Biochemistry Flashcards
Histones
They are rich in lysine and arginine allowing them to bind negatively charged DNA. H1 hinds to the nucleosome and to linker DNA, thereby stabilizing the chromatin fiber. In mitosis, DNA condenses to form chromosomes. DNA and histone synthesis occurs during S phase.
Heterochromatin
Condensed, appears darker on EM. Transcriptionally inactive and sterically inaccessible. HeteroChromatin= highly condensed. Barr bodies are heterochromatin.
Euchromatin
It is less condensed, appears lighter on EM. Transcriptionally active and sterically accessible. Eu=true, truly transcribed.
DNA methylation
Template strand cytosine and adenine are methylated in DNA replication, which allows mismatch repair enzymes to distinguish between old and new strands in prokaryotes. DNA methylation at CpG islands represses transcription. CpG Methylation Makes DNA Mute.
Histone methylation
It usually reversibly represses DNA transcription, but can activate it in some cases depending on methylation location. Histone Methylation Mostly Makes DNA Mute.
Histone acetylation
Relaxes DNA coiling, allowing for transcription. Histone Acetylation makes DNA Active.
Nucleotides
Base plus deoxyribose plus phosphaTe (neucleoTide); it can be linked by 3’-5’ phosphodiester bond to another nucleotide. PURines (A, G) have two rings (PURe As Gold). PYrimidines (C, T, U) have 1 ring (CUT the PY). Thymine has a methyl group (THYmine has a meTHYl). Deamintation of cytosine makes uracil. Uracilis found in RNA, thymine in DNA. G-C bound has three H bonds and is stronger than A-T bond, which has two H bonds. An increase in G-C content causes there to be a higher melting temperature of DNA.
Nucleoside
Base plus deoxyribose (Sugar=nucleoSide)
Purine synthesis
Amino acids necessary for purine synthesis (GAG): Glycine, Aspartate, Glutamine. Purine bases are synthesized starting with the activation of Ribose-5-phosphate by PRPP synthetase to create 5’-Phosphoribosyl-1’-pyrophosphate (PRPP). IMP is converted to adenosine monophosphate (AMP) or guanine monophosphate (GMP). The synthesis of AMP requires GTP and Aspartate, and the synthesis of GMP requires ATP and Glutamine. AMP and GMP are phosphorylated to ADP/GDP or ATP/GTP and used in energy-requiring processes or RNA synthesis. Ribonucleotide reductase reduces the ribose base of ADP and GDP to dADP and dGDP, respectively, then dADP and dGDP phosphorylated to dATP and dGTP for use in DNA synthesis. Ribonucleotide reductase only works on diphosphate nucleotide.
Pyrimidine synthesis
The first reaction in pyrimidine synthesis is: Glutamine + CO2 conversion into Carbamoyl phosphate. This reaction is catalyzed by carbamoyl phosphate synthetase 2. Note that this is different from carbamoyl phosphate synthetase I used in the urea cycle. Following three additional reactions orotic acid is formed. Orotic acid formation requires aspartate and glutamine. Orotic acid + PRPP conversion into UMP. This reaction is catalyzed by UMP synthase. UMP is phosphorylated to UDP, then to UTP, then in a reaction with glutamine, UTP is converted to CTP.
Mycophenolic acid and ribavirin
Mycophenolic acid and ribavirin are reversible inhibitors of IMP dehydrogenase, an enzyme required for GMP synthesis from IMP. These drugs affect rapidly proliferating cell types, such as immune cells, for treatment of autoimmune diseases as well as prevention of transplant rejection.
Hydroxyurea
Hydroxyurea inhibits ribonucleotide reductase decreasing deoxyribonucleotide synthesis and, in turn, DNA replication and is used in treatment of chronic myelogenous leukemia (CML).
Thymidylate synthase
Thymidylate synthase, which requires methylene-THF as a cofactor, methylates dUMP to produce thymidine monophosphate (dTMP). dTMP is phosphorylated to dTTP and used in DNA synthesis.
5-flurouracil (5-FU)
5-flurouracil (5-FU) irreversibly inhibits thymidylate synthase and is used in treatment of breast and colon cancers.
Methotrexate (MTX)
Methotrexate (MTX), a folate analogue, competitively inhibits dihydrofolate reductase, an enzyme required for activation of methylene tetrahydrofolate and is used as an anticancer drug.
Trimethoprim (TMP)
Trimethoprim (TMP) inhibits bacterial dihydrofolate reductase and is used as an antibiotic drug.
Carbamoyl phosphate synthetase II
The first step of pyrimidine synthesis. Converts glutamine and CO2 into carbamoyl phosphate.
Ribonucleotide reductase
It is apart of the pyrimidine synthesis. Converts UDP into dUDP, which is apart of synthesizing dTMP. This enzyme is inhibited by hydroxyurea.
Thymidylate synthase
It converts dUMP into dTMP. This reaction requires THF, which gets converted into DHF. It is inhibited by 5-FU.
