Bio Chemisity Flashcards

Question

Types of RNA

Answer 1

Types of RNA ## Footnote rRNA is the most abundant type. mRNA is the longest type. tRNA is the smallest type. memory aid**: R**ampant, **M**assive, **T**iny.

Answer 2

Start and stop codons mRNA start codons: AUG (or rarely GUG). * memory aid: AUG inAUGurates protein synthesis. Eukaryotes: Codes for methionine, which may be removed before translation is completed. Prokaryotes: Codes for formylmethionine (f-met). mRNA stop codons: UAA, UAG, UGA. * memory aid: * **U** **A**re **A**wesome * **U** **A**re **G**reat * **U G**onna get an **A!** or * memory aid: * UGA = **U** **G**o **A**way. * UAA = **U** **A**re **A**way. * UAG= **U** **A**re **G**one.

Answer 3

Fundional organization of the gene

Answer 4

Promoter Site where RNA polymerase and multiple other transcription factors bind to DNA upstream from gene locus (Kf-rich upstream sequence with TKfA and CAAT boxes). * Promoter mutation commonly results in dramatic decrease in amount of gene transcribed.

Answer 5

Enhancer Stretch of DNA that alters gene expression by binding transcription factors. * Enhancers and silencers may be located close to, far from, or even within (in an intron) the gene

Answer 6

Silencer Site where negative regulators (repressors) bind. * whose expression it regulates.

Answer 7

Eukaryotes RNA polymerases RNA polymerase I makes rRNA (most numerous RNA, rampant). RNA polymerase II makes mRNA (largest RNA, massive). RNA polymerase III makes tR A (smallest RNA, tiny). No proofreading function, but can initiate chains. RNA polymerase II opens DNA at promotor site * I, II, and III are numbered as their products are used in protein synthesis. * alpha-amanitin, found in Amanita phalloides (death cap mushrooms), inhibits RNA polymerase II. Causes severe hepatotoxicity ifingested.

Answer 8

Prokaryotes Polymerases ## Footnote l RNA polymerase (multisubunit complex) makes all 3 kinds of RNA.

Answer 9

RNA processing (eukaryotes) Initial transcript is called heterogeneous nuclear RNA (hnRNA). hnRNA destined for translation is called pre-mRA. * Only processed RNA is transported out of the nucleus. Processing occurs in nucleus. After transcription: * Capping on 5' end (addition of 7-methylguanosine cap) * Polyadenylation on 3' end ("" 200 1\s) * Poly-A polymerase does not require a template. * AAUAAA =polyadenylation signal. * Splicing out of introns * Capped, tailed, and spliced transcript is called mRNA.

Answer 10

Splicing of pre-mRNA ## Footnote 1) Primary transcript combines with snRNPs and other proteins to form spliceosome. 2) Lariat-shaped (looped) intermediate is generated. 3) Lariat is released to remove intron precisely and join 2 exons. Patients with lupus make antibodies to spliceosomal snRNPs.

Answer 11

lntrons vs. exons Exons contain the actual genetic information coding for protein. * Different exons can be combined by alternative splicing to make unique proteins in different tissues (e.g., beta-thalassemia mutations). lntrons are intervening noncoding segments of DNA. **learning aid**: **_ln_**trons are **_in_**tervening sequences and stay **_in_** the nucleus, whereas **_ex_**ons **_ex_**it and are **_ex_**pressed.

Answer 12

tRNA Structure ## Footnote 75-90 nucleotides, secondary structure, cloverleafform, anticodon end is opposite 3' aminoacyl end. All tRNAs, both eukaryotic and prokaryotic, have **CCA** at 3' end along with a high percentage of chemically modified bases. The amino acid is covalently bound to the 3' end of the tRNA. **Memory aid**: **CCA**: **C**an **C**arry **A**mino acids.

Answer 13

tRNA Charging ## Footnote Aminoacyl-tRNA synthetase (1 per amino acid, "matchmaker," uses ATP) scrutinizes amino acid before and after it binds to tRNA. If incorrect, bond is hydrolyzed. The amino acid-tRNA bond has energy for formation of peptide bond. A mischarged tRNA reads usual codon but inserts wrong amino acid. Aminoacyl-tRNA synthetase and binding of charged tRNA to the codon are responsible for accuracy of amino acid selection. **Tetracyclines** bind 30S subunit, preventing attachment of aminoacyl-tRNA.

