Lecture - Ch. 5 - Genetics Flashcards
there are 3 categories of human genetic disorders, what are they?
1) mutation in a single gene with large effects (aka mendelian disorders)
2) chromosomal DOs: structural or numerical alterations in autosomes and sex chromosomes
3) complex multigenic DOs (aka polymorphisms)
describe mendelian/ single gene mutations and give an example
- rare, high penetrance
- sickle cell anemia: strong selective forces maintain it in the population
describe chromosomals DOs
uncommon, high penetrance
what are examples of complex multigenic/ polymorphic DOs
atherosclerosis, diabetes, hypertension, autoimmune dzs, height and weight
what are mutations?
permanent changes in the DNA
what type of mutations give rise to inherited dzs?
germ cell mutations
what type of mutations give rise to cancer and congenital malformations?
somatic cell mutations
what is a missense mutation? give an example
alter meaning of sequence of protein encoded
eg: sickle cell: glutamic acid to valine in beta-globin chain of Hb
what is a nonsense mutation?
give example
stop codon
- if it occurs in beta-globin chain = beta-not-thalassemia
what are transcription factors to be aware of when it comes to mutations in noncoding regions
MYC, JUN, p53
what happens if you get deletions or insertions of 3 base pairs?
reading frame is intact, you just get an abnormal protein
what is a trinucleotide-repeat?
amplilification of a sequence of 3 nucleotides;
almost all contain G and C
what is anticipation and what are some examples?
as genetic disorders are passed down to the next gen, the symptoms appear earlier and worsen in severity
eg: Huntingtons Disease, and myotonic dystrophy
what type of alterations occur in Cystic fibrosis? ABO blood type? and Tay sachs?
CF: 3 base deletion
ABO: single base deletion (frameshift)
Tay Sachs: 4 base insertion (frameshift)
what are Autosomal Dominant disorders to be aware of here?
nervous stystem: HD, neurofibromatosis, myotonic dystrophy
MSK: Marfan, EDS, and Osteogenesis imperfecta
Metabolic: Familial hypercholesteremia
how are AD DOs manifested?
in heterozygous state
where do new AD mutations come from?
seem to occur in germ cells of relatively older fathers
what is familial hypercholesterolemia an example of?
loss-of-function mutation
what is HD an example of?
gain of fx mutation
what are the 2 main patters of diseases that are AD? what patterns would tell you its an AD disorder?
1) affects regulation of complex metabolic pathways, subject to feedback inhibition
2) key structural proteins: collagen cytoskeleton etc
what is an example of an AD disease with a pattern of affected regulation of metabolic pathways?
Fam. Hypercholest.
- LDL receptor concentration decreases by 50% -> secondarily incr. cholesterol -> atherosclerosis in affected heterozygots
what is an example of a key structural protein affected by AD?
osteogenesis imperfecta
in regards to onset, what gives it away that its an AD?
age of onset is delayed In many conditions; sx appear in adulthood
whats is the chance of an affected parents with an AD would pass it on?
50/50
Almost all inborn errors of metabolism are what?
AR
what are some examples of AR DOs?
CF; PKU
What if two parents who are carriers of AR disease have kids? whats their chance of passing it on?
1/4
50/50: carrier
1/4 unaffected
what are the 3 features of AR DOs?
1) parent is usually not affected
2) singlings have 1/4 chance of having the trait
3) if mutation is low frequency in general populations, consanguineous marriage increases the chances above 1/4
how do you differentiate AR from AD?
- expression of defect is more uniform
- complete penetrance
- onset is early In life
- new mutations are rarely detected clinically (takes several gens)
- many mutations Involve ENZYMES (Inborn metabolic errors) (enzyme may be normal but low in abundance, or defective)
what two bugs give you CF?
staphylococcus and psudomonas
what is the primary defect in CF?
abnormal function of an epithelial chloride channel protein
encoded by: CFTR gene
chromosome: 7q31.2
what symptoms do you expect to see? clinically, what should you keep an eye out for?
chronic lung disease (in kids!), male infertility (top two)
- pancreatic insufficiency, steatorrhea, intestinal obstruction
- cirrhosis, malnutrition
whats the incidence of CF?
