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303 Cards in this Set
- Front
- Back
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What are some common findings in Down Syndrome?
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excess nuchal skin, epicanthic folds, protruding tongue, upward sloping palpebral fissures, single palmar crease, wide gap b/n 1 and 2nd toes, atrial and ventricular septal defect, short stature
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What is another name for Patau syndrome?
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trisomy 13
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What are some abnormalities associated with trisome 13?
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brain
cardiac genitalia severe bilateral cleft lip and palate mean survival 7 days |
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What is another name for Edwards' syndrome?
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trisomy 18
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What are some abnormalaties associated with trisomy 18?
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prominent occiput
tightly clenched hands median survival 14.5 days 50% die w/n 7 days 5-10% survive 1 year |
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What are the differences b/n LINEs and SINEs?
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LINE: AT rich
autonomous contains all info to move itself SINE: GC rich non-autonomous few insertions b/c they hardley ever move (Alu repeats) |
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Where do you find Lines and Sines in our genome?
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they are both very common and take up a huge portion of genome--most of our genome non-coding: only 1.5% codes proteins
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What is the coorelation b/n genome size and number of genes?
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there is no correlation: normally the genome size increases by 200 and genes only increase by 4. Ex: we have 25,000 genes and our genome is 2900Mb..this is b/c of alternative splicing
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How many cells do humans have?
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10 x 10^13 cells
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What is the number of DNA molecules in nuclear genome vs. mitochondrial?
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23 or 24 XY ; all linear in nuclear
one circular DNA molecule in mitochondrial |
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Compare the number of genes and introns b/n nuclar and mitochondrial.
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nuclear: 25,000 genes with many introns
mitochondrial : 37 genes and NO introns |
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How much of the nuclear genome is coding v.s mitochondrial?
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nuclear: 1.5%
mitochondrial: 93% |
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Compare the inheritance b/n nuclear genome and mitochondrial genome.
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nuclar: Mendelian for sequences on X and autosomes; paternal for sequences on Y
mitochondrial: exclusively maternal |
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How much of the genome is conserved? How much is coding of that conserved area? HOw much repetitive?
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coding: 1.5%
conserved: 4.5 -5% repetitive: 50% |
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Do smaller or larger genes have a greater proportion of coding sequence?
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smaller genes tend to have a greater proportion of coding sequences
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Approximately how many proteins can 25,000 genes code for?
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greater than 10^5 proteins due to alternative splicing
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Why do chromosomes appear X shaped?
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chromatids no longer held together by cohesin but kinetochore but kinetochore haven't separated
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Where are primary oocytes arrested?
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at Prophase I of meiosis I until menarche
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When does oogonium development occur?
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prior to birth
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How long is a seconary oocyte held in Meiosis II?
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until it is fertilized..if isn't results in menarche
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During Meiosis, when does independent asst. occur?
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during Metaphase I
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During Meisosis, when does recombination occur?
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prophase I: pachytene stage
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When does gametogenesis occur in males and females? Duration?
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males: puberty 60-65 days
females: early embryonic life 10-50 years |
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What are the differences b/n mitoses in gamete formation in males v/s females?
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males:30-500 mitotic events therefore more mutations than in female
females: 20-30 |
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How do you go about preparing a karyotype?
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to study chromosomes take them from dIVIDING cells b/c you need them all to stop at the same time --during Metaphase by using soln that prevents formation of spindle
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Explain the difference b/n G banding and R banding.
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G: most common method
chromosomes treated with trypsin, which denatures their protein content and then stained with Giemsa. Displays pattern of light (gene rich)and dark bands (gene poor) R=reverse banding where chromosomes are heat denatured before staining with Giemsa. Yield light and dark bands which are the reverse of those obtained using G banding |
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Where in chromosoms is heterochromatin found ? What is the exception?
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hetero found in centromeres, except in chromosomes 1 and 9 where it is found noncentromeric
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What chromosomes stain light with G banding?
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stain light = gene rich: 16, 15, and 22 : therefore trisomy 16 end in miscarriages
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What is the definition of a chromosomeal abnormality?
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change in chromosomal number or structure w/o visible loss of material
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What is the differnce b/n polyploidy and aneuploidy?
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aneuploidy: loss or gain of onr or more chromosomes (monosomy, trisomY)
polyploidy: addition of one or more complete haploid complements (triploidy = 69) |
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What is the most common trisomy found in miscarriages?
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trisomy 16
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What are the origins of triploidy?
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if 2 sperm fertilize ovum at same time or if a diploid egg is fertilized *most commonly 2 sperm fertilize
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What results from non-disjxn in meiosis I?
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gamete containing both homologs of one chromosome pair: 2 diploid gametes and 2 nullisomic gametes
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What results from non-disxn in MII?
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2 normal gametes
1 diploid gamete 1 nullisomic gamete |
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When does autosomal non-disjxn often occur?
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during MATERNAL MI
ex: trisomy 21 results 95% of the time due to maternal origin and only 5% of the time due to paternal..this is the same for 47XXX |
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What forms of trisomy are known to survive?
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trisomy 21: downs (80% spont abort)
trisomy 18: Edwards (95% abort) trisomy 13: Patau (95% abort) |
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Anueuploidy w/n sex chromosomes.
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XXX, XXY, XYY relatively minor problems, normal lifespan
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What percent of Turner Syndromes 45X abort?
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95% abort spontaneously
survivors are of normal IQ but infertile |
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What syndrome is 45X?