Answer 14

tRNA wobble ## Footnote Accurate base pairing is required only in the first 2 nucleotide positions of an mRNA codon, so codons differing in the 3rd "wobble" position may code for the same tRNA/amino acid (as a result of degeneracy of genetic code).

Answer 15

Initiation of protein synthesis ## Footnote Activated by GTP hydrolysis, initiation factors (eukaryotic IFs) help assemble the 40S ribosomal subunit with the initiator tRNA and are released when the mRNA and the ribosomal subunit assemble with the complex. **E**ukaryotes: 40S + 60S -+ 80S (**E**ven). Pr**O**karyotes: 30S + 50S -- 70S (**O**dd). **A**TP-tRNA **_A_**ctivation (charging). * *G**TP-tRNA **_G_**ripping and **_G_**oing places (translocation) .

Answer 16

Elongation ## Footnote 1) Aminoacyl-tRNA binds to A site (except for initiator methionine) 2) Ribosomal rRNA ("ribozyme") catalyzes peptide bond formation, transfers growing polypeptide to amino acid in A site. 3) Ribosome advances 3 nucleotides toward 3' end of mRNA, moving peptidyl tRNA to P site (translocation) **Learning aid**: Think of "going **APE**": **A** site = incoming **_A_**minoacyl-tRNA. **P** site = accommodates growing **_P_**eptide. **E** site = holds **_E_**mpty tRNA as it **_E_**xits.

Answer 17

Termination ## Footnote Stop codon is recognized by release factor, and completed protein is released from ribosome.

Answer 18

Antibiotics that act as protein synthesis inhibitors: ## Footnote • Aminoglycosides bind 30S and inhibit formation of initiation complex and cause misreading of mRNA * Tetracyclines bind 30S and block aminoacyl tRNA from entering the acceptor site * Chloramphenicol binds 50S and inhibits peptidyl transferase * Macroslides bind 50S and prevent release of uncharged tRNA after it has donated its amino acid **Learning aid**: The exam you took to apply to med school **_M_**acroslides **_C_**horamphenicol **_A_**minoglycosides **_T_**etracycline

Answer 19

Trimming (Posttranslational modifications) ## Footnote Removal of N- or C-terminal propeptides from zymogens to generate mature proteins.

Answer 20

Covalent alterations (Posttranslational modifications) ## Footnote Phosphorylation, glycosylation, hydroxylation, methylation, and acetylation. Learning aid: **_p_**lease **_g_**ive **_h_**im **_m_**y **_a_**ddress!

Answer 21

Proteasomal degradation (Posttranslational modifications) Attachment of ubiquitin to defective proteins to tag them for breakdown.

Answer 22

Cell cycle phases ## Footnote Checkpoints control transitions between phases of cell cycle. This process is regulated by cyclins, CDKs, and tumor suppressors. Mitosis (shortest phase): prophase-metaphase-anaphase-telophase. G₁ and G₀ are of variable duration.

Answer 23

CDKs ## Footnote Cyclin-dependent kinases; constitutive and inactive.

Answer 24

Cyclins ## Footnote Regulatory proteins that control cell cycle events; phase specific; activate CDKs.

Answer 25

Tumor suppressors (cell cycle) ## Footnote p53 and hypophosphorylated Rb normally **inhibit** G1-to-S progression; mutations in these genes result in unrestrained cell division.

Answer 26

Permanent (cell type) Remain in G₀, regenerate from stem cells. * Neurons, skeletal and cardiac muscle, RBCs.

Answer 27

Stable (quiescent) cell type Enter G1 from G₀ when stimulated. * Hepatocytes, lymphocytes.

Answer 28

Labile (cell type) Never go to G₀, divide rapidly with a short G₁. * Bone marrow, gut epithelium, skin, hair follicles, germ cells.

Answer 29

Rough endoplasmic reticulum * Site ofsynthesis ofsecretory (exported) proteins and of N-linked oligosaccharide addition to many proteins. * Mucus-secreting goblet cells ofthe small intestine and antibody-secreting plasma cells are rich in RER. * Nissl bodies (RER in neurons)- synthesize enzymes (e.g., ChAT [choline acetyltransferase] makes ACh) and peptide neurotransmitters. * Free ribosomes-unattached to any membrane; site of synthesis of cytosolic and organellar proteins.