1/2500 libe births,
most common lethal genetic disease In Caucasians (AR)
What are CF heterozygote carriers prone to?
resp and pancreatic disease
if you kiss a baby with CF, what do they taste like?
salt
what are key clinical findings of CF?
maconium Ileus
male urogentical abnormalities; pseudomonas aeruginosa infections
if babies have a diaper with a smell described as musty or mousy odor, what do you suspect?
PKU (phenylketonuria)
whats the incidence for PKU?
1/10,000 live births; caucasians
what is PKU and what are the clinical findings?
AR, deficiency of phenylalanine hydroxylase (PAH) leading to hyperphenylalaninemia
- phenylalanine cant be converted to tyrosine
- tyrosine is a precursor for melanin
normal at birth
at 6 months, severe mental retardation
hypopigmentation of hair and skin
eczema
what is the tx for PKU?
Dietary restriction
name some X linked DOs
G6PD def.
Fragile X syndrome
what are some things about X linked DOs to be aware of?
- almost all men are recessive (located in male-specific region of Y)
- males, usually infertile
- all daugheters of affected male are carriers
- hetero female dont express full phenotypic change cuz they got a normal paired allele
when taking a family history of X linked DO case, what will stand out?
all males affected, and skips a generation
what can you suspect if you give your pt a drug, and they come back with some sort of hemolytic reaction?
suspect G6PD deficiency
drug Induced hemolytic rxs
Describe the pedigree of X linked recessive if an affected father links w a normal mom; or an affected mom linking with a normal dad
- affected dad, normal mom: sons are unaffected, daughters are carriers
- reverse: both son and daughter have 50/50 of being unaffected; affected son = 25%; daughter carrier = 25%
describe mitochondrial inheritance:
what are mendelian disorders?
- alterations to a single gene: leads to abnormal product, or decrease of a normal product
what are the 4 main catergories of mendelian DOs?
what are the consequences of a mutation in regards to an enzmye for Mendelian DOs?
decrease activity (abn fx) or decr. amount of NL enzyme
what are the 3 major consequences of having enzyme defects?
1) accumulation of substrate
2) decrease amount of end product
3) failure to inactivate a tissue damaging substrate
what is an example of #1)
galactosemia
- galactose-1-phosphate uridyltransferase defeciency
what is an example of decreased amount of end product?
- albinism: lack of tyrosinase leads to less melanin
lesch-nyhan: Incr. Intermediate product and their breakdown product Is toxic
what is an example of failure to inactivate a tissue-damaging substrate?
alpha1- antitrypsin defect:
- unable to inactivate neutrophi elastase In lung -> EMPHYSEMA
what is the most common clinically significant mutation in regards to lung disease?
PiZ; homozygots for the PiZZ protein have alpha1-AT levels that are only 10% of normal
what are two examples of defects in receptors and transport systems?
1) familial hypercholsterolemia: decr. synthesis or decr in fx of LDL receptor = defective transport of LDL into cells = secondary incr in cholesterol synthesis
2) CF: chloride ion transport
what are some examples in alterations in structure, fxs or quantity of non-enzyme proteins?
sickle cell disease: globin structure defect
- thalassemias: globin GENE affects amount of globin chains made
what medication can surface as adverse reactions to drugs in regards to mendelian DOs?
primaquine (anti-malerial) -> severe hemolytic anemia = G6PD def.
whats the genetic scoop on Marfan?
AD
- FBN1*, chr. 15Q21.1
- FABN2,* CHR. 5q23.31 (less common)
- defect in (extracell. glycoprotein) fibrillin-1
whats the marfan syndrome incidence?
1 in 5K
70-85% familial
what are the 2 fundamental mechanisms by which loss of fibillin leads to clinical findings?
1) loss of structural support (where microfibril is rich)
2) excessive activation of TGF-beta signaling
what are physical/ clinical findings of Marfan Syndrome?
- tall, exceptionally long extremeties
- “double jointed,” thumb can be hyperextended to wrist
ectopia lentis (dislocation of lens)
aortic dissection, mitral valve prolapse
cystic medial necrosis
whats the scoop on Ehlers-Danlos syndromes?
