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An exam IV survival guide, hope this helps. (*) indicates it will be covered in Monday’s lecture,
so the material I used came from the notes as is.
Rock on,
-Pat Clements
Codominance?
Achondroplasia
- autosomal dominant trait
- most adults are heterozygotes (homozygotes don’t survive)
- gain of function mutation in fibroblast growth factor receptor 3 (FGFR3)
arginine substitution (i.e. for glycine)
abnormal endochondral ossification
- dwarfism with disproportionate arms and legs
- abnormal pelvis, neuro and cardiopulmonary problems, hearing loss, spine deform
- somatotrophin (synthetic human growth hormone) can treat, in early years
Albinism
- lack of pigmentation
- defect is autosomal recessive
- defect in tyrosinase gene (catalyzes the reactions necessary to make dark pigment)
- heterozygous has normal phenotype, must be homozygous aa to have condition.
Angleman’s syndrome (aka Happy Puppet Syndrome)
- most patients have deletion in the AS region of maternal chromosome 15
- some have paternal uniparental disomy for chromosome 15
- few (3%) have defect in maternal imprinting
- candidate gene: UBE3A - transfers ubiquitin to protein
- targets protein for breakdown by proteasome
- characterized by mental retardation, speech impairment, excitability, inapprop. laughter
- unsteady gait and unsteady limbs
Aniridia
- caused by a PAX6 mutation
- absence of the iris
Ataxia Telangiectasia
- a disease of DNA repair (nothing else mentioned in lecture)
Bloom’s syndrome
- defect in BLM helicase (but other helicases not affected)
helicase works to unwind tetraplex DNA structures
- leads to chromosomal and genetic instability
Causes: Growth retardation Sunlight sensitivity
Decreased fertility Immunodeficiency
Cancer (both solid tumors and leukemias)
Bruton’s agammaglobulinemia
- defective tyrosine kinase defective maturation of B-cells
no Ig production bacterial infection susceptibility at 4-8 months
(initially ok, b/c antibodies from mother’s breastmilk)
Campomelic dysplasia
- mutant SOX9 gene (homologies to SRY, sex determining region of Y chromosome)
- underdeveloped thorax, bent limbs
- sex reversal (i.e. female with XY karyotype)
Craniosynostosis
- caused by Fibroblast growth factor response genes (cell division/migrat/diff.)
- mutant FGFR 2
- irregular shape of skull
- i.e. Crouzon syndrome and Apert syndrome
DiGeorge anomaly of brachial arch defects (related to the other DiGeorge stuff below???)
- defect in thymus development (site of T-cell differentiation and selection)
leads to T-cell deficiency
susceptible to yeast and viral infections
Emphysema
- environmental factors can influence genes
- α1-anti-trypsin, coded by the Serpina genes (multiple alleles)
-blocks degradation of proteins (inhibits trypsin and elastase)
- smoking introduces superoxide anion inhibits this enzyme can’t protect
breakdown of structural proteins emphysema
Faconi Anemia
- bone marrow failure, growth retardation
- skin, G.I., and kidney abnormalities
- increased cancer occurrences, particularly myolegnous leukemia
- increased chromosome damage (more susceptible)
- defect in a Faconi complementation group
possibly knocks out important signal or repair pathway
* Factor V Leiden Trhombophilia
- single point mutation in factor V gene at nucleotide 1691
- G A base substitution leads to Arginine to histidine
- occurs at an APC cleavage site (therefore Activated Protein C resistance)
- causes slower inactivation of Factor V by APC
increases thrombin production
- increased risk of clotting (thrombosis)
- heterozygotes have slightly elevated risk
- detect mutation by MnI 1 enzyme digestion
(mutants have one less cleavage site, so produces 2 DNA fragments instead of 3)
Favism
- example of ecogenetics
- decreased activity in glucose-6-phosphate dehydrogenase
less reduced glutathione oxid. damage to RBC’s
- oxidant drugs can accelerate loss of glutathione
- or ingestion of fava beans
- So is it just me, or does half of what we learned in block 1
relate to Silence of the Lambs?