Answer 30

Smooth endoplasmic reticulum Site of steroid synthesis and detoxification of drugs and poisons. * Liver hepatocytes and steroid hormone producing cells of the adrenal cortex are rich in SER.

Answer 31

Cell trafficking Golgi is the distribution center for proteins and lipids from the ER to the vesicles and plasma membrane. * It modifies **N-oligosaccharides** on _asparagine_. * It adds **O-oligosaccharides** on _serine_ and _threonine_**.** * **I**t adds **mannose-6-phosphate** to proteins for trafficking to **lysosomes**. * 1-cell disease (inclusion cell disease)-inherited lysosomal storage disorder; failure of addition of **mannose-6-phosphate** to lysosome proteins (enzymes are secreted outside the cell instead of being targeted to the lysosome). Results in coarse facial features, _clouded corneas_, restricted joint movement, and _high plasma levels of lysosomal enzymes_. Often fatal in childhood. Endosomes are sorting centers for material from outside the cell or from the Golgi, sending it to lysosomes for destruction or back to the membrane/Golgi for further use. Vesicular trafficking proteins * COPI: Golgi -\> Golgi (retrograde); _Golgi -\> ER._ * COPII: Golgi -\> Golgi (anterograde); _ER -\> Golgi._ * Clathrin: trans-Golgi -\> lysosomes; plasma membrane-\> endosomes (receptor-mediated endocytosis.

Answer 32

Peroxisome Membrane-enclosed organelle involved in catabolism of very long fatty acids and amino acids. * X-linked Adrenoleukodystrophy occurs when defective integral membrane protein responsible for transporting very long-chain fatty acids into peroxisomes for beta-oxidation. Accumulation of these long chain fatty acids in body fluids destroys the myelin sheath in nervous systems. Gene mutated: ABCD1

Answer 33

Proteasome ## Footnote Barrel-shaped protein complex that degrades damaged or unnecessary proteins tagged for destruction with ubiquitin.

Answer 34

Microtubule * Cylindrical structure composed of a helical array of polymerized dimers of alpha- and beta-tubulin. * Each dimer has 2 GTP bound. * Incorporated into flagella, cilia, mitotic spindles. * Grows slowly, collapses quickly. * Also involved in slow axoplasmic transport in neurons.

Answer 35

Microtubule molecular motor proteins Molecular motor proteins is the transport cellular cargo toward opposite ends of microtubule tracks. * Dynein= retrograde to microtubule (+ to -) * Kinesin =anterograde to microtubule (- to +)

Answer 36

Drugs that act on microtubules: * Mebenclazole/thiabenclazole (antihelminthic) * Griseo**f**ulvin (anti**f**ungal) * Vincristine/vinblastine (anti-cancer) * Paclitaxel (anti-breast cancer) * Colchicine (anti-gout) **Memory aid**: **M**icrotubule **G**rowth **V**oiding **P**oisonous **C**hemicals!

Answer 37

Chediak-Higashi syndrome ## Footnote Chediak-Higashi syndrome is mutation in the lysosomal trafficking regulator gene (LYST), whose product is required for the microtubule dependent sorting of endosomal proteins into late multivesicular endosomes. Results in recurrent pyogenic (pus) infections, partial albinism, and peripheral neuropathy (causing numbness or weakness).

Answer 38

Cilia structure 9 + 2 arrangement of microtubules. Axonemal dynein-ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets. * Kartagener's syndrome (primary ciliary dyskinesia) - immotile cilia clue to a dynein arm defect. Results in male infertility (immotile sperm) and decreased female fertility, bronchiectasis (abnormal widening of the bronchi or its branches leading to increased risk of respiratory infection), and recurrent sinusitis (bacteria and particles not pushed out); associated with situs inversus.

Answer 39

Cytoskeletal elements ## Footnote Actin and myosin: Microvilli, muscle contraction, cytokinesis, aclherens junctions.

Answer 40

Microtubule ## Footnote For movement. Cilia, flagella, mitotic spindle, axonal trafficking, centrioles.