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turner
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what is the most common anueploidy of live births?
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trisomy 21
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What are the common findings of Downs patients?
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upward slopoing palpebral fissures
small ears protruding tongue palmar creases congenital cardiac abnormalities (40-45%) excess nuchal skin |
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What percentage of downs are due to trisomy? translocation?
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95% trisomy
4 translocation |
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Unique characteristics of edwards' syndrome?
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trisomy 18: prominent occiput, tightly clenched hands, 50% die w/n days
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unique characteristics of patuau syndrome?
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mean survival: 7 days
sever bilateral cleft lips and palate multiple abnormalities: brain, cardiac, genitalia |
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what syndrome do these characteristics describe: short stature
delayed pubertal development normal intellegence infertile often the result of mosaic |
45X Turner syndrome
most that survive are though to be mosaic: 45X, 46XX |
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In what type of persone will you see long limbs, breast development, and hypogonadism?
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47XXY Klinefelter syndrome
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47XXY is what?
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Klinefelter syndrome
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What happens in a reciprocal translocation?
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breakage of at least 2 chromosomes w/ exchange of the fragments forming 2 new derivative chromosomes..normally balanced meaning there is no net loss or gain of genetic material
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What is occuring in Robersonian Translocation?
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breakage of 2 acrocentric chromosomes (nomally 13,14, 15, 21, 22) at or close to centromeres w/ fusion of long arms. Short arms lost but not clinically important b/c they contain only genes for rRNA (satellites).
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After robertsonian translocation, what is the resulting chromosome number?
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45 but with no net loss or gain of genetic info b/c only removed satallite DNA
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How does one aquire Down's through a translocation?
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from a balanced carrier: 14/21
downs will have the translocation 14/21 with an extra 21 therefore when fertilized, you get trisomy for 21 and disomy (normal) for 14 (inheriting one copy of chr 21 from each parent plus a 14q21q translocation) |
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Why is 14/21 + 14 lethal?
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b/c when fertilized will result in trisomy 14 which is lethal
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What percent are downs translocations de novo?
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2/3
1/3 the parent is unaffected carrier |
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What percent of 13q21q or 14q21q FEMALE carriers will pass on the translocation? Male?
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female: 10%
male: 1-3% |
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What is the outcome of 21q21q carriers if they have children?
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all gametes are nullisomic or disomic so all children will be anueploid and spontaneously abort or have downs
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What is the difference b/n paracentric and pericentric inversions?
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para: 2 breaks in same arm
peri: 2 breaks on diff arms with inversion occuring around the centromere |
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What do pericentric inversions result in?
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duplications and deletions: the larger the duplicaion/deletion the greater the likelihood of miscarriage
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What do paracentric inversions result in?
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acentric and dicentric chromosomes that either cannot segregate or are unstable --embryonic lethality
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What is the Wolf-Hirschorn syndrome?
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4p deletion
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What syndrome do these characterics describe: microcephaly, growth retardation (NOT skeletal dysplasia), seizures?
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4p Wolf Hirschhorn
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How can you confirm deletions such as 4p and 5p?
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with FISH
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what is 5p deletion called?
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Cri du Chat
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What syndrome do these characteristics describe: slow growth, cat like cry, microcephaly, epicanthal folds, downward slanting palebral fissurs?
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5p deletion: Cri du chat syndrome
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Williams microdeletion occurs on what chromosome?
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7 (7q11)
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What type of inheritance exhibits these traits?
50:50 chance of transmitting phenotype to each offspring males and females equally likely to be affected male to male transmission vertical transmission |
Auto Dom
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what are the characteristics of Autosomal dominant?
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50:50 equal chance of transmitting phenotype to each offpring
male to male transmission vertical transmission males and females equally likely to be affected heterozygous individuals affected |
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What type of inheritance exhibits these traits?
25% offspring affected when both parents are carriers males and females equally likely to be affected rarely observe vertial transmission |
autsomal recessive
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What are the characteristics of Autosomal recessive?
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-25% offspring affected when both parents are carriers
-50% offspring will be carriers -males and females equally likely to be affected -rarely observe vertical transmission heterozygous individuals unaffected |
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When do you see pseudodominance?
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when person that is homozygous for autosomal recessive disorder marries a carrier of the same disorder: 50% offspring affected, 50% offspring carriers
ex: blue and brown eyes, blood types O |
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In what situation do you see vertical transmission, but it isn't autosomal dominant?
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psuedodominance: recessive allele is so common that it appears dominant
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What is locus heterogeneity?
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parents homozygous for mutant alleles at different loci resulting in normal children: double heterozygotes
ex. deafness, retinitis pigmentosa, Ehler Danlos |
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What type of inheritance exhibits these traits?
vertical transmission no male-male transmission usually only manifests in males 50% of a (mom)carrier's sons are affected 50% of (mom)carrier's daughters are carriers 100% of affected's (dad) daughters carriesr |
X linked Recessive
ex. Hemophilia, Duchenne Muscular dystrophy |
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If the mother is a carrier of an X linked recessive disorder, what are the chances of her daugthers being carriers and sons being affected?
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50% sons affected
50% daughters carriers |
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If the father is affected by X linked recessive disorder, what are the chances of his sons and daughters being affected?
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100% daughters carriers
0% sons affected b/c NO male -male transmission |
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What type of inheritance exhibits these traits?
