Exam 2 Flashcards
what is the coeficient of relationship?
the expression of probability of sharing a common gene from an ancestor. 50% is added each generation (1/2 for siblings and 1/8 for first cousins)
what sex would be most affected from an x-linked dominant disease? how often would you see it (assuming each generation had both boys and girls)
females (since the boys all get a Y from their father)
you would see it every generation
what are the 3 rules for X chromosome inactivation?
- its random
- its fixed
- its incomplete
what is one of the few active genes in an inactivated X c’some? what does it do?
XIST - it makes a molecule (protein?) that coats the inactive X thus maintaining its inactivation
how do sex-linked genes genes (disorders) appear in males vs. females?
(sex linked is inheritance due to x-linked genes)
they will appear like autosomal recessive genes in females
it males they will appear dominant since they only have the single X
list 3 sex-linked disorders
- hemophilia A
- duchennes muscular dystrophy
- red-green color blindness
name 2 requirements for a daughter to get an x-linked recessive disorder
- is the father must be affected
2. OR it could be from a new mutation
explain how x-linked recessive disorders can “skip a generation”
if the father is affected and the mother is not then they can only have carrier children (father cant give it to son and all daughters will be affected).
if one of the carrier daughters has children with an affected male then it will manifest again
what causes hemophilia A?
a defect in factor VIII gene on chromosome X
what determines the severity of hemophilia?
the percent of normal factor VIII activity
- severe = less that 1%
- moderate = 1 to 5%
- mild = 5 to 25%
what is usually the leading cause of death in patients with duchenne muscular dystrophy?
what is an early diagnostic indicator ?
its characterized by severe, progressive muscular atrophy. cause of death is usually cardiac or respiratory failure around age 25
creatine kinase released by muscles (can be 20X normal limit)
what is the molecular cause of DMD?
a mutation in the dystrophin gene (the largest known human gene) causing the protein to usually be completely absent.
dystrophin is usually found on the cytoplasmic side of the membrane aiding in ctyoskeletal integrity bt binding F-actin and dystroglycan in the membrane
what proteins absorb color for sight?
what is deuteranopia? protanopia?
opsins
deuteranopia - no green vision
protanopia - no red vision
why is red and green vision usually lost together?
is the condition dominant or recessive?
necause they are both on the same chromosome (x) and they are very close together
also because their sequence is similar?
X-linked recessive
whats more common, x-linked recessive or dominant disorders?
do x-linked disorders affect more men or women?
dominant disorders are much more rare
they usually affect women more (because often time the disorder will be fatal in the male who only has one X)
list 3 x-linked dominant disorders and what they do
- hypophophatemic rickets - kidneys can absorb phosphate leading to abnormal ossification where bones bend and distort
- incontinentia pigmenti - abnormal skin pigmentation and teeth
- rett syndrome - causes autism, ataxia and mental retardation
what is another term for y-linked inheritance. what are these disorders usually related to?
holandric inheritance
they usually have something to do with sex determination, spermatogenesis and/or testicular function
where does mitochondrial inheritance come from? why do these genes have a high mutation rate?
they come from the mother because the egg has mitochondria in it (sperm mito doesn’t make it into zygote)
the rate is high because the mito doesn’t have any DNA repair systems for its DNA and there are a lot of free radicals from oxidative phosphorylation
list 3 mitochondrial disorders. what do these disorders do?
- leber hereditary optic neuropathy (LHON) - optic nerve death by age 30. [heteroplasmy rare. missence mutation in protein coding]
- myoclonis epilepsy with ragged red fibers (MERRF) - causes epilepsy, ataxia, dementia and myopathy. very heteroplasmic. [single base change in tRNA]
- mitochondrial encephalomyopathy and stroke-like episodes (MELAS) - self explanitory. heteroplasmic. [single base change in tRNA]
what is heteroplasmy?
the mixture of one or more organelle genomes (ex. mitochondrial DNA) which can lead to variable expression if one copy is mutated
what is the most common form of inheritable mental retardation?
fragile X syndrome. (downs is ore common but its not heritable)
what is the genetic cause for fragile x syndrome?
what are some symptoms/characteristics?
repeated CGG bases at the 5’ end og the FMR1 gene.
