Genetic Disorders Flashcards
Hurler Syndrome
Type, Gene, Symptoms, Rx
Autosomal Recessive
Gene: alpha-L-Iduronidase
Tay- Sachs:
type
What gene?
Build up of what?
Mutation Type and Result?
Autosomal Recessive
Gene: HexA
Build up of GM2 gangliosides leading to neuron damage
Mutation: 4 base insertion causing frameshift mutation. Premature stop codon and truncated protein
Cystic fibrosis
Type
Gene
Mutation type
Result
Autosomal Recessive
gene: CFTR
Mutation type: 1 amino acid lost, but in-frame mutation
Result: prevents CFTR chloride channel. Results in thick mucus sections because water isn’t attracted.
Sickle Cell Disease
Type
Mutation type
Autosomal Recessive
Mutation: wrong amino acid, (A to T)
Beta-Thalassemia
Type
Mutation type
Autosomal recessive
Point mutations decreasing production of beta globin (hemoglobin)
Hereditary hemochromatosis
Type
Gene
Mutation type
Whos affected
Autosomal Recessive
Gene: HFE (high iron)
Mutation: single missense resulting in iron overload
Who is affected? adult males more commonly affected
Huntington disease
Type:
Gene:
Autosomal dominant
Gene: HD, trinucleotide repeat expansion
Achondroplasia
Type:
Gene:
Autosomal dominant
Gene: FGFR-3, glycine to arginine missense, gain of function
Neurofibromatosis Type 1
Type
Gene
Type: autosomal dominant
Gene: NF1, nonsense point mutation resulting in shortened protein
Marfan Syndrome
Type
Gene
Autosomal dominant
Gene: FBN1, elastic fibers in connective tissue
Lesch - Nyhan Syndrome
Type
Gene
X-linked recessive
Gene: HGPRT - involved in purine recycling. Deficient HGPRT results in overproduction of uric acid
Duchenne muscular dystrophy
Type
Gene
mutation type
X-linked recessive
Gene: dystrophin (muscle fibers, largest human gene)
Mutation type: deletion leading to frameshift.
Milder cases have mutations without frame shift (becker) and protein is partially active
Hemophilia B
Type
males or females?
effect
mutation
X linked recessive
Affects males, females have second working X chromosome
Effect: deficiency of factor IX
Mutation: point mutation in promotor region of gene, A to G transition alters transcription factor of factor IX gene
Gowers sign
results from weakness of lower limbs
Use arms to “climb” up the legs to elevate the torso.
Rett syndrome
Type
Gene
variation of Sx
Male or female
X linked dominant
Gene: MeCP2
Variation in females due to skewed x-inactivation patterns
Generally not transmitted through families
Lethal in males
Fragile X Syndrome
Type
Gene
male or female
X linked dominant
Gene: FMR1, CGG repeat expansion in promotor region
More severe in males
Anticipation observed in later generations due to trinucleotide repeat expansion when female carriers pass the trait.
Langer mesomelic dysplasia and Leri-Weill dyschondrosteosis
Type
Mutation
Y chromosome disorder
mutation in pseudoautosomal region of SHOX gene
Swyer syndrome
Type
effect
Y chromosome, SRY gene disorder
Effect: genotypic male develops as a female
46 XX testicular disorder of development
Type
effect
Y chromosome disorder, SRY translocation onto X chromosome
Effect: individuals develop as male, with similar sx to kinefelter
Mitochondrial diseases
CEPO Kearns-Sayre Leigh LHON MERRF MELAS Person Syndrome
Phenylketonuria (PKU)
Type
Gene
Sign
Treatment
Autosomal recessive
Gene: PAH
Signs; phenylalanine and phenylketones in blood. Phenylketones in urine
Treatment: restrict dietary phenylalanine. if caught early, neurological damange can be mitigated
PKU: causes of intellectual disability
high levels of phenylalanine and phenylketones directly toxic to brain
Excess phenylalanine saturates lare neutral amino acid transporter at BBB, leading to excess of phenylalanine in brain and preventing other AAs from entering
Failure to produce adequate dopamine and epi due to lack of tyrosine
Origin of Trisomy 21
95% of cases due to mother’s nondisjunction of chromosome 21
5% due to robertsonian translocation
Trisomy 18 (Edward Syndrome)
Origin
Sxs
Nondisjunction of chromosome 18 in mother
Sx: intellectual disability low weight diaphragmatic hernia heart defects small eyes, mouth, receding jaw kidney defects clenched fists rocker bottom feet
trisomy 13 (Patau syndrome)
Origin
Sx
Origin: 95% nondisjunction in mother. 5% Robertsonian translocation
Sx: intellectual disability Microcephaly, holoprosencephaly postaxial polydactyly cleft lip/palate small eyes, large triangluar nose deafness
Turner syndrome
Cause
Sx
Treatment
45, X
Cause: one X chromosome, so only 1 copy of PAR1 and PAR2 genes
Sx: short stature, learning disabilities, braod neck, visual impairments, kidney abnormalities, ovarian dysgenesis and lack of secondary sexual characteristics
Treatment: growth hormone and estrogen therapy
Klinefelter Syndrome
Origin
Sx
Treatment
47, XXY
Sx: often SUBTLE
Treatment: testosterone therapy, speech therapy, physical therapy
Exons
coding regions that contain DNA sequence that translates to the final protein product
Introns
non-coding regions that contain regulatory information and can be removed by splicing
Molecular fingerprint
uses polymorphisms to identify an individual. identifies using the number of repeats in a sequence.