Answer 41

Intermediate filaments ## Footnote Structure. Vimentin, clesmin, cytokeratin, lamins, glial fibrillary acid proteins (GFAP), neurofilaments.

Answer 42

Plasma membrane composition ## Footnote Asymmetric lipid bilayer. Contains cholesterol, phospholipids, sphingolipicls, glycolipicls, and proteins.

Answer 43

Vimentin Stain ## Footnote Vimentin stain is an Immunohistochemical which stains for intermediate filaments Vimentin stains for Connective tissue specifically

Answer 44

Desmin stain ## Footnote Desmin stain is an Immunohistochemical which stains for intermediate filaments Desmin stains for Muscle specifically

Answer 45

Cytokeratin Stain ## Footnote Cytokeratin stain is an Immunohistochemical which stains for intermediate filaments Cytokeratin stains for Epithelial cells specifically

Answer 46

GFAP Stain ## Footnote Neuroglia is an Immunohistochemical which stains for intermediate filaments **G**FAP stains for Neuro**G**lia specifically

Answer 47

Neurofilaments Stain ## Footnote Neurofilaments is an immunohistochemical stain for intermediate filaments Neurofilaments stains for neurons specially

Answer 48

sodium-potassium pump ## Footnote Na+-K+ ATPase is located in the plasma membrane with ATP site on cytosolic side. For each ATP consumed, 3 Na+ go out and 2 K+ come in. During cycle, pump is phosphorylated. Ouabain inhibits by binding to K+ site. Cardiac glycosides (digoxin and digitoxin) directly inhibit the Na+-K+ ATPase, this leads to indirect inhibition of Na+/ Ca2+ exchange, which leads to increased [Ca²⁺]_i-which leads to increased cardiac contractility.

Answer 49

Collagen Most abundant protein in the human body. Extensively modified by posttranslational modification. Organizes and strengthens extracellular matrix. learning aid: **B**e (**S**o **T**otally) **C**ool, **R**ead **B**ooks. **type l**: Most common (90%)-**B**one, **S**kin, **T**endon, dentin, fascia, cornea, late wound repair. * Type I: bone. Defective in osteogenesis imperfecta. **type ll**: Cartilage (including hyaline), vitreous body, nucleus pulposus. * memory aid: car**two**lage **type lll:** **R**eticulin-skin, blood vessels, uterus, fetal tissue, granulation tissue. * Type **III**: defective in **E**hlers-**D**anlos (Thre**E** **D**). **Type IV: ****B**asement membrane or basal lamina. * Type **IV**: under the **floor** (basement membrane). Defective in **Alport syndrome.**

Answer 50

collagen synthesis inside fibroblasts 1) Synthesis (RER): Translation of collagen a chains (preprocollagen) -usually Gly-X-Y (X and Y are proline or lysine). 2) Hydroxylation (ER): Hydroxylation ofspecific proline and lysine residues (requires vitamin C; deficiency leads to scurvy). 3) Glycosylation (ER): Glycosylation of pro-alpha-chain hyclroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen a chains). Problems forming triple helix leads to osteogenesis imperfecta. 4) Exocytosis: Exocytosis of procollagen into extracellular space. -------------------------------------------------------------- collagen synthesis outside fibroblasts 5) Proteolytic processing: Cleavage of disulfide-rich terminal regions of procollagen, transforming it into insoluble tropocollagen. 6) Cross-linking: Reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by Cu²⁺-containing lysyl oxidase) to make collagen fibrils. Problems with cross-linking leads to Ehlers-Danlos.

Answer 51

Osteogenesis imperfecta- (collagen disease) Genetic bone disorder (brittle bone disease) caused by a variety of gene defects. Most common form is autosomal dominant with abnormal type I collagen (Most common (90%)-Bone, Skin, Tendon, dentin, fascia, cornea, late wound repair.), causing: * Multiple fractures with minimal trauma; * may occur during the birth process * Blue sclera due to the translucency of the connective tissue over the choroidal veins * Hearing loss (abnormal middle ear bones) * Dental imperfections clue to lack of dentin May be confused with child abuse. Incidence is 1 : 10,000.