Dihyrofolate reductase
Converts DHF into THF, which is needed into dTMP synthesis. It is inhibited by MTX, TMP, and pyrimethamine.
Phosphoribosyl pyrophosphate (PRPP) synthetase
It converts ribose 5-P into PRPP, which is needed for pyrimidine and purine synthesis (first step).
Purine salvage pathway
Purine salvage is the process of recycling purines acquired from normal cell turn-over, or obtained in the diet, and converting them into nucleoside triphosphates that can be used again in the body. The three free purine bases are adenine, guanine, and hypoxanthine. The primary enzymes involved in purine salvage are HGPRT (hypoxanthine-guanine phosphoribosyltransferase) and APRT (adenine phosphoribosyltransferase). In addition to purine bases, salvage enzymes require the substrate 5-phosphoribosyl 1-pyrophosphate (PRPP). Purine salvage is separated further into two separate pathways: guanine and hypoxanthine salvage and adenine salvage
Guanine and hypoxanthine salvage
Guanine is converted to GMP via the enzyme HGPRT: Guanine + PRPP is converted into GMP + PP (pyrophosphate). Hypoxanthine is converted to IMP via the enzyme HGPRT: Hypoxanthine + PRPP is converted to IMP (apart of purine synthesis) + PP
Adenine salvage pathway
Adenine is converted to AMP via the enzyme APRT: Adenine + PRPP is converted into AMP + PP.
Hypoxanthine
It can be salvaged by hypoxanthine guanine phosphoribosyltransferare (HGPRT), which converts hypoxanthine into IMP. Or it can be further degraded into xanthine, then uric acid by xanthine oxidase (XO). XO is inhibited by allopurinol or febuxostat. Uric acid is then converted into urine, which is induced by probencid.
Adenosine deaminase (ADA) deficiency
ADA converts adenosine into inosine within the purine salvage pathway. A deficiency leads to an excess of ATP and dATP, which causes an imbalance in nucleotide pool. Excess dATP inhibits ribonucleotide reductase, thereby preventing DNA synthesis and thus decreasing lymphocyte count. It is one of the major causes of autosomal recessive SCID.
Lesch-Nyhan syndrome
Lesch-Nyhan syndrome results from a deficiency in hypoxanthine-guanine phosphoribosyl transferase (HGPRT), causing an excessive buildup of uric acid and de novo purine synthesis due to buildup of PRPP. Lesch-Nyhan syndrome is a X-linked recessive disorder. HGPRT normally converts hypoxanthine to IMP and guanine to GMP. Lesch-Nyhan syndrome clinical presents with: Mental retardation, Self-mutilation, Gout from hyperuricemia, Dystonia. Lesch-Nyhan syndrome is treated with allopurinol or febuxostat as a second line medication. HGPRT: Hyperuricemia, Gout, Pissed off (aggression and self mutilation), Retardation, dysTonia.
Genetic code features
It is unambiguous; each codon specifies only 1 amino acid. It is degenerate/redundant; most amino acids are coded by multiple codons. Exceptions include methionine and tryptophan, which are encoded by only 1 codon (AUG and UGG, respectively). It is commaless and nonoverlapping; it is read from a fixed starting point as a continuous sequence of bases (exceptions are some viruses). It is universal; genetic code is conserved throughout evolution.
DNA replication
Prokaryotic replication uses only 1 ORI (origin of replication). Eukaryotic replication uses multiple ORI’s. DNA replication is semiconservative, in that each resulting dsDNA has 1 strand from the parent DNA and 1 new strand. Regardless of which strand is being replicated, DNA replication proceeds in the 5’ to 3’ direction.
The leading strand in DNA replication
The leading strand of parent DNA is the one whose sequence is complementary to the natural 5’ to 3’ direction of synthesis (i.e. 3’ to 5’), allowing for continuous synthesis.
The lagging strand in DNA replication
The lagging strand must be synthesized in discontinuous Okazaki fragments, because the parent DNA sequence is 5’ to 3’ but DNA replication must still proceed in a 5’ to 3’ direction. These fragments are synthesized in the 5’ to 3’ direction (which is away from the replication fork), then polymerase jumps “behind” the newly made segment (in normal direction of the replication fork), and makes a new fragment until the previous fragment is bumped into.
Helicase
It unwinds DNA at the replication fork.
SSBPs (single-strand binding proteins)
SSBPs (single-strand binding proteins) prevent DNA from reverting to duplex form (re-annealing). The strong hydrogen bonds between nucleotide bases attract one another.
Gyrase
Gyrase (a topoisomerase type II enzyme) introduces negative supercoils, thereby relaxing positive supercoils that form during helicase unwinding.
DNA Primase
DNA Primase synthesizes a short RNA segment on the ssDNA template. No DNA polymerase can start synthesis without a DNA or RNA primer.
DNA Polymerase III
DNA Polymerase III (the main prokaryotic polymerase) adds DNA nucleotides to the hydroxyl group on the 3’ end of the new strand (synthesis is therefore 5’ to 3’).
