngeal endoderm |
|
|
Term
| What is common about the connective tissue that makes up thymus, thyroid gland, the tongue, melanocytes and the meninges? |
|
Definition
| They are all derived from the cranial neural crest cells |
|
|
Term
| Which three structures ultimately arise from the invagination of the ectodermal placodes? |
|
Definition
1) Lens
2) Inner Ear
3) Nasal Epithelium
Remember, these placodes are thickened areas of surface cranial ectoderm (see page 281 of syllabus). They also give rise to cranial nerve ganglia |
|
|
Term
| During the formation of the head ad neck, tissue prominence move in a ______ and ________ medial direction |
|
Definition
| Ventral and Medial (important concept on page 283) |
|
|
Term
| Each branchial arch in the developing embryo consists of mesenchymal tissue containing both neural crest and head mesoderm. What structures arise from each of these tissue types? |
|
Definition
Neural Crest- unique set of cartilages- parts of the viscerocranium
Head Mesoderm- unique set of muscles
Discussed on pg 284 |
|
|
Term
| What effect could malformed prechordal mesodermal cells have on a developing embryo? |
|
Definition
These cells promote early forebrain development (prosencephalon) from the anterior neural plate.
Malformed cells would probably lead to abnormal forebrain development
see pg 286 |
|
|
Term
| What effect would a lack of Shh have on normal neural development? |
|
Definition
1) Expressed in prechordal mesoderm and ventral forebrain- essential to forebrain tissue
2) Expressed by cranial surface ectoderm and required for 1st branchial arch development. |
|
|
Term
| What do FGFs do in the developing forebrain and face? |
|
Definition
FGFs control outgrowth and specification of the forebrain.
FGFs influence the migration and proliferation of neural crest in branchial arch mesenchyme
pg 286 Syllabus |
|
|
Term
| What is the importance of RA in early forebrain and frontonasal regions? |
|
Definition
It regulates FF and Shh expression, thereby modulating the proliferation of forebrain cells. It also may play a role in neural cell differentiation and the survival of head mesenchyme.
pg 287 |
|
|
Term
| True or False: Hox genes are expressed in branchial arches 1-4. |
|
Definition
False!
Hox genes are expressed in 2-4 and are imortant in defining skeletal elements within each arch (ex. upper hyoid in arch 2 and lower hyoid in arch 3)
pg 287 syllabus |
|
|
Term
| What effects might a deletion of TGFB3 have on palatal development? |
|
Definition
Anterior cleft palate- The palatal shelves would not fuse with the premaxilla.
Posterior cleft palate- the two palatine shelves would not fuse
TGFB3 orchestrates the fusion of the palatal cells by promoting epithelia-to-mesenchymal transition of seam cells.
Aside- These conditions could also arise from a disruption in forebrain induction resulting in a small frontonasal prominence or from a deficiency in neural crest cell populations. A deficiency in neural crest cells could also cause he lower jaw to develop insufficiently, not allowing the tongue to protrude forward normally.
pg 289. |
|
|
Term
| A child presents with hypoplasia, malformed external ears, cleft palate and lower eyelid defects. You suspect Treacher Collins Syndrome. How does this condition arise? |
|
Definition
Defects in neural crest cells that contribute to the 1st branchial arch derivatives, probably due to a mutation in the TCOF1 gene that encodes the Treacle protein.
pg290 |
|
|
Term
| A small child is born with pumlmonary stenosis, overriding aorta, VSD and hypertrophy of the right ventricle. You also note cleft palate, hypoplasia of the thymus and facial dysmorphia. What condition is this and how might it have arisen? |
|
Definition
Digeorge's/Velocardiofacial syndrome (DGS/VCFS).
Most patient's with this syndrome have micro deletions of 22q11 and it is believed to be caused by haploinsuffiency of related genes. Most of these deletions include TBX1 (expressed in pharyngeal endoderm, branchial core mesoderm, second heart field cells and head mesenchyme).
While the Tetralogy of Fallot and other affected tissues receive contributions from the neural crest, TBX1 is not expressed in these cells, suggesting a complex, intergenic relationship. |
|
|
Term
| A baby presents with a single eye, a cleft lip and an absent nose. You are very concerned and discover incomplete division of the forebrain into left and right cerebral hemispheres. What condition is this and how might it have arisen? |
|
Definition
Holoprosencephaly
Some patients exhibit point mutations in Shh, which could disrupt prechordal mesoderm function, incorrect induction of cranial neural plate and subsequent deficits in facial structures.
