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303 Cards in this Set

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What are some common findings in Down Syndrome?
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
What is another name for Patau syndrome?
trisomy 13
What are some abnormalities associated with trisome 13?
brain
cardiac
genitalia
severe bilateral cleft lip and palate
mean survival 7 days
What is another name for Edwards' syndrome?
trisomy 18
What are some abnormalaties associated with trisomy 18?
prominent occiput
tightly clenched hands
median survival 14.5 days
50% die w/n 7 days
5-10% survive 1 year
What are the differences b/n LINEs and SINEs?
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)
Where do you find Lines and Sines in our genome?
they are both very common and take up a huge portion of genome--most of our genome non-coding: only 1.5% codes proteins
What is the coorelation b/n genome size and number of genes?
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
How many cells do humans have?
10 x 10^13 cells
What is the number of DNA molecules in nuclear genome vs. mitochondrial?
23 or 24 XY ; all linear in nuclear
one circular DNA molecule in mitochondrial
Compare the number of genes and introns b/n nuclar and mitochondrial.
nuclear: 25,000 genes with many introns
mitochondrial : 37 genes and NO introns
How much of the nuclear genome is coding v.s mitochondrial?
nuclear: 1.5%
mitochondrial: 93%
Compare the inheritance b/n nuclear genome and mitochondrial genome.
nuclar: Mendelian for sequences on X and autosomes; paternal for sequences on Y
mitochondrial: exclusively maternal
How much of the genome is conserved? How much is coding of that conserved area? HOw much repetitive?
coding: 1.5%
conserved: 4.5 -5%
repetitive: 50%
Do smaller or larger genes have a greater proportion of coding sequence?
smaller genes tend to have a greater proportion of coding sequences
Approximately how many proteins can 25,000 genes code for?
greater than 10^5 proteins due to alternative splicing
Why do chromosomes appear X shaped?
chromatids no longer held together by cohesin but kinetochore but kinetochore haven't separated
Where are primary oocytes arrested?
at Prophase I of meiosis I until menarche
When does oogonium development occur?
prior to birth
How long is a seconary oocyte held in Meiosis II?
until it is fertilized..if isn't results in menarche
During Meiosis, when does independent asst. occur?
during Metaphase I
During Meisosis, when does recombination occur?
prophase I: pachytene stage
When does gametogenesis occur in males and females? Duration?
males: puberty 60-65 days
females: early embryonic life
10-50 years
What are the differences b/n mitoses in gamete formation in males v/s females?
males:30-500 mitotic events therefore more mutations than in female
females: 20-30
How do you go about preparing a karyotype?
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
Explain the difference b/n G banding and R banding.
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
Where in chromosoms is heterochromatin found ? What is the exception?
hetero found in centromeres, except in chromosomes 1 and 9 where it is found noncentromeric
What chromosomes stain light with G banding?
stain light = gene rich: 16, 15, and 22 : therefore trisomy 16 end in miscarriages
What is the definition of a chromosomeal abnormality?
change in chromosomal number or structure w/o visible loss of material
What is the differnce b/n polyploidy and aneuploidy?
aneuploidy: loss or gain of onr or more chromosomes (monosomy, trisomY)
polyploidy: addition of one or more complete haploid complements (triploidy = 69)
What is the most common trisomy found in miscarriages?
trisomy 16
What are the origins of triploidy?
if 2 sperm fertilize ovum at same time or if a diploid egg is fertilized *most commonly 2 sperm fertilize
What results from non-disjxn in meiosis I?
gamete containing both homologs of one chromosome pair: 2 diploid gametes and 2 nullisomic gametes
What results from non-disxn in MII?
2 normal gametes
1 diploid gamete
1 nullisomic gamete
When does autosomal non-disjxn often occur?
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
What forms of trisomy are known to survive?
trisomy 21: downs (80% spont abort)
trisomy 18: Edwards (95% abort)
trisomy 13: Patau (95% abort)
Anueuploidy w/n sex chromosomes.
XXX, XXY, XYY relatively minor problems, normal lifespan
What percent of Turner Syndromes 45X abort?
95% abort spontaneously
survivors are of normal IQ but infertile
What syndrome is 45X?
turner
what is the most common anueploidy of live births?
trisomy 21
What are the common findings of Downs patients?
upward slopoing palpebral fissures
small ears
protruding tongue
palmar creases
congenital cardiac abnormalities (40-45%)
excess nuchal skin
What percentage of downs are due to trisomy? translocation?