Answer 52

Ehlers-Danlos syndrome- (collagen disease) Faulty collagen synthesis causing hyperextensible skin, tendency to bleed (easy bruising), and hypermobile joints. There are 6 types. * Type I (Be So Totally- Bone, Skin, Tendon, dentin, fascia, cornea, late wound repair.) or Type V collagen most frequently affected in severe classic Ehlers-Danlos syndrome. Inheritance and severity vary. Can be autosomal dominant or recessive. May be associated with joint dislocation, berry aneurysms, organ rupture.

Answer 53

Alport syndrome- (collagen disease) Due to a variety of gene defects resulting in abnormal type IV collagen. Most common form is X-Iinked recessive. * Type IV collagen is an important structural component of the **b**asement membrane of the kidney, ears, and eyes. * memory aid: Be (so totally) cool, read **_B_**ooks (basement membrane)) Characterized by progressive hereditary nephritis and deafness. May be associated with ocular disturbances.

Answer 54

Elastin (collagen disease) Stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connect vertebrae-+ relaxed and stretched conformations). Rich in proline and glycine, nonhydroxylatecl forms. Tropoelastin with fibrillin scaffolding. * Madan's syndrome-caused by a defect in fibrillin. Cross-linking takes place extracellularly and gives elastin its elastic properties. * Wrinkles of aging are clue to reduced collagen and elastin production. Broken down by elastase, which is normally inhibited by alpha1-antitrypsin. * Emphysema-can be caused by a1-antitrypsin deficiency, resulting in excess elastase activity.

Answer 55

Madan's syndrome ## Footnote Madan's syndrome- caused by a defect in fibrillin.

Answer 56

Emphysema ## Footnote Emphysema-can be caused by alpha 1-antitrypsin deficiency, resulting in excess elastase activity.

Answer 57

Polymerase chain reaction ## Footnote Molecular biology laboratory procedure used to amplify a desired fragment of DNA. Steps: 1. Denaturation-DNA is denatured by heating to generate 2 separate strands 2. Annealing-during cooling, excess premade DNA primers anneal to a specific sequence on each strand to be amplified. 3. Elongation-heat-stable DNA polymerase replicates the DNA sequence following each primer. These steps are repeated multiple times for DNA sequence amplification. Agarose gel electrophoresis- used for size separation of PCR products (smaller molecules travel further); compared against DNA ladder.

Answer 58

Southern blot ## Footnote A DNA sample is electrophoresed on a gel and then transferred to a filter. The filter is then soaked in a denaturant and subsequently exposed to a radiolabeled DNA probe that recognizes and anneals to its complementary strand. The resulting double-stranded, labeled piece of DNA is visualized when the filter is exposed to film. learning aid: **SN**o**W DR**o**P** **S**outhern = **D**NA **N**orthern = **R**NA **W**estern = **P**rotein

Answer 59

Northern blot ## Footnote Similar to Southern blot, except that an RNA sample is electrophoresed. Useful for studying mRNA levels. **note**: I was taught that this method is used to identify tissue types. **learning aid**: **SN**o**W DR**o**P** **S**outhern = **D**NA **N**orthern = **R**NA **W**estern = **P**rotein

Answer 60

Western blot ## Footnote Sample protein is separated via gel electrophoresis and transferred to a filter. Labeled **antibody** is used to bind to relevant protein. **learning aid: SN**o**W DR**o**P** **S**outhern = **D**NA **N**orthern = **R**NA **W**estern = **P**rotein

Answer 61

Southwestern blot ## Footnote Identifies DNA-binding proteins (e.g., transcription factors) using labeled oligonucleotide probes.

Answer 62

Microarrays ## Footnote Thousands of nucleic acid sequences are arranged in grids on glass or silicon. DNA or RNA probes are hybridized to the chip, and a scanner detects the relative amounts of complementary binding. Microarrays are used to profile gene expression levels of thousands of genes simultaneously to study certain diseases and treatments. Microarrays are able to detect single nucleotide polymorphisms (SNPs) for a variety of applications including genotyping, forensic analysis, predisposition to disease, cancer mutations, and genetic linkage analysis.