Risk is increased by prenatal exposure to RA and ethanol
pg 291 of syllabus |
|
|
Term
| Why might you be especially concerned if a pregnant woman was drinking a great deal of alcohol? |
|
Definition
Fetal Alcohol Syndrome- Craniofacial defects, VSD/ASD, growth retardation.
Ethanol specifically affects midline structures like the forebrain and it can impair migration of prechordal mesoderm cells (perhaps through decreases in Shh signaling), as well as neural crest cells
pg 292 of syllabus |
|
|
Term
| How does the intake of accutane during pregnancy relate to the development of retinoic acid embryopathy? |
|
Definition
Cranial neural crest cells are particularly sensitive to vitamin A. This is why you see BOTH head and heart abnormalities. RA can inhibit Shh and influence Hox genes as well.
Babies often present with narrow forehead, flat nasal bridge, palate defects and microphthalmia (many others as well).
pg. 293 of syllabus |
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Term
| What structures does the stomodeum give rise to? |
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Definition
| Mouth and anterior oral cavity |
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Term
| Where are nasal cavities derived from? Anterior palate? Posterior palate? |
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Definition
Nasal cavities- ectodermal placodes
Anterior palate- medial nasal process, ultimately giving rise to pre-axilla
Posterior palate-medial aspets of maxillary prominence int he form of lateral palatal shelves (fuse with premaxilla anteriorly, with one another, and with the devloping nasal septum). |
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Term
| Craniofacial surgery is usually avoided early in development, because of the perceived risk of intervening prior to the completion of structural development. What are some reasons why the surgery might be performed early in spite of this? |
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Definition
1) Function concerns such as obstructive sleep apnea
2) Concerns with psychosocial developmental issues |
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Term
| A patient presents with a diagnosable illness and you are trying to determine accurate dosing of medication. What factors should you consider? |
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Definition
1) Age
2) Body weight
3) Organ failure
4) Other drugs being used
5) Drug monitoring
pg 301 in syllabus |
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Term
| What do infantile neuronal ceroid lipofuscinosis, sickle cell anemia and fanconi anemia have in common? |
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Definition
| Candidates for stem-cell therapies |
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Term
| Why is it useful to take companion diagnostic tests before prescribing certain drugs? |
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Definition
These tests will inform you of the patient's potential responsiveness to a certain drug
pg 301 in syllabus |
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Term
| What are 5 sources of variation in patients responsiveness to drugs? |
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Definition
ADEMP
1) Absorption (GI to circulation for oral drugs)
2) Distribution (circulation to target organs)
3) Excretion (kidney)
4) Metabolism (liver)
5) Pharmacodynamics (action on specific target)
pg 302 syllabus |
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Term
| True: False. Phase 1 drug metabolizing enzymes catalyze conjugation reactions such as acetylation, glucuronidation and sulfation |
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Definition
False!
This is a description of phase 2 drug-metabolizing drugs.
Phase 1 drugs catalyze oxidation, reduction and hydrolysis (usually through the cytochrome P450 family)
Remember, both classes act on endogenous circulation molecules in their water-soluble forms(e.g. hormones, vitamins).
pg 302 in syllabus |
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Term
| Why are genetic polymorphisms in the cytochrome P450 family of enzymes (CYP) of clinical concern? |
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Definition
These enzymes are responsible for a large percentage of drug metabolism reactions. People will these polymorphisms can be
1) Ultra-rapid metabolizers (more than 2 copies of CYP2D6). You need to prescribe them more.
2) Extensive metabolizers- normal
3) Intermediate metabolizers- 1/2 normal rate/often due to heterozygosity for a gene variant that produces a protein with little/no enzyme activity.
4) Poor metabolizers- no drug-metabolizing activity, often homozygous or compound heterozygotes. These patients can have adverse drug reactions (ADR) to normal doses
pg 302 syllabus |
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Term
| A patient presents with a frame shift mutation in the CY2D6 gene. When would you be concerned and why? |
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Definition
When prescribing drugs! This enzyme handles 25% of the market, especially anti-depressants, anti-psychotics and beta-blockers.