Galactosemia
- autosomal recessive, equal gender and race ratios
- can’t metabolize galactose (serum levels higher than 3-4 mg/dl)
- defective galactokinase or uridine diphosphate hexose-4-epimerase
- Most common – defect galactose-1-phosphate uridyltransferase
- can’t convert to UDP-galactose and glucose-1-P
- severity depends on type of variant
- buildup of galactisol (toxic)
- causes cataracts, jaundice, liver enlargement
- TREAT: - restrict galactose in diet (i.e. milk)
Gout
- defective purine metabolism excess uric acid
- Sodium urate crystal deposits in joints painful attacks, often in toes
- multiple possible causes:
- defective PRPP synthase can’t be regulated oversynth of purines
therefore many broken down)
- defective glucose-6-phosphatase increased G6P inc Ribose 5-P via PPP
therefore oversynthesis of purines
- partial HGPRTase deficiency can’t salvage purines properly inc uric acid
(Gout is not actually caused by the evil gout demon with the
stingray barb tail)
- Follow this link for an 18th century newspaper editorial
regarding the treatment of gout
http://www.infopt.demon.co.uk/grub/gout.htm
Hand-foot-genital syndrome
- caused by HOX-A13 mutation
- just like it sounds, defects in the hands, feet, and genitals
* Hereditary Hemochromatosis
- iron overload disorder (transferrin saturation, increased serum ferritin)
- autosomal recessive trait, but phenotype is sex-influenced
- less common in females
(possibly b/c of less dietary iron uptake and losses via menstruation)
- molecular testing on HFE gene (common: C282Y and H63D mutations)
- HFE facilitates transferrin-bound iron uptake from gut
- if mutant, cell fails to sense circulating T.F.-bound iron
increased absorption of dietary iron
high expression of iron transporters, but low ferritin expression
- heterozygotes have elevated serum iron, but no major iron overload complications
- takes long time to develop pathology
- especially toxic to liver and kidneys
Hemophilia A
- X-linked recessive
- higher incidence in males (since hemizygous)
- deficient in factor VIII (clotting factor)
- traced in royal families of Europe
Hermaphroditism (2 classifications)
PSUEDO: - XX male w/ gonadal dysgenesis (can’t undergo puberty)
- SRY factor was transferred to X chromosome
TRUE: - 46, XX
- has both testicular and ovarian tissue, both sex organs, or ambiguous
Heterogeneous Nonpolyposis Colon Cancer
- a disease of DNA repair (nothing else mentioned in lecture)
Homocystinuria
- autosomal recessive
- homocysteine is produced from methionine.
- Classical Homocystinuria - defect serine cystathione synthase (chromosome 21)
- can’t covert homocysteine cystathione
- also disease with B12 deficiency
- can’t re-methylate homocyteine to form methionine
- Methionine synthase deficiency
- converta homocysteine to methionine (requires methyl-THF cofactor)
- blocks the reconversion of methyl-THF THF
- Characterized by developmental delay, childhood osteoporosis, myopia & ectopia lentis
- increased CHD (increased thrombus risk)
- TREAT with folic acid, pyroxidine
- restrict methionine in diet, and supplement cysteine.
Huntington’s Disease
- single gene mutation
- classified as a DNA repeat expansion disorder
- autosomal dominant (“vertical” inheritance, heterozygotes are affected)
- expansion of CAG repeat in the coding region for the protein Huntingtin
causes a polyglutaminyl chain to be added (gain of function)
- extra glutamines causes Huntingtin aggregation in brain cell nuclei
- binds to Huntingtin associated protein (HAP) in brain
- later onset, usually well into reproductive age (30-50 years old)
- all heterozygotes will eventually express phenotype
- 50% express it by age 50
- chorea (abnormal voluntary movement)
- dementia (basal ganglia atrophy and dilation of lateral ventricle)
(degredation in cerebral cortex and basal ganglia)
Hyperammonemia
- autosomal recessive, equal gender ratios
- disorder of urea cycle, many enzyme deficiencies possible
- most common – deficient ornithine transcarbamylase
- can’t convert carbamoyl phosphate citrilline, for shuttle out of mitochondria
- anorexia, hypothermia, edema, respiratory problems, tremors, poor coordination
- TREAT: - stop protein uptake
- supplement non-protein calories
- dialysis
Hyperphenylalaninemia
- autosomal recessive (equal gender ratios, but racial differences exist)
- generally classified with serum phenylalanine higher than 2mg/dl
- Classical Phenylketonuria Hyperphenylalaninemia (most common)