50% offspring affected females are affected 100% of affected father's daughters are affected no male-male male lethal |
X linked domainant
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What is locus heterogeneity?
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parents homozygous for mutant alleles at different loci resulting in normal children: double heterozygotes
ex. deafness, retinitis pigmentosa, Ehler Danlos |
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What type of inheritance exhibits these traits?
vertical transmission no male-male transmission usually only manifests in males 50% of a (mom)carrier's sons are affected 50% of (mom)carrier's daughters are carriers 100% of affected's (dad) daughters carriesr |
X linked Recessive
ex. Hemophilia, Duchenne Muscular dystrophy |
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If the mother is a carrier of an X linked recessive disorder, what are the chances of her daugthers being carriers and sons being affected?
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50% sons affected
50% daughters carriers |
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If the father is affected by X linked recessive disorder, what are the chances of his sons and daughters being affected?
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100% daughters carriers
0% sons affected b/c NO male -male transmission |
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What type of inheritance exhibits these traits?
50% offspring affected females are affected 100% of affected father's daughters are affected no male-male male lethal |
X linked domainant
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What is the process called in which the normal X chromosome is inactivated?
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lyonization
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What is variable expressivity?
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consequence of pleitropy (single gene that may give rise to 2 or more apparently unrelated effects)
-remarkedly diverse symtoms that can result from different mutations in the same gene (ex I have Marfan's and have spidery fingers wherease Ally has Marfan's and is extrememly tall)--clinical features show strking variation from person to person |
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What is reduced penetrance?
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situation in which it appears that a mutation has skipped a generation, but really the mother of the affected must have been a carrier but didn't exhibit symptoms
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What is non-penetrance?
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individuals with NO features of disorder despite being heterozygous for particular gene mutation
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How does mosaicism result?
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from a mutation in early somatic cell line: an individual develops w/ 2 cell lines form same zygote Ex: Turner 45X/46XX
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What is the eqn for H-W principle?
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p2 + 2pq + q2 = 1
p + q = 1 p2=dominant allele AA q2=recessive allele aa |
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What does the H-W eqn assume?
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random mating
no selection allele frequencies remain the same from one generation to the next assumes no outside influence (no immigration, emigration) |
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What part of the H-W eqn is the carrier frequency? incidence? allele frequency?
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carrier frequency: 2pq (2x the allele frequency)
disease incidence: q2 allele frequency: q |
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What factors distrub H-W equn?
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1. non-random mating (assortive and consanguinity)
2. mutation (HW assumes no new mutations) In reality mutation balanced by loss of fitness 3.selection: heterozygote advantage like sickle cell protection from malaria 4.small pop size 5.gene flow (new alleles introduced) |
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Most children born with the ___ trait are the first w/n the extended family?
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AR
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What does the risk of hving a child with AR depend on?
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the pop frequency of mutant alleles ex. CF in N europe and thalassemias in mediterranean
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What is the Founder Affect?
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high freq of AR diseases that you don't see in other populations b/c effective pop size restricted at some point in history Ex: Amish
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Characteristics of Founder Affects.
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high freq of AR diseases
high allele freq that is constant doesn't apply consanquinty will also increase freq of AD traits compared to general pop. |
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What disorder is common to the Ashkenazie Jews?
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Tay Sachs
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What is heterozygous advantage?
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if you are a carrier for AR disease that mutant allele is at high freq providing grater resistance to some diseases which leads to maintenance of allele in population
Ex: resistance to malaria in heterozygotes for sickle cell, thalasemias, and G6PD def |
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Which heterozygous diseases do we see resistance to malaria? resistance to periodic starvation?
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malaria: G6PD, thalasemias, sickle cell disese
periodic starvation: non-insulin dependent diabetes |
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What determines consanquiinty?
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at least one common relative no more distant than great, great grandparent
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What are the 3 main types of abnormalities seen in children of incestous relationships?
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mental retardation
AR disorder (10%) congenital malformaion risks of abnormalities decrease w/ more distant relatives |
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What percent of children of incestuous relationships have AR disorders?
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10%
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What determines the probability that alleles cross over?
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it is related to the distance b/n loci (genetic distance) *the closer genes are on chromosomes, the less likely they will be to cross over in Meiosis
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How do you determine the coefficient of inbreeding of child from consanguineous mating?
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it is 1/2 the proportion of genes you have in common
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What is a mutation?
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heritable change in DNA that is not necessarily pathologic
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Describe the human genome.
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23 molecules/cell
10 x 10^13 cells 3 x 10^9bp in euchromatin 2 m DNA/cell 25,000 genes 0.1% individual variation across genome 5 new mutations in each individual |
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What is polymorphism?
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rare allele exists at a frequency of greater than 0.01% in human populatin
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How many mutations occur per haploid genome/generation?
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10^-9 mutations per haploid genome/generation
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How many mutations occur per person?
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5-6
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what results in de novo cases of many disorders?
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spontaneous mutations that occur all the time
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What increases rate of mutations? limits rate?
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mutagens
DNA repair limits mutations |
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What are the main mutagens of humans?
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radiation from x-rays and gamma rays
chemicals like mustard gas |
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What is the effect of DNA repair on mutagenisis?
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decreases mutation rate by 100fold therefore when applying radiation to tumor use lots of rads to limit effect of cancer DNA repair
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What types of DNA damage occur every day?
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depurination: remove base (5000/day/cell)
deamination: cysteine-uracil (100/day/cell) thymidine dimers by UV damage |
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What is the mechanism of base excision repair?
