Unit 2 Day 7 Flashcards
1
Q
medelian inheritance
A
how hereditary characteristics are passed from parent to offspring
2
Q
law of segregation
A
- every individual possesses pair of alleles for any trait
- each parent passes randomly selected copy of one to offspring
3
Q
law of independent assortment
A
- separate genes for separate traits
- passed independently of one another from parent to offspring
- alleles of diff genes assort independently
4
Q
autosomal dominant
A
- maps to autosome
- homo/heterozygotes
- equal m/f
- passed either parent
5
Q
penetrance
A
- probability that mutant allele /s will have phenotypic expression
- 100% any person shows some symptom
- less than 100% some carry mutation show no symptoms
- often reduced penetrance
6
Q
expressivity
A
severity of manifestation of phenotype among individuals with same disease causing genotype
7
Q
achondroplasia
A
- autosomal dom
- skeletal dysplasia
- 80% mutation rate
- 100% penetrance
- 1/15000-40000 newborns
8
Q
de novo mutation
A
- mutations occur in egg or sperm after fertilization
- explain autosomal dominant in child w/unaffected parents
9
Q
achondroplasia manifestations
A
- short stature
- limb/finger shortening
- genu varum
- trident hands
- large head w/ facial retrusion
- small foramen magnum
10
Q
achondroplasia mutation
A
- FGFR3 (fibroblast growth factor receptor 3)
- regulates bone growth
- chromosome 4p16.3 (1138 position causes)
- aa substitution–>missense mutation
11
Q
what is the highest new mutation rate in male sperm?
A
nt 1138 of FGFR3 gene
12
Q
retinoblastoma
A
- tumor of retina
- 1/15000 births
- RB1 gene on ch 13
- protein regulates cell cycle
- 90% penetrance (incomplete)
13
Q
neurofibromatosis type 1
A
- autosomal dominant
- 1/3000 births
- 50% mutation
- variable expressvity
14
Q
diagnostic criteria of NIH
A
must have 2 or more
- 6 or more café-au-lait spots
- 2 or more neurofibromas
- 1 plexiform neurofibroma
- Freckling in the axillary or inguinal area
- Optic glioma
- 2 or more Lisch Nodules
- Distinctive osseous lesions
- Affected first degree relative
15
Q
neurofibromatosis type 1 mutation
A
NF1
- tumor supressor gene
- ch 17q11.2
- loss of function
- considered dominant
16
Q
locus heterogeneity
A
- mutation in >1 locus causes same clinical condition
- mutations in 1 gene and another, cause same mutation
17
Q
Tuberous Sclerosis
A
- autosomal dom
- 1/6000
- variable expressivity
- 2/3 is de novo
- fully penetrant
18
Q
TS skin findings
A
- hypopigmented patches
- angiofibroma
- shagreen patch
- ungual fibroma
19
Q
Tuberous Sclerosis issues
A
- Kidneys: renal cysts, angiomyolipomas
- Lungs: Lymphangioleiomyomatosis
- heart: Cardiac rhabdomyoma
- CNS issues
- seizures
- neuropsychiatric disorders
20
Q
clinical criterial for TS
A
must have one major and 2 minor features
21
Q
major features TS
A
Angiofibromas Cardiac rhabodmyoma Cortical dysplasias Hypomelanotic macules Lymphangioleiomyomatosis Multiple retinal nodular hamartomas Renal angiomyolipoma Shagreen Patch Subependymal nodule SEGA Ungual Fibroma
22
Q
minor features TS
A
Confetti skin lesions Dental Enamel pits (>3 teeth must be present to see) Intraoral fibromas Multiple renal cysts Nonrenal hamartomas Retinal achromic patch
23
Q
TS mutation
A
- TSC1 and 2
- hamartin, tuberin proteins
- cell growth/proliferation regulation
- ch 9, 16
- loss of function
24
Q
osteogenesis Imperfecta type 1
A
- autosomal dom
- 1/30,000-50,000
- variable expressivity
25
clinical manifestations of osteogenesis imperfecta
- multiple fractures
- short stature
- hearing loss (adult onset)
- blue sclera
26
Osteogenesis imperfecta mutation
- COL1A1
- collagen type 1 alpha 1
- ch 7q21.3
- reduced production pro-alpha 1 chains