Aside- This enzyme activates certain drugs like codeine, and inactivates others such as Venlafaxine. |
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Term
| Under what clinical circumstances might you be most concerned for a patient with mutations in the CYP2C9 gene? |
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Definition
Blood clottting!
This enzyme metabolizes the anticoagulant Warfarin (Coumadin). Excess Warfarin causes bleeding!
Diet (vitamin K), gender, and genetic variation all contribute to Warfarin responsiveness
pg 303 |
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Term
1) Why are mild deficiencies of UDP-Glucouronosyltransferase 11 (UGT1A1) of relatively little concern, but severe deficiencies of very dangerous?
2) What type of therapy should be avoided with such a deficiency? |
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Definition
1) UGT1A1 is a phase 2 drug-metabolizing enzyme that is involved in glucuronidation of bilirubin as well as some drugs.
Mild deficiencies cause Gilbert's syndrome and may present as unconjugated hyperbilirubinemia
Severe deficits result in either Crigler-Najjar types 1 and 2 that result in jaundice, liver damage, and sometimes death!
2) These patients are sometimes highly sensitive to the chemotherapy agent Irinotecan, which is converted to the active SN-38 compound that is a substrate for UGT1A1. Usually, UGT1A1 eliminates in in the bile, but the deficiency could cause buildup!
pg 303 in syllabus |
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Term
| What type of cells arise from the blastocyte and have the unique capability to divide extensively before differentiation? |
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Definition
Embryonic stem cells.
These cells are found in the embryo as well as in a number of stem cell niches. They are pluriponent and become "transit amplifying" cells or "precursors" as they begin to differentiation.
pg 305 syllabus |
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Term
| These cells can be either multipotent or committed to a particular differentiation path depending upon their location. |
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Definition
| Tissue-specific stem cells. |
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Term
| These cells are derived from somatic cells of embryos or adults, but can be "re-programed" to pluripotent states. |
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Definition
These are induced pluripotent stem cells (iPS cells).
Examples include fibroblasts and neural stem cells. iPS and ES cells can both show intrinsic biases for certain paths of differentiation, even though they are pluripotent! |
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Term
| How might a doctor go about isolating particular populations of stem cells? |
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Definition
1) Cell surface marker sorting using flow cytometry (particular antibody cocktail for particular receptors)
2) In vitro propagation
3) Can direct differentiation with gene-specific targeting (zinc-fingure nucleases |
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Term
| Why to ES and iPS cells have to be induced into "transit amplifying" cells before transplantation? |
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Definition
| They must be partially differentiated before implantation, otherwise they can develop into tumors with different cell line lineages (teratoma) |
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Term
| Why is neural stem cell transplantation into the CNS an important option for the treatment of infantile neuronal ceroid lipfuscinosis (INCL)? What are some issues with this option? |
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Definition
Recall that INCL is a lysosomal storage disorder involving the accumulation of lipfuscin because of a mutation in the CLN1 gene, which encodes the PPT1 protein. If PPT1 is provided, it can be internalized via mannose-6-phosphate receptors and transported into lysosomes, where it can be used to degrade toxic metabolites.
Enzyme replacement cannot be used in the CNS because of the BBB.
Viral-gene therapy provides only focalized sources of enzymes, when they are needed globally.
CNS stem cells can migrate effectively from the site of injection and ameliorate some the observed symptoms of INCL, including issues with cognition, vision and motor skills.
Disadvantages include the ethical implications of using cells derived from human embyros, as well as immunological matching of host and patient cells. Using iPS cells solves this second problem, but could still potentially lead to teratoma formation. |
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Term
Why would it be valuable to use ES cell-derived hematopoietic cells or reprogrammed iPS cells to treat sickle-cell anemia be desired over bone-marrow transplants of tissue-specific stem cells?
Are there any disadvantages to this approach? |
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Definition
Using these cells avoids histocompatability issues associated with a limited pool of bone-marrow donors.
iPS cells, in particular, are amenable to gene-specific targeting as well as being accessible from individual patients, thereby avoiding histocompatability issues.