Answer 63

``` Enzyme-linked immunosorbent assay (ELISA) ``` ## Footnote A rapid immunologic technique testing for antigen-antibody reactivity. Patient's blood sample is probed with either: l. Indirect ELISA: uses a test antigen to see if a specific antibody is present in the patient's blood; a secondary antibody coupled to a color-generating enzyme is added to detect the first antibody; or 2. Direct ELISA: uses a test antibody coupled to a color-generating enzyme to see if a specific antigen is present in the patient's blood. If the target substance is present in the sample, the test solution will have an intense color reaction, indicating a positive test result. Enzyme-linked immunosorbent assay (ELISA) is used in many laboratories to determine whether a particular antibody (e.g., anti-HIV) is present in a patient's blood sample. Both the sensitivity and the specificity of ELISA approach 100%, but both false-positive and false-negative results do occur.

Answer 64

Fluorescence in situ hybridization (FISH) ## Footnote Fluorescent DNA or RNA probe binds to specific gene site of interest on chromosomes. Used for specific localization of genes and direct visualization of anomalies (e.g., microdeletions) at molecular level (when deletion is too small to be visualized by karyotype). Fluorescence = gene is present; no fluorescence =gene has been deleted.

Answer 65

Cloning methods ## Footnote Cloning is the production of a recombinant DNA molecule that is self-perpetuating. Steps: l. Isolate eukaryotic mRNA (post-RNA processing steps) of interest. 2. Expose mRNA to **reverse transcriptase** to produce **cDNA**. 3. Insert cDNA fragments into bacterial plasmids containing antibiotic resistance genes. 4. Surviving bacteria on antibiotic medium produce cDNA library.

Answer 66

Gene expression modifications Transgenic strategies in mice involve: * Random insertion ofgene into mouse genome * Targeted insertion or deletion of gene through homologous recombination with mouse gene Cre-lox system- Can inducibly manipulate genes at specific developmental points using an antibiotic-controlled promoter (e.g., to study a gene whose deletion causes embryonic death). RNA interference (RNAi)- dsRNA is synthesized that is complementary to the mRNA sequence of interest. When transfected into human cells, dsRNA separates and promotes degradation of target mRNA, knocking down gene expression.

Answer 67

Karyotyping ## Footnote A process in which metaphase chromosomes are stained, ordered, and numbered according to morphology, size, arm-length ratio, and banding pattern. Can be performed on a sample of blood, bone marrow, amniotic fluid, or placental tissue. Used to diagnose chromosomal imbalances (e.g., autosomal trisomies, sex chromosome disorders).

Answer 68

Lesch-Nyhan syndrome Defective purine salvage due to absent **HGPRT**, which converts hypoxanthine to IMP and guanine to GMP. Results in excess uric acid production and de novo purine synthesis. X-linked recessive. Findings: intellectual disability, self-mutilation, aggression, hyperuricemia, gout, dystonia. Treatment: allopurinol or febuxostat (2nd line). learning aid: **H**e's **G**ot **P**urine **R**ecovery **T**rouble. **HGPRT:** * **H**yperuricemia * **G**out * **P**issed off (aggression, self-mutilation) * **R**etardation (intellectual disability) * Dys**T**onia (neuroloical movement disorder which cause sustained muscle contraction causing twisting and abnormal poster).

Answer 69

Adenosine deaminase deficiency ## Footnote Excess ATP and dATP imbalances nucleotide pool via feedback inhibition of ribonucleotide reductase prevents DNA synthesis and thus decreases lymphocyte count. One of the major causes of autosomal recessive **SCID**. **S**evere **C**ombined **I**mmunodeficiency **D**isease (**SCID**) happens to **kids**. 1st disease to be treated by experimental human gene therapy.

Answer 70

Codominance ## Footnote Both alleles contribute to the phenotype of the heterozygote. example: Blood groups A, B, AB; α1-antitrypsin deficiency.

Answer 71

Variable expressivity ## Footnote Phenotype varies among individuals with same genotype. Example: 2 patients with neurofibromatosis type 1 (NF1) may have varying disease severity.

Answer 72

Incomplete penetrance ## Footnote Not all individuals with a mutant genotype show the mutant phenotype. Example: BRCA1 gene mutations do not always result in breast or ovarian cancer.

Answer 73

Pleiotropy ## Footnote One gene contributes to multiple phenotypic effects. Example: Untreated phenylketonuria (PKU) manifests with light skin, intellectual disability, and musty body odor.