- collagen production reduced by 1/2
27
Marfan Syndrome
- autosomal dom
- 1/5000 births
- 25% new mutation rate
- variable expressivity
28
marfan clinical manifestation
- disorder connective tissue
- ocular
- skeletal
- cardiovascular
29
marfan mutation
- FBN1 (fibrillin-extracellular matrix protein)
- ch 15q21.1
- dominant negative activity
- reduction in microfibrils
30
trinucleotide repeat disorders
- segment of DNA consisting of 3 or more nuts
- slipped mispairing
- anticipation
- parental transmission bias
- AD, AR, X linked transmission
31
slipped mispairing
- mispairng of bases in regions of repetitive replication coupled with inadequate repair systems
- as repeat grows, probability increases
32
anticipation
- severity/onset of disease increases next generation
| - increase in number of copies
33
parental transmission bias
-trinucleotide expansion more prone to occur in gametogenesis of m/f
34
huntingtons
- autosomal dom
- tnr disorder (CAG)
- 1/10000
- anticipation
- parent of origin affects (early onset-paternal, late-maternal)
35
clinical manifestation huntingtons
- progressive neuronal degeneration
- 34-44 age of onset
- death 15 yrs after onset
36
huntingtons muation
- HTT
- ch 4p16.3
- expansion of glutamine may cause an altered structure or biochemical property of protein
37
myotonic dystrophy type 1
- autosomal dom
- tnr disorder (CTG)
- 1/20000
- anticipation
- maternal transmission
38
clinical manifestations of myotonic dystrophy type 1
- adult onset
- progressive muscle wasting/weakness
- myotonia
- cataracts
- cardiac conduction defects
39
mutations in MD1
- DMPK (myotonic dystrophy protein kinase)
- ch 19q13.3
- plays role in muscle, heart, brain cells
40
MD1 CTG repeat
- 5-24=normal
- 34-49=premutation
- >50=full mutation, 100% penetrance
41
x chromosome inactivation
- only one copy of majority of genes on x chromosome is necessary
- 2 copies=detrimental
- one turned off==barr body
- occurs 1st week of embryogenesis
- 50:50 complement (if off can be bad)
- XIST gene inactivates
42
with skewed x chromosome inactivation what happens?
- observed when female shows sign or symptoms of x-linked recessive condition
- eg: duchene MS
43
x-linked disorders
- x chromosome mutations
- male affected mostly
- male-male transmission
- hemizygous for mutations in x-linked genes
44
x-linked recessive inheritance
- phenotype expressed in all males who carry
- expressed in only homozygous females
- hetero females are carriers
45
x-linked dominant
- hypophosphatemic rickets
- alport syndrome
- fragile x
- charcot marie tooth
- incontinentia pigmenti
- rett syndrome
- orofaciodigital syndrome
- focal dermal hypoplasia
46
hypophosphatemic rickets
- x linked dom
- 1/20000
- short stature
- bone deformity
47
hypophosphatemic rickets mutation
- PHEX gene
- regulates fibroblast growth factor
- inhibits kidneys to reabsorb phosphate
48
fragile X syndrome
- x linked com
- FMR1 gene
- tnr disorder-CGG
- 1/2500-4000 males
- 1/7000-8000 fem
- most common cause inherited developmental delay males
- anticipation
- maternal transmission bias
49
fragile x clinical manifestation
- intellectual disabilities
- dysmorphic features
- autistic
- socially anxious
- hand flapping/biting
- agression
50
FMR1 associated conditions
- FXTAS (fragile x associated tremor ataxia syndrome)
| - primary ovarian insufficiency
51
rett syndrome
- x linked dom
- 1/10000 females
- 95% mutation rate
- loss normal movement coordination
- microcephaly
- loss comm skills
- failure to thrive
- seizures
- abnormal hand movements
52
rett syndrome mutation
- gene MECP2
- methyl CpG binding protein
- normal function nerve cells necessary
- boys don't live
53
x linked recessive disorders