95% trisomy
4 translocation
Unique characteristics of edwards' syndrome?
trisomy 18: prominent occiput, tightly clenched hands, 50% die w/n days
unique characteristics of patuau syndrome?
mean survival: 7 days
sever bilateral cleft lips and palate
multiple abnormalities: brain, cardiac, genitalia
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
In what type of persone will you see long limbs, breast development, and hypogonadism?
47XXY Klinefelter syndrome
47XXY is what?
Klinefelter syndrome
What happens in a reciprocal translocation?
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
What is occuring in Robersonian Translocation?
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).
After robertsonian translocation, what is the resulting chromosome number?
45 but with no net loss or gain of genetic info b/c only removed satallite DNA
How does one aquire Down's through a translocation?
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)
Why is 14/21 + 14 lethal?
b/c when fertilized will result in trisomy 14 which is lethal
What percent are downs translocations de novo?
2/3
1/3 the parent is unaffected carrier
What percent of 13q21q or 14q21q FEMALE carriers will pass on the translocation? Male?
female: 10%
male: 1-3%
What is the outcome of 21q21q carriers if they have children?
all gametes are nullisomic or disomic so all children will be anueploid and spontaneously abort or have downs
What is the difference b/n paracentric and pericentric inversions?
para: 2 breaks in same arm
peri: 2 breaks on diff arms with inversion occuring around the centromere
What do pericentric inversions result in?
duplications and deletions: the larger the duplicaion/deletion the greater the likelihood of miscarriage
What do paracentric inversions result in?
acentric and dicentric chromosomes that either cannot segregate or are unstable --embryonic lethality
What is the Wolf-Hirschorn syndrome?
4p deletion
What syndrome do these characterics describe: microcephaly, growth retardation (NOT skeletal dysplasia), seizures?
4p Wolf Hirschhorn
How can you confirm deletions such as 4p and 5p?
with FISH
what is 5p deletion called?
Cri du Chat
What syndrome do these characteristics describe: slow growth, cat like cry, microcephaly, epicanthal folds, downward slanting palebral fissurs?
5p deletion: Cri du chat syndrome
Williams microdeletion occurs on what chromosome?
7 (7q11)
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
what are the characteristics of Autosomal dominant?
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
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
What are the characteristics of Autosomal recessive?
-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
When do you see pseudodominance?
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
In what situation do you see vertical transmission, but it isn't autosomal dominant?
psuedodominance: recessive allele is so common that it appears dominant
What is locus heterogeneity?
parents homozygous for mutant alleles at different loci resulting in normal children: double heterozygotes
ex. deafness, retinitis pigmentosa, Ehler Danlos
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
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?
50% sons affected
50% daughters carriers
If the father is affected by X linked recessive disorder, what are the chances of his sons and daughters being affected?
100% daughters carriers
0% sons affected b/c NO male -male transmission
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
What is locus heterogeneity?
parents homozygous for mutant alleles at different loci resulting in normal children: double heterozygotes
ex. deafness, retinitis pigmentosa, Ehler Danlos
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
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?
50% sons affected
50% daughters carriers
If the father is affected by X linked recessive disorder, what are the chances of his sons and daughters being affected?
100% daughters carriers
0% sons affected b/c NO male -male transmission
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
What is the process called in which the normal X chromosome is inactivated?
lyonization
What is variable expressivity?
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
What is reduced penetrance?
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
What is non-penetrance?
individuals with NO features of disorder despite being heterozygous for particular gene mutation
How does mosaicism result?
from a mutation in early somatic cell line: an individual develops w/ 2 cell lines form same zygote Ex: Turner 45X/46XX
What is the eqn for H-W principle?
p2 + 2pq + q2 = 1
p + q = 1
p2=dominant allele AA
q2=recessive allele aa
What does the H-W eqn assume?
random mating
no selection
allele frequencies remain the same from one generation to the next
assumes no outside influence (no immigration, emigration)
What part of the H-W eqn is the carrier frequency? incidence? allele frequency?
carrier frequency: 2pq (2x the allele frequency)
disease incidence: q2
allele frequency: q
What factors distrub H-W equn?
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)
Most children born with the ___ trait are the first w/n the extended family?