Disadvantages could include tumor formation over the long term. |
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Term
| Why is gene therapy a particularly difficult option for treating Fanconi anemia? What treatments are currently looking the best? What are some concerns? |
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Definition
FA is associated with a decline in the number of hematopoietic stem cells (HSCs), which are the major target of gene therapy!
By using iPS cells from human dermal fibroblasts, it may be possible to re-program those cells into HSCs through hematopoetic progenitors.
Again, tumors are a concerned. |
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Term
| What does it mean for cancer cells to not be "contact inhibited"? |
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Definition
Usually, cells proliferate until they reach the point of "density dependent inhibition," where there are too many cells for the amount of available growth factors such as FGFs.
Cancer cells do not rely on these growth factors, and can divide forever (sometimes they generate their own growth factors, which can stimulate the secretion of aniogenic growth factors that lead to vascularization and support of tumors!).
pg 309 |
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Term
| What characteristics of Cancer cells make them susceptible to uncontrolled growth? |
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Definition
1) Not contact inhibited
2) Less adhesive (less retrained by their enviornment)
3) Unresponsive to differentiation cues
4) Unresponsive to apoptotic cues
5) Secrete proteases that allow their spread
6) Avoid immune surveillence
pg. 309 |
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Term
| What controls the variation in length of the cell cycle? |
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Definition
| Length of M to G2 transition |
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Term
| How does "anchorage dependence" relate to cancer cell growth? |
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Definition
| Cells require anchorage (cell shape regulation) to pass the G1 checkpoint, but do not require it to complete the cell cycle. Cancer cells that specifically alter proliferation genes can cause cells to by-pass the G1 restrictions (oncogenes). These mutations are dominant. |
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Term
| What are the two major classes of cancer causing genes and how do they operate? |
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Definition
1) Oncogenes- dominant mutations that allow cells to proliferate, by-passing the G1 restrictions.
2) Tumor suppressor genes- recessive mutations in these "anti-proliferation genes" cause cells to divide forever. |
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Term
| What are oncogenes? How do they differ from proto-oncogenes? |
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Definition
Abnormally expressed or mtuated forms of corresponding proto-oncogenes. Normal gene has "c" prefix, while oncogene has "v" prefix signifying its viral origin.
Unlike proto-oncogenes, oncogenes are integrated into the viral genome (under control of the VIRAL promotor), and can therefore be expressed at high levels in a diversity of cell types.
They also encode proteins that differ in structure and function to their normal counterparts.These differences arise from mutations, fusion's or translocations (chronic myelogenous leukemia), or amplification (neuroblastoma)
pg 312. |
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Term
| Why are tumor suppressor genes sometimes referred to as "caretakers" and "gatekeepers"? How do these genes relate to the "Two Hit Hypothesis"? |
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Definition
Gatekeepers- regulate cell growth directly, acting as anti-proliferation cells.
Caretakers- Repair DNA and maintain genomic integrity (indirect causes of cancer if disrupted)
This hypothesis explains how one inherited mutated copy of a TSF can become carcinogenic when the second, normal copy is mutated (example is Retinoblastoma) |
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Term
| A 16 month-old child presents with leukocoria (white eyes) and strabismus (poorly aligned eyes). Upon chromosomal analysis, you detect a deletion in 13q14. What condition is this? What protein is affected and how so? |
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Definition
Retinoblastoma (60% sporadic and 40% hereditary).
Rb tumor suppressor protein is a nuclear phosphoprotein that regulates the cell cycle at the G1 stage, before they commit to S phase. It also alters transcription by binding transcription factors. It is activated by phosphorylation from cyclin-cdk complexes, and inactivated in hyperphosphorylated states.
Cyclins activate CDKs, which phosphorylate Rb.
CDKs can be inhibited by Cyclin-dependent Kinase Inhibitors (CKIs), thereby deactivating Rb. |
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Term
| Why are mutations in p53 a concern? |
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Definition
p53 is a transcription factor that regulates the expression of cell cycle regulatory and pro-apoptotic factors. It induces the expression of CDK-inhibitors.
Certain point mutations change p53 from a TSG into a dominant-acting oncogene!
p53 stability is altered by MDM-2 (oncogene), which binds p53 and targets it for ubiquitination and degredation.
P19ARF can bind MDM-2, and suppress this effect. |
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