EDS
- defect in synthesis/structure of fibrillar collagen
- skin is hyperextensible, joints are hypermobile
- extra stretchy skin, extremely fragile and vulnerable to trauma
*gaping defects, caused by minor injury. surgery is difficult cuz they lack normal tensile strength
because EDS is a basic defect in connective tissue, whats serious internal complications can you expect?
- rupture of colon and large arteries (vascular EDS)
- rupture of cornea and retinal detachment (kyphoscholiosis EDS)
- and diaphragmatic hernia (Classic EDS)
what are the clinical findings of Classic EDS and its gene defects?
COL5A1, COL5A2
Skin and joint hypermobility, atrophic scars, easy bruises
what are the clinical findings and gene defects for vascular EDS?
COL3A1
- thin skin
- arterial or uterine rupture
- bruising
- small joint hyperextensibility
what are the clinical findings and gene defects for
kyphoscholiosis EDS?
lysyl hydroxylase
hypotonia, joint laxity, congenital scoliosis, ocular fragility
what should lead you to the suspicion of familial hypercholesterolemia?
MI before 20 yo
facts on familial hypercholesterolemia?
- receptor dz
- mutation in receptor for LDL
- one of the most frequent mendelian DOs
1/500 from birth have 2-3 fold Increase In cholesterol and dfvelope tendinous xanthomas
- Incr. cholesterol leads to premature atheroschlerosis leading to increased risk of MIs
what if someone is homozygous for FH?
5-6 times the plasma cholesterol
- skin xanthomas (as well as coronary and cerebral and vascular atherosclerosis at a young age; MI BEFORE 20 yo
what does the LDL receptor recognize? where does the LDL come from? explain that train
liver cell secretes VLDL (with ApoC, ApoB-100, ApoE) –> lypolysis of VLDL –> IDL with ApoE and ApoB-100 —> conversion of IDL to LDL (with ApoB-100),
LDL RECEPTOR ON LIVER RECOGNIZES ApoB-100
what happens in lysosomal storage Dzs?
catabolism of subsrates of the missing enzyme remains incomplete, leading to the accumulation within the lisosomes = primary accumulation
- lysosomes are also used for autophagy, so when THAT is the route that is taken, the impaired autophagy gives rise to secondary accumulation of autophagic substrates
what are the 3 approaches to treating lysosomal dzs?
1) enzyme replacement therapy
2) substrate reduction therapy
3) some random shit based on our understanding of the molecular basis of the deficient enzyme (not even mentioned)
what is the enzyme deficient and major accumulating metabolites for tay sachs disease?
enzyme: alpha-subunit of hexosaminidase
metabolite: G-M2 ganglioside
what is the defective enzyme and accumulated metabolite in Gaucher dzs?
glucocerebrosidase
- glucocerebroside
what is the defective enzyme and major accumulated metabolite in Niemann-Pick disase (type A and B)
sphingomyelinase
sphingomyelin
what is the defective enzyme and major accumulated metabolite in muchopolysaccharidoses (MPS): MPS I
AKA HURLER Dz
alpha-l-iduronidase
dermatan sulfate, heparan sulfate
what is the defective enzyme and major accumulated metabolite in MPS II
aka Hunter Dz
l-iduronosulfate sulfatase
dermatan sulfate, heparan sulfate
whats Tay Sachs aka
Gm2 gangliosidosis: hexosminidase alpha-subunit deficiency)
where does the tay sachs mutation occur?
alpha-subunit locus on chromosome 15 –> severe deficiency of hexosaminidase A
what is the incidence and clinical presentation for tay sachs?
- eastern european (Ashkenazic Jews): 1 In 30 carrier rate
- normal at birth; 6month = motor and mental detrioriation
- by 1-2 years: vegetative state; deathy by 2-3 yo
- CHERRY RED SPOT IN MACULA
where do you find accumulations of Gm2 ganglioside?
neurons, retina,
heart, spleen, liver
what are the cytoplasmic inclusions for tay sachs?
fat stains on oil red O
and Sudan black B are positive
describe the Niemann-Pick Dz, types A and B
- lysosomal acumulations of sphingomyelin due to Inherited def. of sphingomyelinase
what do you see in a histo slide of Niemann-Pick Dz?
foamy cytoplasm
what are the raw stats on niemman-pick dz/
ashkenazi jews
AR
chr- 11p15.4
describe type A, B, C
A: severe Infantile form, complete lack of enzyme, missense mt; extensive neuro, sx by 6m, death before 3yo
B: No CNS involvenemt, reach adulthood
C: most common, NPC1, progressive neuro damage, ataxia
if you see zebra bodies, what is it?