AR
What does the risk of hving a child with AR depend on?
the pop frequency of mutant alleles ex. CF in N europe and thalassemias in mediterranean
What is the Founder Affect?
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
Characteristics of Founder Affects.
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.
What disorder is common to the Ashkenazie Jews?
Tay Sachs
What is heterozygous advantage?
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
Which heterozygous diseases do we see resistance to malaria? resistance to periodic starvation?
malaria: G6PD, thalasemias, sickle cell disese
periodic starvation: non-insulin dependent diabetes
What determines consanquiinty?
at least one common relative no more distant than great, great grandparent
What are the 3 main types of abnormalities seen in children of incestous relationships?
mental retardation
AR disorder (10%)
congenital malformaion
risks of abnormalities decrease w/ more distant relatives
What percent of children of incestuous relationships have AR disorders?
10%
What determines the probability that alleles cross over?
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
How do you determine the coefficient of inbreeding of child from consanguineous mating?
it is 1/2 the proportion of genes you have in common
What is a mutation?
heritable change in DNA that is not necessarily pathologic
Describe the human genome.
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
What is polymorphism?
rare allele exists at a frequency of greater than 0.01% in human populatin
How many mutations occur per haploid genome/generation?
10^-9 mutations per haploid genome/generation
How many mutations occur per person?
5-6
what results in de novo cases of many disorders?
spontaneous mutations that occur all the time
What increases rate of mutations? limits rate?
mutagens
DNA repair limits mutations
What are the main mutagens of humans?
radiation from x-rays and gamma rays
chemicals like mustard gas
What is the effect of DNA repair on mutagenisis?
decreases mutation rate by 100fold therefore when applying radiation to tumor use lots of rads to limit effect of cancer DNA repair
What types of DNA damage occur every day?
depurination: remove base (5000/day/cell)
deamination: cysteine-uracil (100/day/cell)
thymidine dimers by UV damage
What is the mechanism of base excision repair?
remove abnormal bases
What is the mechanism of nucleotide excision repair?
cut on either side of damage base and remove chunk (way to remove thymidine dimers)
What are the most common mutations?
substitutions: one base for another
What are null mutations?
mutations in which you get NO protein product from mutant allele: nonsense, frameshifts, deletions of part or all of genes
Which mutations can be thought of as incompletely penetrant?
splice site mutations depending on how much intron you retain or how much exon you remove will determine how much penotype you express
What are transitions? Transversion?
transitions: purine-purine
transversion: purine-pyrimidine
Do we observe more transition or transversion mutations?
transitions
Where is DNA seq. conservation the highest? why?
at exon-intron boundaries for splicing to proceed normally
How can intron retention come about?
mutation in exon splice acceptor or activation of cryptic splice acceptor in intron leaving portion of intron
What does backward slippage during replicaton cause?
insertion
What does forward slippage during replication cause?
deletion
Indels that are not multiples of 3bp rsult in what?
frameshifts
Why is old theory of PTC incorrect?
b/c when PTC's are introduced, mRNA decays and no protein is created
How does nonsense mediated decay prevent the synthesis of truncated polypeptides?
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
What is the structure of mRNA?
not linear
held in circular fashion
most beta thalassemias are due to what?
deletions of the entire gene
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
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
How does nonsense mediated decay prevent the synthesis of truncated polypeptides?
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
What is the structure of mRNA?
not linear
held in circular fashion
most beta thalassemias are due to what?
deletions of the entire gene
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
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
What is the occurence rate b/n DMD and BMD?
DMD: 1 in 5000 males
BMD: 1 in 18000 males
How is DMD and BMD inherited?
x linked
Are the promoters in the dystrophen gene the same?
no, different isoforms in different tissues due to use of differnt promoters
Compare causes of DMD and BMD.
dmd: near absence of dystrophin due to deletions, frameshift, nonsense
bmd: partially fxnl dystrophen due to inframe-deletions
compare alternative splicing in dmd vs bmd.
dmd: not multiples of 3 exons therefore nonsense mutations
bmd: multiples of 3-maintain reading frame
what technique can you use to determine DMD deletions?
pcr
Inborn errors of metabolism are the result of what? how are they inherited?
result of enzyme deficiency
AR
What causes PKU?
phenylalanine hydroxylase def causing builup of Phe and deficiency in Tyrosine
What is excreted in urine in PKU?
phenylpyruvic acid decreasing mental capacity
Why are PKU patients seen with fair skin and blue eyes?
def in tyrosine therefore can't make melanin
how do you treat PKU?
treat with low Phe diet
pregnant women need to remain on diet to protect fetus' mental development
What is excreted in urin in alkaptonuria?
homogentisic acid
why is PKU an example of allelic heterogeneity?