CODIS is used by the FBI to search a set of 15 VNTR loci
Everyone has 2 sets of chromosomes with their own repeat polymorphism pattern
STRP
2-5 bp
VNTR
14-500 bp
CNV
2 million bp
Paternity testing
uses VNTR analysis and compares bands of potential fathers to child.
If no bands are shared, the individual is not the father.
Nonsense mutation
introduces new stop codon
silent sense mutation
base change that doesn’t alter the amino acid
missense mutation
wrong amino acid
Frameshift mutations
1-2 bp deleted or added (or multiples) cause codons to be read in the wrong frame.
In-frame mutation
3bp added or deleted, extra amino acid is inserted/deleted but remaining codons are read correctly
DNA 3’ and 5’ ends
3’ OH group, 5’ terminal phosphate.
Techniques for genotyping or sequencing DNA
PCR, southern blot, cloning
Detects and quantitates specific genes
Measures gene expression
northern blot, microarray, qRT-PCR, Next Gen sequencing
Measures protein expression
Western blot, ELISA
detects presence and relative quantity of protein
4 steps of PCR
denature, anneal, elongate, repeat for 20-35 cycles
Principle of independent assortment
an allele transmitted at one locus has no influence on which allele is transmitted at another locus
Gene frequency
how often a particular gene sequence (allele) occurs in a population
genotype frequency
how often a given genotype occurs in a population
Occurrence risk
risk of producing an affected child when no children have yet been produced
Recurrence risk
risk of producing an affected child when one or more children with the disease have been produced
Autosomal Dominant Diseases
Huntingtons Disease (HD),
Achondroplasia (FGFR-3)
Neurofibromatosis type 1 (NF1)
Marfan Syndrome (FBN-1)
Familial hypercholesterolemia (LDL receptor gene)
6 Characteristics of autosomal recessive inheritance
1/4 of offspring btwn heterozygous affected
if parents are carriers, multiple affected children likely
sometimes no family hx of disease
carrier individuals are present in skipped generations
males and females equally likely
cosanguinity present
Hardy Weinberg Principle
(p+q)^2 = p^2 + 2pq + q^2 = 1
(p+q)^2 = gene frequency
p^2 = homozygous dominant frequency
q^2 = homozygous recessive frequency
2pq = heterozygous frequency
Find 2pq (heterozygous frequency)
q^2 = tt frequency. find this (given)
square root it (you end with q)
subtract q from 1 (you end with p)
calculate 2pq
Principle of segregation
genes remain intact and distinct in next generation, they are not blended.
Lysosomal storage disorders
Hurler syndrome, Tay-Sachs
Autosomal recessive diseases
Hurler syndrom (a-L-iduronidase, glycosaminoglycan)
Tay Sachs (HexA, GM2 gangliosides)
Cystic Fibrosis (CFTR)
Sickle Cell (B-globin gene
B-Thalassemia (B-globin)
Hereditary hemochromatosis (HFE)
Sporadic occurance
de-novo mutation
achondroplasia, NF1
Germline mosiacism
Germline consists of more than one distinct population of cells.