NP diease
what are some other clinical findings of NP dz?
- massive splenomegaly (10x normal weight)
- 33-50% have cherry red retinal spot
whats the scoop on Gaucher Dz?
- AR
- glucocerebrosidase mutation
- accum of glucocerebroside In phagocytes
- this accumulation leads to activation of macrophages -> secrete IL-1, IL-6, TNF
what is the most common lysosomal storage disorder?
gaucher
what are the 3 types?
type I: chronic, 90% of cases, european jews, NO CNS
TII: ACUTE NEUROPATHIC; Infantile cerebral pattern, early death, NOT JEWISH
TIII: intermediate; progressive CNS, begins in adolescence of early adulthood
whats the morphology of Gaucher?
distended phagocytic cells = gaucher cells in liver, spleen, bone marrrow (bone erosion –> pathologic fx), LN,
whats it look like under a scope?
crumpled tissue paper
what organ is enlarged in gaucher dz?
spllen, more than 10kg;
also, pancytopenia or thrombocytopenia
whats the defect in mucopolysaccharidoses?
def enzymes degrading glycosaminoglycans
whats some facts on MPS?
All of the syndromes are AR, except Hunter syndrome (X-linked recessive)
- coarse facial features, clouding of the cornia, joint stiffness, mentally retarded
facts on hurler:
MPS 1-H;
normal at birth, hepatosplenomegaly at 6-24 months, death by 6-10 yo due to cardiovasc complications
**corneal clouding; dwarfism
facts on Hunters syndrome
MPS II; X-LINKED;
NO CORNEAL CLOUDING (mild clinical course)
where do you find the mucopolysaccharides in MPS?
what are common histo findings?
mononuclear phagocytic cells
balloon cells + zebra bodies
what is common to all MPS?
hepatosplenomegaly; (esp. coronary deposists); brain lesions
what is the COD for MPS?
myocardial infarction and cardiac decompensation
what is glycogenoses?
glycogen storage disease
what does glygenoses result in?
glycogen storage in the liver or muscle
what are the 3 types?
hepatic form: von Gierke
myopathic form: McArdle
Misc: Pompe Dz
for von gierke (type I) what enzyme is deficient, what can you expect to see in the clinic?
deficiency of: glucose-6-phosphatase
Increased glycogen storage in liver = low blood glucose (hypoglycemia)
—-
clinic: hyperlipidemia, hyperuricemia; convulsions; gout and skin xanthomas; bleeding tendency
in Mc Ardle dz, what is the defective enzyme and major accumulated metabolite in ?
muscle phosphorylase deficiency
no Incr. In blood lactate after exercise
leads to muscle cramps and weakness after exercise
in Pompe Dz, what is the defective enzyme and major accumulated metabolite in?
glucosidase (acid maltase) deficiency
also, lack of branching enzymes
early death
cardiomegaly
what can be said about complex multigenetic disorders?
they are of multifactorial inheritance = Implies interaction of environmental influences with two or more genes
most common genetic cause of congenital malformations
what can you suspect from a cleft lip, cleft palate and neural tube defects?
there was a reduced intake of folic acid preconceptionally
what type of severity can you expect frmo multifactorial inheritance’?
variable expressivity
reduced penetrance of a single mutant gene
euploid
any exactl multiple of haploid number (23)
aneuploid; how do they occur?
NOT an exact multiple of 23
- nondisjunction: gametes have +/- 1 chromosome
- anaphase lag: one normal cell + one monosomy cell
when monosomy occurs, whats the fate?
monosome doesnt form
trisomies do happen tho
whats mosaicism?
mitotic errors; gives rise to two or more populations of cells with different chromosomal complements
where is mosaicism common?
sex chromosomes
whats a ring chromosome?
where breaks occur at both ends of chrmosomes and the ends fuse
whats inversion? what are the two examples?