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)
What causes alkaptonuria?
homogentisic acid oxidase def
accumulation of homogentistic acid
What causes oculocutaneous albinsm?
tyrosinase def
inability to convert tyrosine to melanin
*lack of eye pigment
compare Marfans with homocystinuria.
marfans: AD, long limbs, lens dislocation superiourly
homocystinuria: AR, long limbs, lens dislocation inferiorly
What causes homocystinuria?
def of cystathionine beta synthetase (CBS) to break down homocysteine to cysteine
What causes maple syrup urine disease?
deficiency of branced chain ketoacid decarboxylase
can't break down BCFA-excreate val, leu and isoleu..imbalance of aa has effect on brain
What is the most common urea cycle disorder?
OTC deficiency, X linked
buildup of CPS
How are glycogen storage diseases grouped?
depending on effect on liver or muscle..cause hapatomegaly in liver and hypotonia in muscle
What is the world's most common enzyme def?
G6PD
400 million
10% african american males affected
usually presents as a drug-induced hemolysis
What does G6PD produce?
NADPH which protects cells from oxidant damage
Why do people with G6PD have sensitivy to fava beans?
b/c they lack G6PD and can't produce adequate NADPH to protect from oxidants in fava beans
What is the most common steriod def due to genetics?
21-hydroxylase def: Congenital Adranal Hyperplasia (CAH)
in what disease do we see virilization in all individuals?
21-hydroyxlase def
What happens in 21 hydroxylase def?
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
Why do we see salt wasting in some 21 hydroxylse def patients?
b/c of incresae of androgens
What are the times of onset of classic vs non-clssic 21 hydroxylase def?
classic: prenatal onsent severe enzyme def
non: postnatal onset
moderate enzyme def
What are almost all 21 hydroxylase gene mutations due to?
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
What gene is involved in mutations in 21-OH def?
CYP21
What is the problem in testicular feminisation?
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
What do mucopolysaccharidoses cause?
build up of GAGs
What do sphingolipidoses cause?
progressive deposition of lipid or glycolipid in brain, liver, spleen
What is MPS I? How inherited?
Hurler syndrome
AR
What sydrome do the following traits describe?
corneal clouding
poor growth
coarse facies
hepatomegaly
death in mid teens
Hurler MPS I
Which MPS is most severe in terms of mental retardation and short lifespan?
Hurler MPS I
What is the difference b/n Hunter and Hurler sydromes?
hurler: corneal clouding, AR
hunter: good vision, x linked, later presentation (2-5yrs)
What are Hurler kids deficient in?
iduronidase
what are hunter kids deficient in?
iduronodate sulphatase
What is differnt about Hunter and Hurler from Sanfillipo syndrome?
extreme behavioural probelmes
live longer
what is unique about Morquio syndrome (MPS IV)?
no mental retardation..normal IQ
What is I cell disesae?
mucolipidosis II
def of GlcNac transferase
looks like Hurlers..but cells have inclusions. No pex present
Tay Sachs is due to what?
def in Hex A
build up in gangliosides leading to mental retardation and blindness. death by age 3
diagnosed at 6 mo
what population does tay sachs affect greatly?
ashkenazi jews 1/3600
what chategorizes tay sachs?
poor feeding
lethargic
loss of milestones
blindess
death by age 3
accumulation of lipid
what mutation in tay sachs is the most common in ashkenazie jews?
4bp insertion mutation accounts for 80% frequency
the severity of gauchers is related to what?
residual enzyme activity of def in B-glucosylceramidase
What is the freq of Gauchers in Ashkenazi?
1/855 Type I
Types II and III more common in non Caucasians
Exception of Fabrys from other spingolipidosis?
fabrys: x linked and do not die in early childhood
What type of treatment is available for spingolipidosis?
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
What is the inheritance of erythropoietic porphryrias vs. hepatic porphyrias?