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remove abnormal bases
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What is the mechanism of nucleotide excision repair?
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cut on either side of damage base and remove chunk (way to remove thymidine dimers)
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What are the most common mutations?
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substitutions: one base for another
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What are null mutations?
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mutations in which you get NO protein product from mutant allele: nonsense, frameshifts, deletions of part or all of genes
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Which mutations can be thought of as incompletely penetrant?
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splice site mutations depending on how much intron you retain or how much exon you remove will determine how much penotype you express
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What are transitions? Transversion?
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transitions: purine-purine
transversion: purine-pyrimidine |
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Do we observe more transition or transversion mutations?
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transitions
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Where is DNA seq. conservation the highest? why?
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at exon-intron boundaries for splicing to proceed normally
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How can intron retention come about?
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mutation in exon splice acceptor or activation of cryptic splice acceptor in intron leaving portion of intron
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What does backward slippage during replicaton cause?
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insertion
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What does forward slippage during replication cause?
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deletion
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Indels that are not multiples of 3bp rsult in what?
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frameshifts
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Why is old theory of PTC incorrect?
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b/c when PTC's are introduced, mRNA decays and no protein is created
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How does nonsense mediated decay prevent the synthesis of truncated polypeptides?
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normally, stop codon is on last exon. In case of PTC, ribosome stalls at PTC even though there is evidence of EJC's from splicing downstream. NMD machinery investigates stalled ribosomes and when notices downstream EJC's it destabilizes 5'cap and decays mRNA-no protein results b/c transcript degraded by NMD pathway
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What is the structure of mRNA?
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not linear
held in circular fashion |
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most beta thalassemias are due to what?
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deletions of the entire gene
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What condition exhibits the following symptoms?
progressive symmetrical muscular weakness, proximal greater than distal, calf hypertropy, symptoms present at age 5, wheelchair dependent at 13, decreased neck flexor muscle strength |
duchenne muscular dystrophy
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What condition exhibits the following symptoms?
progressive symmetrical muscular weakness, proximal greater than distal, calf hypertrophy, activity induced cramping, wheelchair dependent after 16, preservation of neck flexor muscle strength |
becker muscular dystrophy
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How does nonsense mediated decay prevent the synthesis of truncated polypeptides?
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normally, stop codon is on last exon. In case of PTC, ribosome stalls at PTC even though there is evidence of EJC's from splicing downstream. NMD machinery investigates stalled ribosomes and when notices downstream EJC's it destabilizes 5'cap and decays mRNA-no protein results b/c transcript degraded by NMD pathway
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What is the structure of mRNA?
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not linear
held in circular fashion |
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most beta thalassemias are due to what?
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deletions of the entire gene
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What condition exhibits the following symptoms?
progressive symmetrical muscular weakness, proximal greater than distal, calf hypertropy, symptoms present at age 5, wheelchair dependent at 13, decreased neck flexor muscle strength |
duchenne muscular dystrophy
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What condition exhibits the following symptoms?
progressive symmetrical muscular weakness, proximal greater than distal, calf hypertrophy, activity induced cramping, wheelchair dependent after 16, preservation of neck flexor muscle strength |
becker muscular dystrophy
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What is the occurence rate b/n DMD and BMD?
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DMD: 1 in 5000 males
BMD: 1 in 18000 males |
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How is DMD and BMD inherited?
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x linked
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Are the promoters in the dystrophen gene the same?
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no, different isoforms in different tissues due to use of differnt promoters
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Compare causes of DMD and BMD.
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dmd: near absence of dystrophin due to deletions, frameshift, nonsense
bmd: partially fxnl dystrophen due to inframe-deletions |
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compare alternative splicing in dmd vs bmd.
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dmd: not multiples of 3 exons therefore nonsense mutations
bmd: multiples of 3-maintain reading frame |
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what technique can you use to determine DMD deletions?
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pcr
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Inborn errors of metabolism are the result of what? how are they inherited?
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result of enzyme deficiency
AR |
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What causes PKU?
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phenylalanine hydroxylase def causing builup of Phe and deficiency in Tyrosine
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What is excreted in urine in PKU?
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phenylpyruvic acid decreasing mental capacity
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Why are PKU patients seen with fair skin and blue eyes?
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def in tyrosine therefore can't make melanin
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how do you treat PKU?
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treat with low Phe diet
pregnant women need to remain on diet to protect fetus' mental development |
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What is excreted in urin in alkaptonuria?
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homogentisic acid
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why is PKU an example of allelic heterogeneity?
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b/c you see a range of different mutations of same gene: there could be a mutations in gene for phenylalanine hydroxylase that resut in classic or variant PKU or mutation in gene encoding enzymes for BH4 metabolism leading to PKU (differnt mutations in different genes but same phenotype overall)
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What causes alkaptonuria?
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homogentisic acid oxidase def
accumulation of homogentistic acid |
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What causes oculocutaneous albinsm?
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tyrosinase def
inability to convert tyrosine to melanin *lack of eye pigment |
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compare Marfans with homocystinuria.
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marfans: AD, long limbs, lens dislocation superiourly
homocystinuria: AR, long limbs, lens dislocation inferiorly |
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What causes homocystinuria?
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def of cystathionine beta synthetase (CBS) to break down homocysteine to cysteine
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What causes maple syrup urine disease?