- 2 breaks occur within a single chromosomes with reincorporation of the Inverted Intervening segment
1) paracentric: only one arm involved
2) pericentric: breaks are on opposite sides of the centromere
whats isochromosome?
on arm of the chromosome is lost, and the remaining arm duplicates
- chromo has either 2 short arms or two long arms
whats translocation?
segment of one chromosome is transferred to another one
whats balanced reciprocal translocation?
single breaks in each of 2 chromosomes; but NO LOSS OF MATERIAL
NORMAL PHENOTYPE
What is an example of a Robertsonian translocation?
Trisomy 21
what are the 2 physical give aways of trisomy 21?
slanted palpebral fissures
single palmar crease
what is the most common chromosomal disorder?
trisomy 21
what is the number one cause of mental retardation?
trisomy 21
what is the US incidence of trisomy 21?
1 in 700; 95% of affected individuals have trisomy 21, 47 chromosomes
what is the strongest influence on incidence for trisomy 21?
maternal age
what are the diagnostic clinical features of trisomy 21?
- flat facial profile
- oblique palpebral fissures
- epicanthic folds
40% of pts have congenitcal heart disease (ASD and VSD); responsible for majority of deaths in infancy
what are they at risk of developing?
10 to 20 fold incr. risk of developing acute leukemia
what are the 3 trisomies?
down: tri 21
patau: tri 13 (1 in 15,000 births)
edwards: tri 18 ( 1 in 8K)
what is the DiGeorge syndrome chromosome that is deleted?
Ch. 22q11.2
1/4K births
what can you expect from DiGeorge syndrome?
- congenital heart defects
- abnormalities of the palate,
facial dysmorphisms
developmental delays
T-cell Immunodeficiency (gets viral Infections) and hypocalcemia
what clinical findings do you find with DiG synd.
thymic hypoplasia = T-cell immunodef.
parathyroid hypoplasia = HYPOcalcemia, cardiac malformations
velocardiofacial syndrome: long face, narrow palpebral fissures, overfolded ear helix, pear shaped nose, cleft palate
CATCH 22
whats worse, imabalances of sex chromosomes or autosomal imbalances?
sex chromosomes are better tolerated
what two factors are peculiar to the sex chromosomes?
lyonization (inactivation) of all but one X chromosome
- modest amount of genetic material carried by the Y chromosome
whats the Lyon hypothesis?
1) only one X chromosome is genetically active
2) other X undergoes heteropyknosis, rendered Inactive
3) inactivation occurs at random
4) inactivation of same X chromo persists in cells derived from each precursor cell
what is a Barr body?
inactive X can be seen in the interphase nucleus as a darkly staining small mass in contact with the nuclear membrane
what determines the presence of the male sex?
presence of a single Y
when are sex chromosomes usually detected?
at puberty; they are suble, and chronic problems related to sexual development and fertility
what increases your chances of mental retardation?
an incr in X chromosomes
what is the most common cause of hypogonadism in males?
klinefelter syndrome: 47, XXY
what is the indicence of KS?
1 in 660; usually not detected til puberty
what are people with klinefelter syndrome at an increased risk of getting?
type 2 diabetes and metabolic syndromes
- 50% of them have mitral valve prolapse
- osteoporosis
lack of secondary male characteristics: deep voice, beard, and male distribution of pubic hair
20X incr risk of breast cancer; incr risk of lupus
what else does klinfelter syndrom cause?
male infertility and reduced spermatogenesis
buzzword for Kleinfelter?
gynecomastia
buzzwords for Turner syndrome?
- webb neck
- broad chest with spaced nipples
STREAK OVARIES
What is the karyotype for Turner syndrome?
45, X
*complete or partial monosomy of X chr; hypogonadism in phenotypic females
other karyotypes: 45, X/ 46, XX;
45,X/ 46, XY;
45,X / 47, XXX;
What is the most common sex chromosomal abn in females?
turner syndrome; 1/2,500 births
what is cystic hygroma?
infant with edema; swelling of the neck due to lymph statis; it subsides but leaves behind bilateral neck webbing
what is turner syndrome the single most important cause of?
primary amenorrhea (1/3 of the cases)
what are the clinical findings of turner syndrome?