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
What is unique about acute intermittent porphyria?
not photosensitive
penetrance approx 10%
haploinsuffiency of porphobilinogen deaminase
What is the enzyme def in AIP?
porphobilinogen deaminase **rate limiting enzyme therefore AD
buildup of ALA synthase that is exacerbated by hormones, drugs and diet
Congenital eyrthropoietic porphyria (CEP) is different from AIP how?
CEP is AR, and exhibits photosensitivy
AIP is AD with NO photosensitivity
What is the enzyme def in CEP?
urophorphorinogen II cosynthase
Thing Getry..crusted erosions with associated scarring
What disease is common to Africaaners (founder effect)?
variegate porphyria (VP)..protoporphyrinogen oxidase haploinsufficiency
Autosomal Dominant**
What syndrome do these traits describe?
prominent forehead
punctate calcifications in epiphyses
lack of peroxisomes
zellwegger syndrome, a PEX biogenesis disorder
What treatment is there for andrenoleukodystrophy (ALD)?
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
What inheritence of ALD?
x linked
What is a common disorder of purine metabolism that shows gout, self mutilation, spasticity, and increased sytnhesis of purines..X linked?
lesch nyham syndrome: def of hypoxanthine guanine phosphoribosyl transferase (HPRT) that is X linked
What is the most common lethal AR disorder in the Caucausian population affecting 1 in 3000 newborns in the US?
CF
How many individuals in the US Caucasion pop are CF carriers?
1 in 28
What would a child with CF present with?
failure to thrive
obstructive lung disease
exocrine pancreatic insufficiency
male infertility due to congenital malformation of vas deferens
and elevated concentration of sweat electrolytes
What is the cloride channel defect in the sweat duct of CF patient?
lack of CFTR causes increased sodium and chloride in sweat b/c normally the CFTR brings Cl and Na into cells out of lumen
What is the chloride channel defect in the airway of CF?
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
How is CF a progressive disease?
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
What type of receptor is CFTR?
beta adrenergic R
functions as a chloride channel and as a regulator of other channels
on what chromosome is CFTR found?
chromosome 7
What common mutation in CF accounts for 70% of CF alleles?
delta F508
What are the common CF phenotypes seen with CFTR genotype?
exocrine pancreatic insufficiency
sweat chloride values
age of onset
lung disease
What associated CF problem has no coorelation to the others?
lung disease
the severity of lung disease is not dependent on CF mutation even though it accounts for 90% of CF mortality!
Why do CF kids without pancreatic insuffiency have a greater chance of living?
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
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
What does CFTR genotype coorelate with? not coorelate with?
coorelates with pancreatic insufficiency but NOT predictive of the severity of lung disease, the life limiting feature of CF
How many mutations are in the recommended panel for CF carrier screening?
25 mutations
account for 85% of CF alleles and are associated with classic and non classic CF but not CBAVD
What percent of CF patients are pancreatic sufficient?
15%. means they have functioning exocrine pancreas
How high of a coorelation is there for pancreatic suffiency among siblings?
96% indicating the severity of pancreatic disease is geneticaly determined..this is also true for lung sererity
If you have CF and are pancreatic sufficient what are your chances of lung disease?
less severe pulmonary phenotype b/c not calorie restricted thus more healthy
what is the modifier gene that might be responsible for the severity of lung disease in CF patients?
TGF-beta..it doesn't cause you to have lung disease, but in the presence of CF it increases your chances of lung disease
mutations in dominantly inherited diseases normally involve?
structural proteins and TF's
What does haploinsufficiency cause?
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)
Loss if fxn is due to what type of mutations?
nonsense
missense
splic
frameshifts
deletions
translocations
Do diff mutations in the same gene result in diff phenotypes for haplo?
no, same phenotype
NPS is an example of what?
haplo
pleitropy..variable express
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
Problem with NPS?
absence of Lmx1b-gene for TF that leads to development of doral features thefore develop ventral chara. on dorsal surface--mirror image
Why do we see patella aplasia in NPS?
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
Why do people with NPS have muscle hypoplasia?
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
Why do NPS patients develop kidney disease?
improper form of podocyts that help filter w/n kidney basement membrane
-decreased expression of type 4 collagen therefore no basal lamina made
Why do NPS patients develop glaucoma?
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
Explain conservation of Lmx1b
highly conserved b/n species
mice 99.7% identical to human-only single aa difference *cross-species alignment
How do we identify Lmx1b deletions?
real time PCR
What disease is result of heterozygous loss of fxx mutations in Lmx1b?