Answer 74

Anticipation ## Footnote Increased severity or earlier onset of disease in succeeding generations. Example: Trinucleotide repeat diseases (e.g., Huntington disease).

Answer 75

Loss of heterozygosity ## Footnote If a patient inherits or develops a mutation in a **tumor suppressor gene,** the **complementary allele** must be deleted/mutated before cancer develops. This is not true of oncogenes. Retinoblastoma and the “two-hit hypothesis.”

Answer 76

Dominant negative mutation ## Footnote Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning. Example: Mutation of a transcription factor in its allosteric site. Nonfunctioning mutant can still bind DNA, preventing wild-type transcription factor from binding.

Answer 77

Linkage disequilibrium ## Footnote Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance. **Measured in a population, not in a family,** and often varies in different populations.

Answer 78

Mosaicism ## Footnote Presence of genetically distinct cell lines in the same individual. Arises from mitotic errors after fertilization. Somatic mosaicism—mutation propagates through multiple tissues or organs. Gonadal mosaicism—mutation only in egg or sperm cells. Example: McCune-Albright syndrome is lethal if the mutation is somatic, but survivable if mosaic.

Answer 79

Locus heterogeneity ## Footnote Mutations **at different loci** can produce a similar phenotype. Example: Albinism.

Answer 80

Allelic heterogeneity ## Footnote Different mutations **in the same locus** produce the same phenotype. Example: ß-thalassemia.

Answer 81

Heteroplasmy ## Footnote Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease.

Answer 82

Uniparental disomy ## Footnote Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. **Heterodisomy** (heterozygous) indicates a **meiosis I error.** **Isodisomy** (homozygous) indicates a **meiosis II** error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair. Example: **U**niparental is e**U**ploid (correct number of chromosomes), not aneuploid. Most occurrences of UPD lead to normal phenotype. Consider UPD in an individual manifesting a recessive disorder when only one parent is a carrier.

Answer 83

Hardy-Weinberg population genetics If a population is in Hardy-Weinberg equilibrium and if p and q are the frequencies of separate alleles, then: p2 + 2pq + q2 = 1 and p + q = 1, which implies that: p2 = frequency of homozygosity for allele p q2 = frequency of homozygosity for allele q 2pq = frequency of heterozygosity (carrier frequency, if an autosomal recessive disease). The frequency of an X-linked recessive disease in males = q and in females = q2. Example: Hardy-Weinberg law assumptions include: * No mutation occurring at the locus * Natural selection is not occurring * Completely random mating * No net migration

Answer 84

Imprinting ## Footnote At some loci, only one allele is active; the other is inactive (imprinted/inactivated by methylation). With one allele inactivated, deletion of the active allele leads to disease. Example: Both Prader-Willi and Angelman syndromes are due to mutation or deletion of genes on chromosome 15. Can also occur as a result of uniparental disomy.

Answer 85

**P**rader-Willi syndrome ## Footnote Maternal imprinting: gene from mom is normally silent and **P**aternal gene is deleted/ mutated. Results in hyperphagia (excessive hunger), obesity, intellectual disability, hypogonadism, and hypotonia. example: 25% of cases due to maternal uniparental disomy (two maternally imprinted genes are received; no paternal gene received).

Answer 86

Angel**M**an syndrome ## Footnote Paternal imprinting: gene from dad is normally silent and **M**aternal gene is deleted/mutated. Results in inappropriate laughter (“happy puppet”), seizures, ataxia, and severe intellectual disability.

Answer 87

Autosomal dominant ## Footnote Often due to defects in structural genes. Many generations, both male and female, affected. Often pleiotropic (one gene effecting multiple seemingly unrelated phenotypes). Family history crucial to diagnosis. Legend: purple= uninfected pink= infected

Answer 88

Autosomal recessive ## Footnote 25% of offspring from 2 carrier parents are affected. Often due to enzyme deficiencies. Usually seen in only 1 generation. Commonly more severe than dominant disorders; patients often present in childhood. Increased risk in consanguineous families.

Answer 89

