Unit 2 Day 7 Flashcards
medelian inheritance
how hereditary characteristics are passed from parent to offspring
law of segregation
- every individual possesses pair of alleles for any trait
- each parent passes randomly selected copy of one to offspring
law of independent assortment
- separate genes for separate traits
- passed independently of one another from parent to offspring
- alleles of diff genes assort independently
autosomal dominant
- maps to autosome
- homo/heterozygotes
- equal m/f
- passed either parent
penetrance
- 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
expressivity
severity of manifestation of phenotype among individuals with same disease causing genotype
achondroplasia
- autosomal dom
- skeletal dysplasia
- 80% mutation rate
- 100% penetrance
- 1/15000-40000 newborns
de novo mutation
- mutations occur in egg or sperm after fertilization
- explain autosomal dominant in child w/unaffected parents
achondroplasia manifestations
- short stature
- limb/finger shortening
- genu varum
- trident hands
- large head w/ facial retrusion
- small foramen magnum
achondroplasia mutation
- FGFR3 (fibroblast growth factor receptor 3)
- regulates bone growth
- chromosome 4p16.3 (1138 position causes)
- aa substitution–>missense mutation
what is the highest new mutation rate in male sperm?
nt 1138 of FGFR3 gene
retinoblastoma
- tumor of retina
- 1/15000 births
- RB1 gene on ch 13
- protein regulates cell cycle
- 90% penetrance (incomplete)
neurofibromatosis type 1
- autosomal dominant
- 1/3000 births
- 50% mutation
- variable expressvity
diagnostic criteria of NIH
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
neurofibromatosis type 1 mutation
NF1
- tumor supressor gene
- ch 17q11.2
- loss of function
- considered dominant
locus heterogeneity
- mutation in >1 locus causes same clinical condition
- mutations in 1 gene and another, cause same mutation
Tuberous Sclerosis
- autosomal dom
- 1/6000
- variable expressivity
- 2/3 is de novo
- fully penetrant
TS skin findings
- hypopigmented patches
- angiofibroma
- shagreen patch
- ungual fibroma
Tuberous Sclerosis issues
- Kidneys: renal cysts, angiomyolipomas
- Lungs: Lymphangioleiomyomatosis
- heart: Cardiac rhabdomyoma
- CNS issues
- seizures
- neuropsychiatric disorders
clinical criterial for TS
must have one major and 2 minor features
major features TS
Angiofibromas Cardiac rhabodmyoma Cortical dysplasias Hypomelanotic macules Lymphangioleiomyomatosis Multiple retinal nodular hamartomas Renal angiomyolipoma Shagreen Patch Subependymal nodule SEGA Ungual Fibroma
minor features TS
Confetti skin lesions Dental Enamel pits (>3 teeth must be present to see) Intraoral fibromas Multiple renal cysts Nonrenal hamartomas Retinal achromic patch
TS mutation
- TSC1 and 2
- hamartin, tuberin proteins
- cell growth/proliferation regulation
- ch 9, 16
- loss of function
osteogenesis Imperfecta type 1
- autosomal dom
- 1/30,000-50,000
- variable expressivity
clinical manifestations of osteogenesis imperfecta
- multiple fractures
- short stature
- hearing loss (adult onset)
- blue sclera
Osteogenesis imperfecta mutation
- COL1A1
- collagen type 1 alpha 1
- ch 7q21.3
- reduced production pro-alpha 1 chains
- collagen production reduced by 1/2
Marfan Syndrome
- autosomal dom
- 1/5000 births
- 25% new mutation rate
- variable expressivity
marfan clinical manifestation
- disorder connective tissue
- ocular
- skeletal
- cardiovascular
marfan mutation
- FBN1 (fibrillin-extracellular matrix protein)
- ch 15q21.1
- dominant negative activity
- reduction in microfibrils
trinucleotide repeat disorders
- segment of DNA consisting of 3 or more nuts
- slipped mispairing
- anticipation
- parental transmission bias
- AD, AR, X linked transmission
slipped mispairing
- mispairng of bases in regions of repetitive replication coupled with inadequate repair systems
- as repeat grows, probability increases
anticipation
- severity/onset of disease increases next generation
- increase in number of copies
parental transmission bias
-trinucleotide expansion more prone to occur in gametogenesis of m/f
huntingtons
- autosomal dom
- tnr disorder (CAG)
- 1/10000
- anticipation
- parent of origin affects (early onset-paternal, late-maternal)
clinical manifestation huntingtons
- progressive neuronal degeneration
- 34-44 age of onset
- death 15 yrs after onset
huntingtons muation
- HTT
- ch 4p16.3
- expansion of glutamine may cause an altered structure or biochemical property of protein
myotonic dystrophy type 1
- autosomal dom
- tnr disorder (CTG)
- 1/20000
- anticipation
- maternal transmission
clinical manifestations of myotonic dystrophy type 1
- adult onset
- progressive muscle wasting/weakness
- myotonia
- cataracts
- cardiac conduction defects
mutations in MD1
- DMPK (myotonic dystrophy protein kinase)
- ch 19q13.3
- plays role in muscle, heart, brain cells
MD1 CTG repeat
- 5-24=normal
- 34-49=premutation
- > 50=full mutation, 100% penetrance
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
with skewed x chromosome inactivation what happens?