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deficiency of branced chain ketoacid decarboxylase
can't break down BCFA-excreate val, leu and isoleu..imbalance of aa has effect on brain |
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What is the most common urea cycle disorder?
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OTC deficiency, X linked
buildup of CPS |
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How are glycogen storage diseases grouped?
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depending on effect on liver or muscle..cause hapatomegaly in liver and hypotonia in muscle
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What is the world's most common enzyme def?
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G6PD
400 million 10% african american males affected usually presents as a drug-induced hemolysis |
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What does G6PD produce?
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NADPH which protects cells from oxidant damage
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Why do people with G6PD have sensitivy to fava beans?
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b/c they lack G6PD and can't produce adequate NADPH to protect from oxidants in fava beans
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What is the most common steriod def due to genetics?
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21-hydroxylase def: Congenital Adranal Hyperplasia (CAH)
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in what disease do we see virilization in all individuals?
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21-hydroyxlase def
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What happens in 21 hydroxylase def?
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lack of steriod product impairs neg feedback control of ACTH secretion from pituitary.. leads to excessive adrenal androgen biosynthesis. Impaired pituitary feedback-chronic stimulation of adrenal cortex by ACTH-adrenal hyperplasia
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Why do we see salt wasting in some 21 hydroxylse def patients?
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b/c of incresae of androgens
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What are the times of onset of classic vs non-clssic 21 hydroxylase def?
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classic: prenatal onsent severe enzyme def
non: postnatal onset moderate enzyme def |
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What are almost all 21 hydroxylase gene mutations due to?
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seq exchange with a closely related pseudogene-acct for 75% of mutations
25% remaining accounted for by 21-0H fusion gene (inactive) or gene deletion |
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What gene is involved in mutations in 21-OH def?
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CYP21
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What is the problem in testicular feminisation?
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androgen insensitivity
mutations in androgen receptor (x linked) reduced reponse to testosterone- make testosterone but cells dont respond testes develop but not fully need to remove testicular tissue that can cause inguinal hernias look like women but are 46XY |
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What do mucopolysaccharidoses cause?
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build up of GAGs
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What do sphingolipidoses cause?
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progressive deposition of lipid or glycolipid in brain, liver, spleen
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What is MPS I? How inherited?
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Hurler syndrome
AR |
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What sydrome do the following traits describe?
corneal clouding poor growth coarse facies hepatomegaly death in mid teens |
Hurler MPS I
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Which MPS is most severe in terms of mental retardation and short lifespan?
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Hurler MPS I
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What is the difference b/n Hunter and Hurler sydromes?
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hurler: corneal clouding, AR
hunter: good vision, x linked, later presentation (2-5yrs) |
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What are Hurler kids deficient in?
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iduronidase
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what are hunter kids deficient in?
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iduronodate sulphatase
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What is differnt about Hunter and Hurler from Sanfillipo syndrome?
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extreme behavioural probelmes
live longer |
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what is unique about Morquio syndrome (MPS IV)?
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no mental retardation..normal IQ
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What is I cell disesae?
|
mucolipidosis II
def of GlcNac transferase looks like Hurlers..but cells have inclusions. No pex present |
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Tay Sachs is due to what?
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def in Hex A
build up in gangliosides leading to mental retardation and blindness. death by age 3 diagnosed at 6 mo |
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what population does tay sachs affect greatly?
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ashkenazi jews 1/3600
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what chategorizes tay sachs?
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poor feeding
lethargic loss of milestones blindess death by age 3 accumulation of lipid |
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what mutation in tay sachs is the most common in ashkenazie jews?
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4bp insertion mutation accounts for 80% frequency
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the severity of gauchers is related to what?
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residual enzyme activity of def in B-glucosylceramidase
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What is the freq of Gauchers in Ashkenazi?
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1/855 Type I
Types II and III more common in non Caucasians |
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Exception of Fabrys from other spingolipidosis?
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fabrys: x linked and do not die in early childhood
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What type of treatment is available for spingolipidosis?
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enzyme replacement therapy
works especially well for type I: cerezyme b/c it doesn't have to cross the blood brain barrier ERT also available for Fabry's disease |
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What is the inheritance of erythropoietic porphryrias vs. hepatic porphyrias?
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eryth: AR
hepatic: AD this is unique b/c they are AD but still enzyme deficiency. the enzyme however is the rate-limiting step therefore they are AD |
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What is unique about acute intermittent porphyria?
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not photosensitive
penetrance approx 10% haploinsuffiency of porphobilinogen deaminase |
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What is the enzyme def in AIP?
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porphobilinogen deaminase **rate limiting enzyme therefore AD
buildup of ALA synthase that is exacerbated by hormones, drugs and diet |
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Congenital eyrthropoietic porphyria (CEP) is different from AIP how?
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CEP is AR, and exhibits photosensitivy
AIP is AD with NO photosensitivity |
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What is the enzyme def in CEP?
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urophorphorinogen II cosynthase
Thing Getry..crusted erosions with associated scarring |
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What disease is common to Africaaners (founder effect)?
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variegate porphyria (VP)..protoporphyrinogen oxidase haploinsufficiency
Autosomal Dominant** |
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What syndrome do these traits describe?
prominent forehead punctate calcifications in epiphyses lack of peroxisomes |
zellwegger syndrome, a PEX biogenesis disorder
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What treatment is there for andrenoleukodystrophy (ALD)?