osteogenesis imperfecta
Delayed age of onset
diseasae doesn’t manifest until adulthood
huntington disease, hemochromatosis
Reduced penetrance
not everybody carrying the genotype will express the associated phenotype
Retinoblastoma (Rb, 90% penetrance)
Variable Expression
affects severity of disease independent of penetrance
NF-1
Pleiotropy
exerts its effects on multiple aspects of physiology or anatomy
Cystic fibrosis, Marfan Syndrome
Heterogeneity
mutations at different gene loci can produce the same disease phenotype
Osteogenesis imperfecta
Genomic Imprinting
paternal and maternal chromosomes contribute different amounts of gene product
Prader willi (from father), angelman (from mother)
Anticipation
displays an earlier age of onset/more severe expression in more recent generations
Myotonic dystrophy, fragile X, huntington
Cosanguinity
mating between related individuals
Rare recessive diseases
X-Activation, incompletion
15% of genes on X chromosome remain active
XIST gene
PAR1/PAR2 genes behave like autosomes, their products are found on x and y chromosomes
replicative segregation in mtDNA
random distribution of mtDNA among daughter mitochondria, and random distribution of mitochondria between daughter cells
Homoplasmy and heteroplasmy
homoplasmy = daughter cell received pure population of mito, all with normal or all with mutated DNA
Heteroplasmy = daughter cell received mixed population of mitrochondria, some with and some without mutated mtDNA
polygenic model
trait in which variation thought to be a combined effect of multiple genes
additive polygenic model states the number of phenotypic classes increases as the number of genes controlling a trait increases.
Applied to quantitative traits
Threshold model
applied to qualitative traits, all-or-nothing traits.
Must meet a threshold of liability to develop disease
Threshold may be different in different populations
Pyloric stenosis
Threshold model example
males more effected
sx: recurrent vomiting, dehydration, electrolyte imbalance.
Factors affecting recurrence risk
of affected family members
degree of relationship to proband
increases if proband is of less commonly affected sex
severity of disease in proband
Twin types
monozygotic = identical twins
Dizygotic = fraternal twins
heritability (h)
the proportion of variation in a disease trait that can be attributed to genes
h = 2(Cmz - Cdz)
amniocentesis
optimal time: 15-20 weeks
tests: cytogenic analysis, DNA testing, Fetal a-fetoprotein (AFP)
High AFP = high risk of neural tube disorders
Low AFP = risk of trisomies
Chorionic Villus Sampling
optimal time: 10-12 weeks
sample collected: fetal trophoblastic tissue
tests: cytogenic analysis, DNA testing
Conditions: chromosomal abnormalities
Ultrasonography
Optimal time: 16-18 weeks
Visualization of fetus for structural abnormalities
Maternal serum screening and Nuchal Translucency
optimal time: 11-14 weeks
Sample collected: maternal serum + ultrasounds
Tests: AFP in mothers serum, increased nuchal translucency suggests risk of chromosomal anomalies
Conditions: trisomies and neural tube disorders
High AFP = neural tube
Low AFP = trisomies
Triple Screen
combines three proteins: maternal AFP, hCG and estriol
Accurate at 16-18 weeks
concerns with false positives
Cell-free fetal DNA testing
measures fetal DNA shed into mothers blood during pregnancy
simple blood draw for mom
Results should be confirmed with another method
Tests for trisomies, aberrant numbers of sex chromosomes, sex of baby
acrocentric chromosomes
13, 14, 15, 21, 22
Involved in Robertsonian translocations
Cell cycle beginning
mitogen binds to receptor
Phosphorylation cascade via Ras
MAPK activated, increases synthesis of MYC
MYC transcription factor increases expression of cyclin D.
Cyclin-CDK complexes in cell cycle
G1 early - cyclin D-CDK4/6
G1 late - Cyclin E- CDK2
G1/S .- Cyclin A-CDK2
S/G2 - Cyclin A-CDK1
M - Cyclin B-CDK1
“Do Enter After the Bell”
Antimetabolites
Methotrexate
S phase of cell cycle
inhibits synthesis of dTMP and purines thereby disrupting DNA production
Mitotic inhibitors
Paclitaxel
G2/M phase
bind to microtubules, arrests mitosis in metaphase
induces apoptosis by blocking function of apoptosis inhibitor Bcl-2
Anti-tumor antibiotics
Doxorubicin, anthracycline, daunorubicin
Intercalating into DNA
Alkylating agents
Cisplatin, carboplatin
interphase
forms covalent interstrand and intrastrand crosslink with purine bases
interferes w/ DNA repair, synthesis and transcription
Immunotherapy
Herceptin/Trastuzumab
binds to extracellular domain of HER2 that has RTK activity, blocking downstream signalling
reduces number of cells in S phase
inhibition of cancer promoting proteins
Imatinib/Gleevac
a signal transduction inhibitor via RTK
Inhibiting angiogenesis
Avastin
Inhibitor of VEGF receptor.