- caused by lack of phenyalanine-4-hydroxylase [PAH] (can’t catabolize)
- allelic heterogeneity allows for different levels of enzyme (different severities)
- Non-classical PKU (BH4 deficiency hyperphenylalaninemia)
- deficiency in tetrahydrobiopterin (BH4)
- this is a necessary cofactor for PAH
Hyperphenylalaninemia characterized by:
- increased serum phenylalanine
- decreased tyrosine, melanin, fumarate, and catecholamines
- irritability, eczema-like rash, musty urine odor
- microcephaly, mental retardation
- TREAT: - supplement BH4 and tyrosine
- avoid high protein foods
- high carbs and fats instead for energy
Hyperuricemia
- defective purine metabolism
- leads to increased uric acid in blood and urine
Kearns-Sayre syndrome
- caused by deletions in mitochondrial DNA (mtDNA)
- multisystem disorder, mainly brain and muscle dysfunction (can’t do OXPHOS)
- also short stature, hearing loss, mental retardation
Klinefelter syndrome
- 47, XXY (aneuploidy)
- longer arms and legs
- imbalanced sexual development
- underdeveloped genetials
- infertility
- abnormal breast development (gynecomastia)
- fat distribution in body similar to females
Lesch-Nyhan Syndrome
- absence of HGPRT (hypoxanthine-guanine phosphoribosyl transferase)
- hyperuricemia (2 ways)
increased PRPP increased purine synthesis increased uric acid
decreased GMP increased purine synthesis
- since brain is reliant on salvage pathway neurological effects
- self-mutilation, mental retardation, etc
Marfan Syndrome
- autosomal dominant (“vertical” inheritance, heterozygotes are affected)
- mutant glycoprotein fibrillin-1 gene (FBN1)
can’t properly synthesize elastic connective tissue
ruptured aorta, skeletal manifestations, dislocated lenses
- variable expression in humans (different phenotypes in everybody)
Maternal Diabetes
- teratogenic
- causes large birthweight, brain anomalies, heart defects
Megaloblastic Anemia
- abnormally large RBC precursors (megaloblasts)
abnormally large RBC’s (macrocytic)
- insufficient nucleotide synthesis in rapidly dividing cells
- either folate or B12 deficiency (pernicious anemia)
- important to find out though, b/c B12 deficiencies have other effects too
i.e. demylenation of neurons (Folate defic. can mask B12 defic.)
- find out using serum folate, B12, and methylmalonic acid levels
Melanoma
- has been targeted with gene therapy (experiemental)
- removed T cells from body (therefore ex vivo)
- insert gene for specific T-cell receptor (TCR), inject cells into patient
t-cells can recognize and trigger immune response against melanoma
Mucopolysaccharidoses
- autosomal recessive lysosomal storage disease
- can’t degrade mucopolysaccharides
- Sanfilippo syndrome most common, 4 subtypes
- hydrocephalus, angina, obstructive airway disease, ophthalmologic, musc/skel disease
- many die early in life
- TREAT: bone marrow transplant can help with some of the effects, prolong life
Myotonic dystrophy
- a DNA repeat disorder
- CTG repeat occurs after the stop codon
Neurofibromatosis Type I
- autosomal dominant
- mutant NF1 gene
decrease in neurofibromin (a tumor suppressor protein)
- nuerofibromas
- abnormally dilated blood vessels, stenosis, hypertension, aneurisms, optic nerve gliomas
Non-Syndromic Deafness
- example of locus heterogeneity
- mutations on different loci (therefore different genetic causes)
all can lead to deafness (different genotype same phenotype)
Noonan Syndrome
- similar to Turner syndrome, but has a normal karyotype
- both sporatic and autosomal dominant cases have been observed
- mutant protein tyrosine phosphatase non-receptor type II (PTPN11)
gain of function? (pathophys not completely understood)
- facial irregularities, most dangerous is the congenital heart disease
Osteogenesis Imperfecta
- dominant negative mutation
- defective type I collagen (made of 2 α-1 chains and 1 β-2 chain)
- α-1 (COL1A1 gene)
- β-2 (COL1A2 gene)
- T1 collagen is major struct. component of bone/fibrous tissue
- mild type (I) decreased production of collagen, but normal chains
- more severe types (II, III, IV) missense mutation = amino acid change
abnormal collagen
- brittle bone disease, also shortened and bowed femur
- presents as multiple current/healed fractures
- Molecular Testing: - analysis of collagen
- mutation analysis
Patau syndrome – see trisomy 13
Pearson’s Syndrome
- caused by mitochondrial DNA (mtDNA) deletion
- non-neurological childhood pancytopenia (low RBC’s and WBC’s) and pancreatic dys.