- individules with > 230 repetes are affected
- between 50 to 230 are carriers (transmitting males)
- less than 50 are not affected
-long faces, prominent jaw, long ears, metal retardation
what parental chromosome deletion leads to the following conditions:
- prader-willi:
- angelment:
- prader-willi: paternal deletion (maternal imprinting)
2. angelment: maternal deletion (paternal imprinting)
what is classical galactosemia? what are symptoms?
a defect in the enzyme galactose-1-phosphate uridyl transferase which prevents the conversion of galactose to glucose
- failure to thrive
- hepatic insufficiency
- cataracts (from galacticol)
- developemental delays
- in the long term, poor growth and mental retardation
what is hereditary fructose intolerance?
a defect in fructose 1,6 bisphosphate aldolase (AKA aldolase B)
affected individuals cant ingest fructose
what is von gierke disease? what are symptoms?
a defect in glucose-6-phosphase. its a glycogen storage disorder where glucose from glycogen is not released from the liver
symptoms include hepatomegaly and hypoglycemia (liver, skeletal muscle and kidneys are affected)
what is phenylketonuria?
a defect in the phenylalanine hydroxylase gene leading to an accumulation of phenylalanine.
high phenylalanine disurpts brain:
- myelination
- protein synthesis
- eventually produces retardation
what is maple syrup urine disease?
a disorder where yuo can digest branched chain amino acids (valine, leucine, isoleucine)
the accumulation of the branches chain AAs can lead to neurodegeneration and death in months
most common in mennonite communities
what is MCAD deficiency?
a deficiency in medium-chain acyl-coenzyme A dehydrogenase which leads to an accumulation of intermediate fatty acids which basically results in the inability to make ketones which the brain needs.
patients will experience episodes of hypoglycemia after fasting. fasting for too long can cause edema and exhaustion of glucose followed by death
what is congenital adrenal hyperplasia (CAH)?
a block in corticosteroid synthesis. this causes a buildup of the precursors which are usually androgens or converted to weak androgens. the result is a mascinulization of females in utero.
severe forms can result in salt-wasting (large amount of renal salt excretion when the body needs it) which leads to weight loss, lethargy, dehydration and death
what is zellwegger syndrome?
a mutation in the proteins needed for peroxisome biogenesis.
symptoms are neonatal hypotonia, progressive white matter disease, distinctive face and death in infancy
what are mucopolysaccharidoses?
a lysosomal storage disorder characterized by a reduced degradation of glycosaminoglycans (hepran, dermatan, keratan and condroitin [all sulfates])
there are 10 enzymes than cause 6 disorders
what is sphingolipidoses? list 3 specific disorders and what causes them.
anyother type of lysosomal storage disease where shpingolipid degeneration is deficient
- gaucher disease: beta-glucosidase deficiency (ashkanazi jews, cherry red macula)
- tay-sachs: beta-hexosamididase
- niemann-pick: sphingomyelinase deficiency
what is I-cell disease?
the phosphotransferase that attaches mannose-6-phosphate to proteins (which is used to target it to the lysosome) is deficient leading to the formation of lysosomes that cant digest anything. they become inclusion bodies
what are the 4 urea cycle disorders? what are the common symptoms of them all?
they are caused by defects that cause accumulation of precursors
- carbamoyl phosphate synthetase (CPS)
- ornithine transcarbamoylase (OTC) [most common, x-linked]
- argininosuccinate synthetase (ASA)
- argininosuccinase (AS)
lethargy and coma. depending on the deficiency, the buildup will be different but it ultimately all leads up to buildup of toxic ammonia
what is cystine?
two cysteins with a disulfide bond
what is cystinuria? dominant or recessive?
a defect in transported for dibasic amino acids (cystern) which prevents its excretion.
the buildup of cystein can lead to the formation of kidney stones
its autosomal recessive (and common)
what is wilson disease?
a defect in copper excretion (ATP7B gene) to the biliary tract causing accumulation of Cu in the liver (also accumulates in the eye and joints)
causes:
- Kayser-fleischer ring in the eye (a dark pigment around the outside of the iris)
- acute or chronic liver disease
- dysarthria (poor speech)
- diminished coordination
- arthropathy (joint disease)
- cardiomyopathy
- kidney damage
- hypoparathyroidism
what is hereditary hemochromatosis? how do yuo diagnose it?