```
Lesch-Nyhan Syndrome
Dystrophinopathies
Hunter’s Disease
Menkes Disease
Glucose 6 phosphate dehydrogenase deficiency
Hemophilia A and B
Wiscott Aldrich Syndrome
Colorblindness
```
54
lesch-nyhan syndrome
- x linked
- 1/380000
- cerebral palsy
- uric acid overproduction
- self injury
- cognitive issues
55
lesch-nyhan mutation
- HPRT1
| - recycles purines
56
dystrophinopathies
- x linked recessive
- spectrum m. disease
- 3 distinct conditions: duchenne, Becker, DMD cardiomyopathy
57
dystrophinopathies mutation
- DMD gene, x chromosome
- ch Xp21-21.1
- dystrophin
- largest human gene
58
DMD
- duchenne muscular dystrophy
- progressive muscular weakness
- calf hypertrophy
- CK levels 10x normal
- onset before age 5, wheelchair before 13
- absence of dystrophin causes death 30's
59
Becker muscular dystrophy
- similar symptoms, later onset to DMD
- CK levels 5x normal
- wheelchair bound after 16
- death in 40's
- abnormal quantity/quality of dystrophin
60
DMD-associated DCM
- present btw. 20-40 years
- early death
- no sm involvement
- no dystrophin in myocardium
- female carriers affected w/ cardiomyopathy
61
hemophilia A
- x linked recessive
- 1/4000 male births
- 10% female carriers affected
- can't clot, excessive bruising, royal fam
62
hemophilia A mutation
- gene F8 on x chrom
- Xq28
- deficiency factor 8
- 22A inversion causes 50%
63
mitochondria
- perform oxidative phosphorylation
- encodes 37 genes
- produce components respiratory chain
- maternal inheritance
- replicative segregation
- threshold effect
- affected females pass to all children
64
replicative segregation
- at cell division, multiple copies of mtDNA
| - replicate/randomly sort among newly synthesized mitochondria
65
heteroplasmy
-presence of more than 1 type of organellar genome within cell or individual. important factor in considering the severity of mitochondrial diseases
66
mitochondrial disease
- group disorders caused by dysfunction of respiratory chain
| - disorders tend to affect tissues that rely on oxidative phosphorylation
67
Kearns-Sayre Syndrome
- mitochondrial
- 1-3/100000
- most commonly caused by somatic mutation
- triad
- cardiac conduction defects, ataxia, deafness, kidney issues
- large deletion of mtDNA
- removes 12 genes most commonly
68
MELAS
- mitochondrial encephalomyopathy, lactic acidosis, and stroke-lie episodes
- 1/300000
- low new mutation rate
- can present in children btw 2-10 years
- muscle weakness, seizures, strokes, lactic acidosis
- multiple mitochondrial genes
69
MERRF
- myoclonic epilepsy with ragged red fibers
- mitochondrial inheritance
- 1/400000
- low new mutation rate
- muscle symptoms, seizures, ataxia, dementia
- mitochondrial gene mutations
- MT-TK
70
Leber Hereditary Optic Neuropathy
- mitochondrial inheritance
- 1 in 30-50000 europeans
- bilateral subacute vision failure
- occurs young adulthood
71
effects of paternal grandparent diet on grandchildren
- good or poor diet during the slow growth period had effect on pre-adolescence
- increased mortality associated with feast year
72
genetic mother mouse feeding tests
- mice fed with high methyl donor ingredients=larger, light offspring
- AGOUTI gene turned off in lower methyl donor diet offspring
73
epigenetic characteristics
- different gene expression pattern/phenotype, identical genome
- inheritance through cell division, even through generations
- like a switch-on/off (not gradient, gene itself is on/off)
- erase-able (inter-convertible, reversible)
74
wadding tons landscape as epigenetic visualization
- cell can go to various states
- think of in terms of energy states
- each cell is existing in stable low-energy state
- go from pleuripotent to differentiated
75