- congential heart disease (25-50% of pts; coarctation of aorta)
- cardiovasc. abn. are most important cause of incr. mortality
- shortness of stature
- amenorrhea
- streak ovaries (atrophi ovaries = fibrous strands, devoid of ova and follicles)
- hypothyroidism
- glucose intolerance, obesity, and insulin resistance
true hermaphrodite vs pseudo
true: presence of both ovaries and testis
psudo:
- female pseudohermaphro: ovaries, but a dick
- male pseudoherm: testis, but a vagina
what are the 4 categories of single-gene disorders with nonclassical inheritance
- diseases causing trinucleotide-repeat mts
- dos caused by mutations in mitochondrial genes
- genomic Imprinting
- gonadal mosaicism
what is the repeated sequence in fragile X syndrome?
CGG
protein: FMRP
what is the repeat in HD?
CAG
- huntingtin
what can you expect from trinucleotide-repeat mutations
neuro disorders
what are the 3 general principles of trinucleotide-repeat mutations?
1) asscted with expansion of a stretch of trinucl., usually include G and C
2) shit depends on sex of transmitting parent
3) the unstable repeats cause disease (via 3 mechanisms)
what are the 3 mechanisms by which unstable repeats cause disease?
1) loss of fx
2) toxic gain of fx
3) toxic gain of fx mediated by mRNA
what is a morphologic hallmark of trinucleotide-repeats?
accumulation of aggregated mutant proteins in large intranuclear inclusion
fragile X syndrome
loss of fx
trainscriptional silencing
CGG triplet in UTR
fragile-X tremor ataxia
accumulation of toxic mRNA
- transcriptional dysregulation
CGG triplet in UTR
friedreich ataxia
loss of fx
transcriptional silencing
GAA triplet
intron
HD
toxic gain of fx
polyglutamine expansions with misfolding
CAG triplet in exon
what is the second most common genetic cause of mental retardation?
fragile X syndrome
where does the trinucleotide mutation occur in FXs?
FMR1
(familial mental retardation-1)
- normal pop: 6-55 repeats;
- affected pop: 200-4000 repeats
*when FMR1 gene exceeds about 230 repeats, the DNA of that region becomes super methylated = silencing of the FMR protein
what is the incidence of Fragile X syndrome?
1 in 1550 men
1 in 8000 women
phenotype for fragile X syndrome
long face, large mandible
large ears,
macro-orchidism (affects more than 90% of males)
- hyperextensible joints
- high arched palate
- mitral valve prolapse
fragile X lazy slide
HD facts
- 15 years of life after dx
- AD disease
- dementia and progressive jerky movemnts
- HTT located on chromonome 4p16.3
anticipation
affected mothers of mitochondrial diseases pass the mutations to who?
all their children
mitochondrial fathers pass mito mutations to who?
no one
what is LHON?
progressive bilateral loss of central vission; first noted between ages 15-35, leading to eventual blindness
whats heteroplasmy and threshold effecct?
tissues have both normal and mutatnt mtDNA
- minimum number of mutant mtDNA needed in cell to give rise to disease
what is genomic imprinting?
selective inactivation of either maternal or paternal allele
when and where does imprinting occur?
in ovum or sperm, before fertilization
what are the 3 mechanisms of genomic impriting?
1) deletions: 70% of cases: eg: 15q12
2) Uniparental disomy: eg: prader-willi syndrome; they have two maternal copies of ch 15
3) defective Imprinting: 1-4% of prader-willi folks, the paternal chromo carries the maternal imprin
reverse is true for angelman syndrome
prader-willi syndrome
mental retardation
short statur
- hypotonia
profound hyperphagia
obesity
small hands and feet
hypogonadism
deletions of 15 (q11.2;q13)
angelman syndorme
same deletion but derived from mothers
- ataxic gait, seizures, happy puppets
what will deletion of maternal chromosome render? paternal?
angelman
prader