NPS
Where do missense mutations tend to cluster in NPS?
LIM and HD domains where DNA binds
What are the characteristics of CCD?
AD
hypoplastic clavicles
dysplastic and supernumerary teeth
hypoplastic cranial ossification
What is the gene for bone development that is mutated in CCD?
CBFA-1
Explain ossification centers in CCD heterozygotes.
disorganized
Where does DNA bind w/n CBFA1 gene?
RUNT
What mutations are usually associated with gain of fxn?
missense usually
In gain of fxn mutations, diff mutations result in what types of phenotypes?
different..think Fgfr3
What diseases are associated with mutations in Fgfr3?
thanatophoric dysplasia-neonatal lethal
achondroplasia-most common form of dwarfism
hypochondroplasia-short stature
In what region of Fgfr3 do 99% of all achondroplasia mutations occur?
G380R: most mutable gene in genome
In Fgfr3, how do different mutations in the same gene occur?
by single base changes at same place w/n gene resulting in diff phenotypes
Why don't we see skeletal dysplasia in Wolf Hirschorn although the deletion includes Fgfr3 gene?
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
If you knock out Fgfr3 in mice what will happen?
will exhibit long bone overgrowth (great prolif in chondryocytes) b/c no fgfr3 is present..normally fgfr3 inhibits bone growth
If you knock in Fgfr3 in mice what will happen?
too much inhibition of bone growth b/c one of fgfr3 genes is mutated--achondroplasia
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
What disease exhibits gain of fxn of fgfr3?
achondroplasia
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
Fibrodysplasia ossificans progressiva (FOP) is an example of what?
gain of fxn
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
What mutation and what causes FOP?
ACVR1 gene at R206H that is a BMP R that says where bone should be put down
What does ACVR1 code for?
tyrosine kinase receptor that dimerizes when ligand isnt present leading to stim of bone making genes in inappropriate areas
What mutations cause dom neg diseases?
missense and splice with maintenance of reading frame
*mutant protein interferes with normal
What does dom neg mutation generally apply to?
structural proteins--collagens
Osteogenesis Imperfecta is due to what?
mutations in Type I collagen
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
In type 2 OI what are the chances of forming normal procollagen molecules?
25% chance
75%chance abnormal that remove normal protein from circulation
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
What are some types of Type II collagen mutations?
Achondrogenesis II-neonatal lethal
spondyloepipyseal displasia (SED)
Kneist dysplasia
stickler syndrome
wht type 2 colagen mutations are dom neg?
Achondrogenesis and SED due to glycine sub
Kneist do to inframe deletion
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
What are the characteristics of MFS?
disproportionatly long limbs (dolichostelemolia) 5% greater than ht
arachnodactyly
pectus excavatum
ectopia lentis (superiorly)
MVP
aortic dilatation/dissection
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
what gene encodes fibrillin that is defected in MFS?
FBN1 gene on Chr 15 with C1039G mutation
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
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)
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
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
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
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
What are the occurence rates of Hem A and B?
A: 1 in 4000 live male births
B: 1 in 20000 live male births
Severity in both forms of Hem result of what?
decreased residual activity of F8 or 9
mild cases of Hem B reult of what?
missense mutations w/n promoter region
is there a greater incidence of Hem A or B?
A b/c of the recurrent inversion
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
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
How do we confirm Williams?
FISH
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
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
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
How are duplications and deletions recipricols?
for every deletion there shold be a corresponding dupliation
Often, what are chromosomal rearrangements often the result of?
recombination b/n very similar sequnces
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
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
What controls the expresion of Hb in embryo, fetal and adult dna?
locus control region
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
where are alpha thals most prevelant?
s.E. asia from deletion of alpha globin chians
How do alpha thals occur?
misaligment of repeats leading to loss of gene
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
what describes: no alpha globin syn, severe anemia, heart failure, edema
hydrops fetalis
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
What is the problem with beta and gamma tetramers?
oxygen affinities comparable to myoglobin...don't want to release to tissues theefore tissues starve
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
in alpha thal, what causes anemia?
beta tetramer
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
B thals are due to what?
null mutations
Hb Lepore is due to waht?
unequal crossover b/n beta and gamma genes
HPFH is due to what?
deletions
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