X-linked recessive ## Footnote Sons of heterozygous mothers have a 50% chance of being affected. **No male-to-male** transmission. Commonly more severe in males. Females usually must be homozygous to be affected.

Answer 90

X-linked dominant ## Footnote Transmitted through both parents. Mothers transmit to 50% of daughters and sons; fathers transmit to all daughters but no sons. **Hypophosphatemic rickets**—formerly known as vitamin D–resistant rickets. Inherited disorder resulting inphosphate wasting at proximal tubule. Results in rickets-like presentation.

Answer 91

Mitochondrial inheritance ## Footnote Transmitted only through the mother. All offspring of affected females may show signs of disease. Variable expression in a population or even within a family due to heteroplasmy. **Mitochondrial myopathies**—rare disorders; often present with myopathy, lactic acidosis and CNS disease. 2° to failure in oxidative phosphorylation. Muscle biopsy often shows “ragged red fibers.”

Answer 92

Autosomal dominant polycystic kidney disease (ADPKD) ## Footnote Formerly known as adult polycystic kidney disease. **Always bilateral**, massive enlargement of kidneys due to multiple large cysts. 85% of cases are due to mutation in PKD1 (chromosome **16**; **16** letters in “polycystic kidney”); remainder due to mutation in PKD2 (chromosome 4). Autosomal dominant diseases

Answer 93

Familial adenomatous polyposis ## Footnote Colon becomes covered with adenomatous polyps after puberty. Progresses to colon cancer unless colon is resected. Mutations on chromosome **5** (APC gene); **5** letters in “polyp.” Autosomal dominant diseases

Answer 94

Familial hypercholesterolemia ## Footnote Elevated LDL due to defective or absent LDL receptor. Leads to severe atherosclerotic disease early in life, and tendon xanthomas (classically in the Achilles tendon). Autosomal dominant diseases

Answer 95

Hereditary hemorrhagic telangiectasia ## Footnote Inherited disorder of blood vessels. Findings: telangiectasia, recurrent epistaxis, skin discolorations, arteriovenous malformations (AVMs), GI bleeding, hematuria. Also known as Osler-Weber-Rendu syndrome. Autosomal dominant diseases

Answer 96

Hereditary spherocytosis ## Footnote Spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia; increased MCHC. Treatment: splenectomy. Autosomal dominant diseases

Answer 97

**Hunting**ton disease ## Footnote Findings: depression, progressive dementia, choreiform movements, caudate atrophy, andlevels of GABA and ACh in the brain. Gene on chromosome **4**; trinucleotide repeat disorder: (CAG)_nincreased repeats lead to lower age of onset. Autosomal dominant diseases Memory aid: **HUNTING** **4** food

Answer 98

Marfan syndrome ## Footnote Fibrillin-1 gene mutation lead to connective tissue disorder affecting skeleton, heart, and eyes. Findings: tall with long extremities, pectus excavatum, hypermobile joints, and long, tapering fingers and toes (arachnodactyly); cystic medial necrosis of aortaaortic incompetence and dissecting lead to aortic aneurysms; floppy mitral valve. Subluxation of lenses, typically upward and temporally. Autosomal dominant diseases

Answer 99

Multiple endocrine neoplasias (MEN) ## Footnote Several distinct syndromes (1, 2A, 2B) characterized by familial tumors of endocrine glands, including those of the pancreas, parathyroid, pituitary, thyroid, and adrenal medulla. MEN 2A and 2B are associated with *ret* gene. Autosomal dominant diseases

Answer 100

**Neurofibroma**tosis type 1 (von Recklinghausen disease) ## Footnote Neurocutaneous disorder characterized by café-au-lait spots and cutaneous neurofibromas. Autosomal dominant, 100% penetrance, variable expression. Caused by mutations in the NF1 gene on chromosome **17**; **17** letters in “von Recklinghausen.” Autosomal dominant diseases

Answer 101

Neurofibromatosis type 2 ## Footnote Findings: bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas. NF2 gene on chromosome **22**; type **2** = **22.** Autosomal dominant diseases

Answer 102

Tuberous sclerosis ## Footnote Tuberous sclerosis: Neurocutaneous disorder with multi-organ system involvement, characterized by numerous benign hamartomas. Incomplete penetrance, variable expression. Autosomal dominant diseases

Answer 103

von Hippel-Lindau disease ## Footnote Disorder characterized by development of numerous tumors, both benign and malignant. Associated with deletion of VHL gene (tumor suppressor) on chromosome **3** (3p). Von Hippel-Lindau = **3** words for chromosome **3**. Autosomal dominant diseases

Bio Chemisity Flashcards

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