- if survival to childhood, becomes Kearns-Sayre syndrome
Pernicious anemia
- caused by decreased intrinsic factor can’t absorb B12
- causes deterioration of stomach lining
Chronic atrophic gastritis (an autoimmune disorder)
- can be cured with monthly B12 injections
Phocomelia
- rare genetic disorder
- causes severe shortening of the arms and legs
- the toxic effects of thalidomide prenatally are considered a phenocopy of phocomelia
Situs Inversus
- caused by mutant ZIC3 gene (zinc-finger gene)
- abnormal left/right organ alignment in body
Skeletal dysplasia
- caused by Fibroblast growth factor response genes (cell division/migrat/diff.)
- mutant FGFR 3
- i.e. Achondroplasia (see for more info)
Synpolydactyly
- caused by a HOX-D13 mutation
- bony fusions and accessory bones in hands and feet
Tay-Sachs
- frameshift mutation (4 BP insertion)
- neurologic degeneration, blindness, deaf, paralysis, death by 3 yr
- defect β-N-acetylhexosaminidase (Hexosaminidase A)
gangliosides with GalNAc cannot be degraded
lipid deposits form in neurons
Thalassemia
- group of hereditary anemias, caused by defective globin chain synthesis (α/β)
- possible genetic causes: - defect mRNA processing (intron mutations)
i.e. sickle cell
- nonsense mutations (termination codon added)
- termination code mutations
- α-thalassemia is an example of modifying loci (gene modifies other gene)
- leads to decreased severity of sickle cell disorder
(less Hb decreased amount to polymerize and change cell shape)
Thalidomide embryopathy
- phocomelia and heart/ear anomalies
Triploidy
- 3N, having an extra sex chromosome (XXX or XXY)
- lethal, early spontaneous abortion
- trunk:head disproportion and syndactyly (fused fingers)
- Causes: - 2nd polar body doesn’t eject from egg [diagyny]
- fertilization by two sperm (improper polyspermy block) [diandry]
- nondisjunction in meiosis I/II
- nondisjunction in mitosis (cleavage furrow before complete separation)
Diandry: - extra paternal set (contributes more to membranes and placenta)
- huge placenta, larger than fetus (partial hydatidiform mole)
Diagyny: - [think gyn = woman]
- extra maternal set (contributes more to embryo proper)
- small placenta, normal fetus development with enlarged head
Turner syndrome
- 45, X (aneuploidy)
- often spontaneously aborted due to fluid imbalance
- severe lymphedema (lymphatic blockage)
- cystic hygroma (fluid filled sac in the back of the head)
UV Light Damage
- causes pryimidine dimer (thymine)
- thymines can be reversed with photolyase (breaking cyclobutane ring of the dimer)
- enzyme activated by UV light exposure (smart )
Waardenburg Syndrome
- autosomal dominant, loss of function mutation
- “vertical” inheritance, heterozygotes are affected
- defect in HuP2 (PAX3) homeobox gene ( TF)
- causes white forelock, premature graying,
different colored eyes, deafness
Werner’s syndrome
- defective WRN helicase
- this helicase may be involved with recombination
- chromosomal and genetic instability
- causes excessive aging
cardiovascular disease, arthritis, cancer
William’s Syndrome
- rare, deletion involving elastin gene (ELN)
- cardiovascular problems (i.e. supravalvular arotic stenosis)
- connective tissue problems, hypercalcemia, distinct facial features
Xanthinuria
- Deficiency is xanthine oxidase (converts xanthine uric acid)
- increased excretion of xanthine and hypoxanthine
- decreased uric acid production
- causes kidney stones (xanthine lithiasis)
Xeroderma Pigmentosum
- autosomal recessive
- growth and neurological defects
-extreme sensitivity to light
- defect in excision repair
- protein XPA binds to damaged site
complex unwinds DNA
30 nucleotide sequence removed and repaired
- since such a large chunk removed for repair,
higher likelihood of error
- increased cancer occurrence
DONE!!!