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lorenzo's oil..diet low in VLCFA b/c the disease is a PEX single enzyme def with a lack of VLCFA transporter leading to buildup of VLCFA in brain destroying myeling sheaths of neurons
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What inheritence of ALD?
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x linked
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What is a common disorder of purine metabolism that shows gout, self mutilation, spasticity, and increased sytnhesis of purines..X linked?
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lesch nyham syndrome: def of hypoxanthine guanine phosphoribosyl transferase (HPRT) that is X linked
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What is the most common lethal AR disorder in the Caucausian population affecting 1 in 3000 newborns in the US?
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CF
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How many individuals in the US Caucasion pop are CF carriers?
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1 in 28
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What would a child with CF present with?
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failure to thrive
obstructive lung disease exocrine pancreatic insufficiency male infertility due to congenital malformation of vas deferens and elevated concentration of sweat electrolytes |
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What is the cloride channel defect in the sweat duct of CF patient?
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lack of CFTR causes increased sodium and chloride in sweat b/c normally the CFTR brings Cl and Na into cells out of lumen
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What is the chloride channel defect in the airway of CF?
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CF patients have decreased chloride secretion and increased sodium and water reabsorption leading to dehydration of the mucus layer coating epithelial cels, defective mucociliary action and mucus plugging of airways. Normally CFTR in airway causes Cl secretion and slight Na and Water reaborption
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How is CF a progressive disease?
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in the airway the mucus is being dehydrated causing bacteria to get stuck in mucus and eventually starts ripping holes in lungs..lymphocytes can't reach the bacteria b/c of mucus and niether can antibiotics
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What type of receptor is CFTR?
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beta adrenergic R
functions as a chloride channel and as a regulator of other channels |
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on what chromosome is CFTR found?
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chromosome 7
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What common mutation in CF accounts for 70% of CF alleles?
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delta F508
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What are the common CF phenotypes seen with CFTR genotype?
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exocrine pancreatic insufficiency
sweat chloride values age of onset lung disease |
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What associated CF problem has no coorelation to the others?
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lung disease
the severity of lung disease is not dependent on CF mutation even though it accounts for 90% of CF mortality! |
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Why do CF kids without pancreatic insuffiency have a greater chance of living?
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b/c the are able to produce enzymes needed to digest foods as compared with thouse with pancreatic insuffiency who's pancreatic ducts are plugged with mucin and the parenchymal glands are atrophic
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What different mutations do we see in classic CF?
|
deltaF508: abnormal protein folding due to deletion of single Phe and CFTR doesn't reach cell membrane
2nd most common: G551D CFTR gets to membrane but doesn't open |
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What does CFTR genotype coorelate with? not coorelate with?
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coorelates with pancreatic insufficiency but NOT predictive of the severity of lung disease, the life limiting feature of CF
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How many mutations are in the recommended panel for CF carrier screening?
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25 mutations
account for 85% of CF alleles and are associated with classic and non classic CF but not CBAVD |
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What percent of CF patients are pancreatic sufficient?
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15%. means they have functioning exocrine pancreas
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How high of a coorelation is there for pancreatic suffiency among siblings?
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96% indicating the severity of pancreatic disease is geneticaly determined..this is also true for lung sererity
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If you have CF and are pancreatic sufficient what are your chances of lung disease?
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less severe pulmonary phenotype b/c not calorie restricted thus more healthy
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what is the modifier gene that might be responsible for the severity of lung disease in CF patients?
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TGF-beta..it doesn't cause you to have lung disease, but in the presence of CF it increases your chances of lung disease
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mutations in dominantly inherited diseases normally involve?
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structural proteins and TF's
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What does haploinsufficiency cause?
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loss of fxn b/c you only have 1/2 the required amt of protein(gene)which isn't sufficient (you only make half the amt or 1/2 amt isnt normal)
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Loss if fxn is due to what type of mutations?
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nonsense
missense splic frameshifts deletions translocations |
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Do diff mutations in the same gene result in diff phenotypes for haplo?
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no, same phenotype
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NPS is an example of what?
|
haplo
pleitropy..variable express |
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What are the tetrad of abnormalities seen in NPS?
|
nail dysplasia
elbow dysplasia absent/hypoplastic patella exostoses of ilia *also see duplicatoin of flexor tendons and misalignment of tendons causing hyperextensability and contractures |
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Problem with NPS?
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absence of Lmx1b-gene for TF that leads to development of doral features thefore develop ventral chara. on dorsal surface--mirror image
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Why do we see patella aplasia in NPS?
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b/c when limbs develop they rotate in opp direction. kneecaps start dorsal and end up ventral. If you lack Lmx1b, you don't develop it all b/c you lack dorsal TF
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Why do people with NPS have muscle hypoplasia?
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b/c joint attachments are off
cant work out to increase muslces b/c lack extensor mm often times develop elbow ptygeria "webbing" and can't fully extend arms to lift wts |
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Why do NPS patients develop kidney disease?
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improper form of podocyts that help filter w/n kidney basement membrane
-decreased expression of type 4 collagen therefore no basal lamina made |
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Why do NPS patients develop glaucoma?
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Lmx1b is expressed in periocular mesenchyme that forms sclera, cornea, ciliary body..therefore absence of Lmx1b structures form incorrectly and drainage angle not formed therefore fluid not able to drain
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Explain conservation of Lmx1b
|
highly conserved b/n species
mice 99.7% identical to human-only single aa difference *cross-species alignment |
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How do we identify Lmx1b deletions?