- observed when female shows sign or symptoms of x-linked recessive condition
- eg: duchene MS
x-linked disorders
- x chromosome mutations
- male affected mostly
- male-male transmission
- hemizygous for mutations in x-linked genes
x-linked recessive inheritance
- phenotype expressed in all males who carry
- expressed in only homozygous females
- hetero females are carriers
x-linked dominant
- hypophosphatemic rickets
- alport syndrome
- fragile x
- charcot marie tooth
- incontinentia pigmenti
- rett syndrome
- orofaciodigital syndrome
- focal dermal hypoplasia
hypophosphatemic rickets
- x linked dom
- 1/20000
- short stature
- bone deformity
hypophosphatemic rickets mutation
- PHEX gene
- regulates fibroblast growth factor
- inhibits kidneys to reabsorb phosphate
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
fragile x clinical manifestation
- intellectual disabilities
- dysmorphic features
- autistic
- socially anxious
- hand flapping/biting
- agression
FMR1 associated conditions
- FXTAS (fragile x associated tremor ataxia syndrome)
- primary ovarian insufficiency
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
rett syndrome mutation
- gene MECP2
- methyl CpG binding protein
- normal function nerve cells necessary
- boys don’t live
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
lesch-nyhan syndrome
- x linked
- 1/380000
- cerebral palsy
- uric acid overproduction
- self injury
- cognitive issues
lesch-nyhan mutation
- HPRT1
- recycles purines
dystrophinopathies
- x linked recessive
- spectrum m. disease
- 3 distinct conditions: duchenne, Becker, DMD cardiomyopathy
dystrophinopathies mutation
- DMD gene, x chromosome
- ch Xp21-21.1
- dystrophin
- largest human gene
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
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
DMD-associated DCM
- present btw. 20-40 years
- early death
- no sm involvement
- no dystrophin in myocardium
- female carriers affected w/ cardiomyopathy
hemophilia A
- x linked recessive
- 1/4000 male births
- 10% female carriers affected
- can’t clot, excessive bruising, royal fam
hemophilia A mutation
- gene F8 on x chrom
- Xq28
- deficiency factor 8
- 22A inversion causes 50%
mitochondria
- perform oxidative phosphorylation
- encodes 37 genes
- produce components respiratory chain
- maternal inheritance
- replicative segregation
- threshold effect
- affected females pass to all children
replicative segregation
- at cell division, multiple copies of mtDNA
- replicate/randomly sort among newly synthesized mitochondria
heteroplasmy
-presence of more than 1 type of organellar genome within cell or individual. important factor in considering the severity of mitochondrial diseases
mitochondrial disease
- group disorders caused by dysfunction of respiratory chain
- disorders tend to affect tissues that rely on oxidative phosphorylation
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
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
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
Leber Hereditary Optic Neuropathy
- mitochondrial inheritance
- 1 in 30-50000 europeans
- bilateral subacute vision failure
- occurs young adulthood
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
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
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)
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
epigenetic gene expression patterns
-cell differentiates, some “light switches”/genes go off/on
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
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
histone H3 modifications affect gene expression
- repressive histone marks-off
- active histone marks-on
- ones sticking out from the strand are easiest to modify
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)
epigenetic phenomena
- chromatin-mediated gene silencing
- dosage compensation v. important
- important factor in many diseases
silencing of tumor suppressor gene
- 5meC can lead to cancer
- unmethylated–>methylated
- enzymes maintain repression-histone deacytelases
epigenetic therapy
- disrupt tumor suppression
- combinational therapy on multiple regulatory mechanisms
causes of genetic disease
- alteration of DNA changes products (mRNA, protein)
- mutations that alter functional proteins
loss of function mutations
-single gene disorders almost always result from mutations in the function of a protein
what are the 4 common mechanisms of human genetic disease?
- no gene
- no rna
- no protein
- protein nonfunctional
DMD Xp21.2
-sex linked
-premature termination from nonsense/stop mutations, frameshift, deletions
-gower maneuver
-boys
duchenne muscular dystrophy
-frameshift-lof mechanism
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
what happens with unequal crossing over between 17p12?
- pmp22 gene
- supposed to line up normally-misalign
- crossover that can occur, duplication or deletion
allelic disorders
- conditions genetically related
- HNPP and CMT1A are in sense that diff mutations in same gene lead to diff phenotypes
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
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
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
novel property mutations
- eg: sickle cell anemia
- mutation: no effect O2 carrying
- novel property of polymerizing under low O conditions
- long hemoglobin polymers
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
hereditary persistence of fetal hemoglobin
- altered or ectopic expression
- binds tightly
- protective against malaria
- normal product expressed at the wrong time
trinucleotide repeats
- affect different parts of the gene
- knowing locations may shed light on underlying mechanisms