epigenetic gene expression patterns
-cell differentiates, some "light switches"/genes go off/on
76
DNA methylation
- locks in repressed state
- occurs on cytosines of CpG
- doesn't affect base pairing of 5-meC with G
- contributes to gene silencing by solidifying the repressed state
- requires cofactor SAM
- can be changed by diet/smoking
77
maintenance methyltransferases and epigenetic markers
- occurs at level of DNA replication-all epigenetic inheritance begins
- menthyl grops are programmed for inheritance to occur
- prevents methyl group from being diluted
78
histone H3 modifications affect gene expression
- repressive histone marks-off
- active histone marks-on
- ones sticking out from the strand are easiest to modify
79
inheritance of chromatin state
- dna methylation begins at replication
- 2 sister chromatins made result in large disturbance to chromatin
- must maintain nucleosome modifications
- newly made histones must be induced to maintain what type they are (since combo of half old/half new)
80
epigenetic phenomena
- chromatin-mediated gene silencing
- dosage compensation v. important
- important factor in many diseases
81
silencing of tumor suppressor gene
- 5meC can lead to cancer
- unmethylated-->methylated
- enzymes maintain repression-histone deacytelases
82
epigenetic therapy
- disrupt tumor suppression
| - combinational therapy on multiple regulatory mechanisms
83
causes of genetic disease
- alteration of DNA changes products (mRNA, protein)
| - mutations that alter functional proteins
84
loss of function mutations
-single gene disorders almost always result from mutations in the function of a protein
85
what are the 4 common mechanisms of human genetic disease?
- no gene
- no rna
- no protein
- protein nonfunctional
86
DMD Xp21.2
-sex linked
-premature termination from nonsense/stop mutations, frameshift, deletions
-gower maneuver
-boys
duchenne muscular dystrophy
-frameshift-lof mechanism
87
hereditary neuropathy with liability to pressure palsies
- deletion of pmp22 gene-lof
- integral membrane protein in glycoprotein nerves
- autosomal dominant
- incomplete recovery
- arm numbness that never comes back
88
what happens with unequal crossing over between 17p12?
- pmp22 gene
- supposed to line up normally-misalign
- crossover that can occur, duplication or deletion
89
allelic disorders
- conditions genetically related
| - HNPP and CMT1A are in sense that diff mutations in same gene lead to diff phenotypes
90
osteogenesis imperfecta type 1
-normal state-make 3 polypeptide chains, 2 pro alpha, 1 pro alpha
-important structure in our bones
-termination codon that is premature
-dominant
COLA1 makes 2, COLA2 make 1
91
hemoglobin kempsey
- beta hemoglobin gene
- Asp99Asn missense mutation
- higher O2 affinity
- prevents shift from locked to relaxed, gain of function
- unloads less O2 in tissues
92
charcot marie tooth syndrome
- type 1A
- duplication PMP22 gene
- gain of function
- autosomal dom
- presents lower extremities with weakness and muscle atrophy and mild sensory loss
93
novel property mutations
- eg: sickle cell anemia
- mutation: no effect O2 carrying
- novel property of polymerizing under low O conditions
- long hemoglobin polymers
94
Osteogenesis imperfecta type 2, 3, 4
- make COL1A1 okay, but the second one you make abnormally
- novel property mutation
- better to have half the amount of normal collagen, than produce bad trimers
95
hereditary persistence of fetal hemoglobin
- altered or ectopic expression
- binds tightly
- protective against malaria
- normal product expressed at the wrong time
96
trinucleotide repeats
- affect different parts of the gene
| - knowing locations may shed light on underlying mechanisms