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real time PCR
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What disease is result of heterozygous loss of fxx mutations in Lmx1b?
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NPS
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Where do missense mutations tend to cluster in NPS?
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LIM and HD domains where DNA binds
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What are the characteristics of CCD?
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AD
hypoplastic clavicles dysplastic and supernumerary teeth hypoplastic cranial ossification |
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What is the gene for bone development that is mutated in CCD?
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CBFA-1
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Explain ossification centers in CCD heterozygotes.
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disorganized
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Where does DNA bind w/n CBFA1 gene?
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RUNT
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What mutations are usually associated with gain of fxn?
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missense usually
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In gain of fxn mutations, diff mutations result in what types of phenotypes?
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different..think Fgfr3
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What diseases are associated with mutations in Fgfr3?
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thanatophoric dysplasia-neonatal lethal
achondroplasia-most common form of dwarfism hypochondroplasia-short stature |
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In what region of Fgfr3 do 99% of all achondroplasia mutations occur?
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G380R: most mutable gene in genome
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In Fgfr3, how do different mutations in the same gene occur?
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by single base changes at same place w/n gene resulting in diff phenotypes
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Why don't we see skeletal dysplasia in Wolf Hirschorn although the deletion includes Fgfr3 gene?
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b/c you need mutant protein to be present (heterozygous) to exhibit achondroplasia. Wolf pts. are short but it is not due to Fgfr3 deletion b/c deletion normally causes long bone overgrowth
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If you knock out Fgfr3 in mice what will happen?
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will exhibit long bone overgrowth (great prolif in chondryocytes) b/c no fgfr3 is present..normally fgfr3 inhibits bone growth
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If you knock in Fgfr3 in mice what will happen?
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too much inhibition of bone growth b/c one of fgfr3 genes is mutated--achondroplasia
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What type of ossification is primarily at risk in achondroplasia?
|
endocondral due to resrictive prolif of chondrocytes therefore can't lie down Type II collagen to form long bones correctly
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What disease exhibits gain of fxn of fgfr3?
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achondroplasia
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What does fgfr3 code for?
|
tyrosine kinase receptor that dimerize when bound growth factor
in achondroplasia, low ligand conc can cause indepenedent dimerization leading to overinhibition of bone growth |
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Fibrodysplasia ossificans progressiva (FOP) is an example of what?
|
gain of fxn
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What is characteristic of FOP?
|
congenital malformation of big toes
progressive heterotropic ossification of sk mm, tendons, ligaments and fascia that progresses from dorsal to ventral RARE, AD, most cases sporatic |
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What mutation and what causes FOP?
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ACVR1 gene at R206H that is a BMP R that says where bone should be put down
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What does ACVR1 code for?
|
tyrosine kinase receptor that dimerizes when ligand isnt present leading to stim of bone making genes in inappropriate areas
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What mutations cause dom neg diseases?
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missense and splice with maintenance of reading frame
*mutant protein interferes with normal |
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What does dom neg mutation generally apply to?
|
structural proteins--collagens
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Osteogenesis Imperfecta is due to what?
|
mutations in Type I collagen
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A missense mutation in OI leads to what characteristic phenotype?
|
sever OI-Type 2
Glycine sub disrupting triple helix formation: now half alpha 1 chains are mutated and alpha 2 chains unaffected. Normally 2 alpha 1 chains and 1 alpha 2 chain |
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In type 2 OI what are the chances of forming normal procollagen molecules?
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25% chance
75%chance abnormal that remove normal protein from circulation |
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What type of mutation results in Type I OI?
|
null mutation..major mutation
no mutant protein formed thefore not dom neg. haplo instead Results in 1/2 amt alpha 1 chains, now you have excess alpha 2 making 1/2 amt procollagen |
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What are some types of Type II collagen mutations?
|
Achondrogenesis II-neonatal lethal
spondyloepipyseal displasia (SED) Kneist dysplasia stickler syndrome |
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wht type 2 colagen mutations are dom neg?
|
Achondrogenesis and SED due to glycine sub
Kneist do to inframe deletion |
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What type of mutation is Stickler syndrome? characteristics?
|
haploinsufficiency-nonsense
mild SED flat mid face mypopia deafness b/c Type 2 collagen impt in ear formation |
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What are the characteristics of MFS?
|
disproportionatly long limbs (dolichostelemolia) 5% greater than ht
arachnodactyly pectus excavatum ectopia lentis (superiorly) MVP aortic dilatation/dissection |
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Why don't FBN1 mutations act in dom neg manner?
|
b/c when C1039G mutant in normal mouse we see no effect but if C1039G mutation knocked into FBN-1 gene you have 1/2 amt mutation and 1/2 normal and you see MFS indicating haplo
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what gene encodes fibrillin that is defected in MFS?
|
FBN1 gene on Chr 15 with C1039G mutation
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How are mice heterozygous for null mutation similar to C1039G mutation?
|
similar aortic abnormalities b/c you are making half normal in both cases therefore haplo: diff mutations--diff phenoytpes
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What is the most commone cause of F8 deficiency?
|
intrachromosomal inversion that accts for 50% of all severe cases (severe = less than 1% residual F8 activity)
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Where does the inversion in F8 occur?
|
recombination b/n sequences located in intron 22 of F8 and homologus seq telomeric to F8
result: deletion of the carboxyl terminus of F8 |
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|
How can't you detect Hem A w/ PCR?