a condition characterized by an excessive iron absorption in the intestines
you take a liver biopsy and look for hemosiderin accumulation
what is a centimorgan?
one centimorgan is a 1% chance of recombination between two genes. therefore the less cMs the more likely the genes will not undergo independent assortment from each other
what is a LOD score used for? what values are significant?
calculating the likelihood that two genes are linked or not
- value >3 is significant for linkage
- value <-2 suggests no linkage
list 3 advantages for using microsatellites for markers in genome mapping
- they are highly polymorphic (its more helpful if the polymorphisms are different between the 2 homologous chromosomes)
- they are scattered throughout the genome
- they are easy to screen (one assay for all forms)
in which sex does genetic recombination occur more frequently?
the lady-folk
what is linkage disequilibrium?
mutations can be tracked using a closely linked marker. because of the close linkage they will stay together for a long time. however, eventually the marker and the mutation can become separated via recombination, this would be an example of linkage disequilibrium.
because of the rarity of separation, this can also be an indicator of mutation age
how does the HLA-B27 allele relate to the ankylosing spondylitis condition? what does this condition cause?
people with HLA-B27 are more likely to develop the condition even though it doesn’t contribute to the problem (it can be used to screen)
it causes ossification of spinal discs, joints and ligaments
list the 4 major families of paracrine signaling molecules.
- fibroblast growth factors (FGF)
- hedgehog proteins
- wingless family (Wnt)
- transforming growth factor-beta (TGF-beta)
list 2 ways disease can arise from paracrine signaling
- paracrine factor (ligand) gets mutated
2. the receptor gets mutated
what is the result of FGFR3 mutations? is this condition recessive or dominant?
FGFR3 is expressed in growing bones and it interacts with 22 FGFs. mutation in the receptor causes various skeletal dysplasias like:
1. achondroplasia - moderately active receptor –> short legs,macrocephaly (most common)
- hypochondroplasia - less active receptor –> less abnormalities/milder
- thanatophoric dysplasia - highly active receptor –> very short limbs/fatal
this particular mutation is autosomal dominant
name 3 important transcription factor families
- homeobox –> HOX, PAX, EMX, MSX
- high-motility group (HMG) –> SOX family
- T-box family –> TBXs
what is the consequence of mutation of SOX9?
two results:
1. campomelic dysplasia (bowing of the femur and tibia)
- sex-reversal of XY individuals (because the Sry gene on the Y-chromosome that determines testis formation needs SOX9 to regulate the genital ridges)
list one of the genes that is implicated in causing hirschprungs? what is defective in these individuals?
SOX10
its a neural crest cell defect where the enteric neurons in the colon do not develop which leads to colon hypomotility and sever constipation (in sever cases portions of the colon atrophy and die)
what do integrins do?
they link the ctyoskeleton with the ECM
what causes ostergenesis imperfecta? what are the symptoms?
mutation in the type 1 collagen gene.
collagen is a highly modified protein. normal collagen has a glycine every 3rd residue. mutations in that glycine will disrupt its overall structure leading to a disrupted bone formation (ranges from mild to lethal)
what causes marfan syndrome? what are the symptoms?
mutation in fibrillin-1
- tall statue with long fingers
- hypermobile joints
- lens displacement
- abnormal heart and blood vessels
what causes suprevalvular aortic stenosis?
a mutation in elastin
-abnormal heart and blood vessels
what causes junctional epidermolysis bullosa? symptoms?
laminin is mutated (important in anchoring cells to ECM), specifically the LAMC2 gene
- epithelia is not attached to each other (skin just wipes off)
- large blisters form on skin
what is the function of sonic hedgehog (SHH) in development? what happens if this gets mutated?
it helps determine the right/left axis and well as neural tube, somite and limb developement
mutation of SHH disrupt the midline development (including the brain).