|
b/c it will apear normal, when in reality an inversion has occured and no longer codes for F8
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|
why do flip inversions show a higher mutation rate in male than in female germ cells?
|
the long arm of X does not pair with a homologus chromosome in male meiosis so that there is a much greater opportunity for intra chromosomal recombination to occur via looping of the distal end of the long arm
|
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|
What type of inheritance does Hem display?
|
both types are X linked recessive
if mom is carrier: 50% chance daughters carriers and 50% sons affectd |
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|
What are the occurence rates of Hem A and B?
|
A: 1 in 4000 live male births
B: 1 in 20000 live male births |
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|
Severity in both forms of Hem result of what?
|
decreased residual activity of F8 or 9
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|
mild cases of Hem B reult of what?
|
missense mutations w/n promoter region
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|
is there a greater incidence of Hem A or B?
|
A b/c of the recurrent inversion
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|
What characterizes Williams syndrome?
|
supravalvular aortic stenosis
low IQ < 80 long philtrum, full lower lip cocktail party manner |
|
|
What is Williams due to?
|
microdeletion at chromosome 7q11 due to misalingment of the repeats, excluding one copy of the gene that encodes elastin
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|
Why do we see congenital abnormalities of the great vessels in Williams?
|
b/c haplo at 7q11 leads to one copy of the gene that encodes elastin
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|
How do we confirm Williams?
|
FISH
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|
What is the diff b/n deletion of 7q11 v/s duplication?
|
deletion-williams
duplication-williams dup share some similarities in cognitive abilities but contrasting phenotypes in facial and behavior WBS: full lips, no lang delay WBS dup : think lips, lang delay |
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|
How is CMT1a inherited?
|
AD
geneticaly heterozygous (>4loci) |
|
|
What characterizes CMT1A?
|
slowly progressive weakeness and atrophy of distal leg mm
hyporeflexia muscle denervation axonal denervation uniform slowing of nerve condxn velocity resulting from demyelination |
|
|
Wht causes CMT1a?
|
duplication of PMP22 gene within 17p11
|
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|
What are the similarities b/n CMT1a and HNPP?
|
both involve PMP22 gene w/ deletion (HNPP) or duplication (CMT1a) of 17p11
**similar phenotypes unlike WBS and WBS dup |
|
|
What is PMPP 22 coding for?
|
major component of myelin
exprssed in myelin fibers of PNS predom produced by schwann cells |
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|
How are duplications and deletions recipricols?
|
for every deletion there shold be a corresponding dupliation
|
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|
Often, what are chromosomal rearrangements often the result of?
|
recombination b/n very similar sequnces
|
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|
How many new cases of hemoglobinopathies are born everyday?
|
650-700 new cases born every day
|
|
|
What is the normal structure of Hb?
|
tetramer: 2alpha 2 beta
|
|
|
explain Hb switching.
|
embryotic life in yolk sac: zeta and epsilon
fetal expression in liver: zeta and gamma adult exprssion in BM: alpha and beta with some delta |
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|
Why don't we see beta thals until after birth?
|
b/c you only make the switch to HbA after birth.. and that is when beta chains are expressed
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|
What controls the expresion of Hb in embryo, fetal and adult dna?
|
locus control region
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|
What chromsome is beta chain on? alpha chain?
|
beta: 11 with 1 gene for beta chain, 1 gene for delta chain
alpha: 16 with 2 genes for 1 alpha chain |
|
|
What does imbalance of globin chain production result in?
|
accumualtion of free globin chains in RBC precursors that are insoluble so they precipitate resulting in hemolysis of RBC..with HYPERplasia of BM b/c BM is trying to make more RBC for globin to carry oxygen
|
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|
where are alpha thals most prevelant?
|
s.E. asia from deletion of alpha globin chians
|
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|
How do alpha thals occur?
|
misaligment of repeats leading to loss of gene
|
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|
What is missing in Hydrops Fetalis/Hb Barts?
|
all alpha genes resulting in gamma tetramer b/c they don't survive to birth and never expess beta globin either
|
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|
what describes: no alpha globin syn, severe anemia, heart failure, edema
|
hydrops fetalis
|
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|
Wht is the problem with HbH?
|
only 1 alpha gene..majority of Hb is beta tetramer
milder than Hb Barts |
|
|
What is the problem with Hb Constant spring?
|
you have a mutation in stop codon in alpha globin gene wich leads to long unstable protein thefore you have very little alpha to interact with beta..end up with beta tetramers like in Hb H
|
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|
What is the problem with beta and gamma tetramers?
|
oxygen affinities comparable to myoglobin...don't want to release to tissues theefore tissues starve
|
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|
another name for beta thal?
|
cooley's anemai that usually presents as severe before 12 months old..swelling in bones of face bc BM tryingto compensate by making more RBC
|
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|
in alpha thal, what causes anemia?
|
beta tetramer
|
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|
in beta thal, waht causes anemia?
|
alpha tetramer but milder than alpha thal b/c you are making delta globin that can peir with alpha and get less tetramers
|
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|
B thals are due to what?
|
null mutations
|
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|
Hb Lepore is due to waht?
|
unequal crossover b/n beta and gamma genes
|
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|
HPFH is due to what?
|
deletions
|
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|
sickle cell anemia results from what?
|
point mutation in beta chain: aa substitution:glu for val
normal alpha production |
|
|
Hb S exhibits what?
|
pleiotropy due to sickling in different tissues
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