-sever cases cause holoprosencephaly
what is smith-lemli-opritz syndrom? what causes it?
its an inborn error in cholesterol synthesis which leads to mild intellectual disability to lethal malformation of the brain.
the SHH protein helps form the brain and needs cholesterol in the membranes to bind. without that it can’t leading to brain malformations
what body axis is the first to form? what genes are responsible for this patterning?
anterior/posterior
HOX genes
how many HOX genes are there. list the 2 ways these genes are expressed
there are 4 clusters of 13 HOX genes each on four chromosomes (total of 39, not 13 different per cluster)
- temporal colinearity - within each cluster, the 3’ gene is expressed the earliest
- spacial colinearity - 3’ genes expressed more anteriorly
the combinations of genes expressed together at specific locations determine what develops there
what is a paralog
a genes that arises from duplication but developed its own function
what proteins are responsible for dorsal and ventral axis formation? how do they form the axes?
- noggin and chordin are DORSALIZING signals
- bmp4 is a VENTRALIZING signal
nogging and chordin (dorsal) prevent bmp4 from binding its receptor on the dorsal side of the body (where they are produced?)
what is one cause of left/right axis defect?
an early asymmetric expression of SHH (which causes left side expression of nodal [a TGF-beta])
what is the result in ZIC3 mutation?
- in males - randomization defects
- in females - right/left axis reversal
I THINK? not 100% on this one
what signaling molecule can induce the formation of a limb?
what mediates that molecule? from where?
what 2 molecules maintain that molecules expression?
Tgf8
Fgf10 from the mesoderm
Wnt2b and Wnt8c maintain Fgf10
what occures in FGF8 knockouts?
the mutants have very reduces to no limbs at all
list 3 signaling proteins involved in proximal/distal growth of limbs
what molecule does the ZPA use to maintain the AER?
- FGF2
- FGF4
- FGF8
SHH
what is holt-oram syndrome?
caused by a mutation in the T-box gene TBX5.
it causes an anterior defect in the thumb and/or radius
what is ulnar-mammary syndrome?
caused by a mutation in TBX3 (which is closely linked to TBX5)
causes defects in the posterior digits and ulna
what is the IPF1 protein responsible for? what is the consequence of it being mutated?
its required fro beta-cells in the pancreas to express insulin
its also responsible for the maturation and development of the pancreas as a whole so a mutation in that gene would lead to an malformed/absent pancreas
what are the two types of retinoblastoma according to knudson’s two-hit model?
- bilateral - run in the family (person inherited one hit from parents so more likely to occur in both eyes)
- unilateral - appears sporadically (since no hit was inherited therefore the likelihood of both eyes getting it simultaneously is rare)
what are the 3 classes of genes that can be mutated to form cancer? give examples of some that can be inherited with one hit?
- tumor suppressor genes (RB1, CDK inhibitors)
- oncogenes (not many inherited forms)
- DNA repair genes (BRCA1, BRCA2, mismatch repair genes)
what checkpoint does RB1 usually function at?
the G1/S checkpoint
explain the inheritance paradox for predisposition for cancer
on a pedigree they appear dominant because heterozygous individuals for this always causes a predisposition for that particular cancer.
however, at the cellular level it seems recessive since the healthy allele can compensate for the mutant and no cancer will occur so long as the healthy allele is intact
what would the loss of a marker when mapping cancer genes indicate?
in would indicate a loss in heterozygous near the gene of interest. this means that one of the parents alleles is gone resulting in an allele that is hemizygous
what benefit does telomerase provide to cancer cells?
it prevents cell senescence (normal cells senesce after 50-70 divisions)
what is the inherited cancer caused by mutation in NF1? what does NF1 do?
neruofibromatosis (from numerous large skin tumors to safe au lait spots)
NF1 is a tumor supressor on chromosome 17 that down-regulates Ras signaling by activating its GTPase activity
what gene is mutates in over 50% of all cancers?
what does it do?
p53
it has many functions including:
- binds to the CDKN1A promoter which causes increased expression of p21 (which is a cell cycle inhibitor)
- interacts with BAX gene which codes for a pro-apoptotic protein
- interacts with PTEN gene which codes for a tumor suppressor
- also regulates DNA repair
what is li-fraumeni syndrome?
an inherited p53 mutation leading to the predisposition to many different cancer types
usually an early onset of cancer, before age 50
list 2 types of familial colon cancer
- familial adenomatous polyposis coli - many polyps form
2. hereditary non-polyposis colon cancer (HNPCC) - fewer polyps
what is the progression of familial adenomatous polyposis coli?
- the APC gene (a tumor suppressor) gets a hit
- APC usually down regulates beta-catenin which works to promote cell proliferation
- unregulated beta-catenin causes adenomas (benign epithelial tumors)
- K-RAS receives a gain-of-function mutation 50% of time
- p53 mutation causing adenomas to convert to adenocarcinomas
- musation of SMAD4 can lead to metastasis
what genes are most often mutated in HNPCC? what do those genes do?
two genes are common
- MSH2
- MLH1
they are involved in DNA mismatch repair
list two genes whose mutations greatly increase the risk of breast cancer. which also increases risk in men? what pathway do these genes work in?
- BRCA1
- BRCA2 - also increases risk for men
they repair double-stranded DNA breaks
what gene is often mutated in familial melanoma? what does it do?
CDKN2A (aka p16). it inhibits CDK4 (like p21 does) which slows the cell cycle
what gene is mutated in the inherited for of multiple endocrine neoplasm? what makes this gene unique?
MEN2
it’s one of the few inherited oncogenes
what more common, sporadic or inherited cancer?
sporadic
what does polygenic mean?
its when multiple genes contribute to a single trait (therefore the train as many different phenotypes, bell curve)
what is a liability distribution? what about a threshold liability?
liability distribution is a distribution of possible phenotypes where only one side of the curve represents individuals affected with a certain condition
the threshold is the exact point in that curve where people are affected (this can differ by sex)
give one example where the threshold liability differs between men and women
pyloric stenosis
1/200 men
1/1000 women
list 5 factors that determine the risk of an individual getting
- higher risk if more than one affected individual in the family
- higher risk if the proband (affected related person?) has a sever case
- higher risk if the proband is of the less affected sex (ex. women in pyloric stenosis)
- decreases as the relationship is more distant
- risk of siblings ca be determined by taking the square root of the general population risk
differentiate concordant and discordant in twins
- concordant - both twins affected
- discordant - only one affected
what is a phenocopy?
a single trait that is affected by the environment (during early development)
what is a quantitative trait loci (QTL)?
stretches of DNA that contain, or are linked to quantitative trait genes
list 3 important multifactorial disorders
- heart disease (mainly coronary artery disease [CAD])
- hypertension
- diabetes
what condition increases risk of CAD? what sex is the less affected sex?
familial hypercholesterolemia (also a quantitative trait)
females
what is familial hypercholesterolemia?
an autosomal dominant disease that results in approximately double the serum cholesterol.
patients commonly develop xanthomas
where do you get cholesterol?
- ingested
2. obtained from lipoprotein particles
what do LDLRs do?
LDL receptors are found on membranes and work to bind and endocytose them into cells
list the 5 classes of LDLR mutations
class 1 - no protein (LDLR) found
class 2 - it cannot leave the ER, gets degraded
class 3 - LDLR cannot bind LDL
class 4 - it doesn’t migrate to coated pits (rare)
class 5 - cannot dissociate from LDL, therefore not recycled to cell curface
list 3 possible therapies for LDLR mutations
- decrease intake of cholesterol and fats - modest effect
- bile-acid binding resins (cholestyramine) - limits recycling from the intesting, liver increases synthesis of LDLR and cholesterol
- statins to block cholesterol synthesis - HMG CoA reductase activity targeted, LDLR synthesis increased
list 4 conditions/mutations that can lead to a stroke/stroke-like-symtpoms
- MELAS (mitochondrial disease)
- mutation in NOTCH3 (can cause dementia)
- mutation in protein C and S (both normally function to inhibit clotting)
- factor V leiden
list 4 conditions that can cause hypertension and what causes them
- liddle syndrome - defective epithelial sodium channel (ENaC)
- gordon syndrome - increased renal salt reabsorption (WNK2 or WNK4)
- rare disorders in corticosteroid productions
- renin-angiotensin system mutations?
what are the 3 types of diabetes
type I - early onset, immune destruction of islet cells
type II - late onset, associated with obesity, insulin resistance
MODY - maturity onset diabetes of the young, intermediate onset, autosomal dominant, not associated with obesity