DNA Pol III also has a 3’ to 5’ proofreading ability w/ exonuclease function to correct mistakes.
DNA polymerase I
DNA polymerase I (a prokaryotic polymerase) degrades the RNA primer that blocks cohesiveness between Okazaki fragments. Because Okazaki fragments are synthesized in the 5’ to 3’ direction just like leading strand synthesis, DNA polymerase therefore has 5’ to 3’ exonuclease activity. It is the only polymerase with this unique activity.
Eukaryotic DNA replication
Eukaryotic DNA replication is similar to prokaryotic replication, with analagous enzymes that have different names. DNA Pol α acts in a complex with RNA primase in the following manner: RNA primase lays down a short series of RNA molecules (as DNA primase does in prokaryotes)
DNA Pol α
DNA Pol α (eukaryotic polymerase) elongates the RNA primer with ~20 DNA nucleotides. Once this short strand of nucleotides is finished, the DNA Pol α/RNA primase dissociates and DNA Pol δ takes over.
DNA Pol δ
The main eukaryotic DNA polymerase. It has 3’ to 5’ exonuclease proofreading and is analogous to prokaryotic DNA Pol III.
Telomerase
Telomerase is a reverse transcriptase enzyme with an intrinsic RNA template that adds DNA to the end of the parent strand of a replicating chromosome to avoid chromosome shortening with each round of replication. Stem cells and cancer cells upregulate telomerase activity to enhance replicative ability.
DNA ligase
Catalyzes the formation of a phosphodiester bond within a strand of double stranded DNA.
Transition mutation
In a transition, a purine is substituted for a purine or a pyrimidine is substituted for a pyrimidine (adenine for guanine).
Transversion mutation
In a transversion, purine get converted into pyrimidine or pyrimidine get converted into purine (adenine for thymine).
Order of severity of mutations
Order of increasing severity: silent, missense, nonsense, frameshift.
Silent mutation
mutation that yields the same amino acid (often a base change in the 3rd position of a codon yields the same amino acid due to tRNA wobble)
Amino acid mutations in other positions can also lead to silent mutations because the genetic code is degenerate. This means that amino acids can be coded for by more than one codon. (the exceptions are methionine, which is only encoded by AUG, and tryptophan encoded by UGG).
Missense mutation
mutation that creates a change in the amino acid
Conservative mutation
a type of missense mutation that yields a new amino acid with a similar chemical property as the original amino acid (e.g. hydrophobic)
Nonsense mutation
mutation that creates an early stop codon, making the protein truncated. (It’s early, stop the nonsense!)
Frameshift mutation
deletion or addition of any number of nucleotides not divisible by 3, that causes all downstream codons to change. Occurs because the genetic code is commaless & non-overlapping (read from a single starting point in a continuous string)
Lac operon
This is a classic example of a genetic response to an environmental change. Glucose is the preferred metabolic substrate in E. cole, but when glucose is absent and lactose is available, the lac operon is activated to switch to lactose metabolism. Low glucose triggers an increase adenylyl cyclase activity, which generates cAMP from ATP. This activates catabolite activator protein (CAP), increasing transcription. High lactose unbinds repressor protein from repressor/operate site, increasing transcription.
Nucleotide excision repair (NER)
Special structure-specific endonucleases recognize bulky distortions alter the shape of the DNA double helix. A small region of DNA on either side of the damaged base (about 20 base pairs total) is removed from the DNA helix. Sequential action of DNA polymerase and DNA ligase fills in the gap left by the NER enzymes. UV light-induced damage is primarily managed through nucleotide excision repair. The characteristic DNA lesion produced by UV light is the pyrimidine dimer (e.g. thymine dimer). The electrochemical ramifications of this dimer cause the bulky distortion recognized by NER enzymes. Defects in nucleotide excision repair enzymes cause xeroderma pigmentosum. Patients with xeroderma pigmentosum have a greatly increased risk of developing skin cancer, often during childhood. Xeroderma pigmentosum is an autosomal recessive disorder. Nucleotide excision repair occurs in the G1 phase of the cell cycle.
Base excision repair
Base excision repair is another method of repairing single-strand DNA damage. It is characterized by the following steps: 1. Glycosylase enzymes recognize and remove incorrectly paired and chemically altered bases without interrupting the phosphodiester backbone. 2. AP-endonuclease (AP can stand for both apyrimidinic and apurinic) enzymes detect that a base is missing and begin the process of excision by making an endonucleolytic cut on the 5′-side of the AP location. 3. Lyase cuts at the 3’-end to remove the baseless sugar-phosphate molecule. 4. DNA Pol I (prokaryotic) or DNA Pol β (human) then replaces the damaged base and DNA ligase seals the new DNA strand. Base excision repair is the DNA repair modality used to repair spontaneous deamination of cytosine to uracil, which occurs randomly and consistently throughout the body’s cells. Base excision repair occurs in all phases of the cell cycle.
Mismatch repair
Mismatch repair is a third single-strand DNA repair modality, which recognizes and fixes mispaired bases (G-T or A-C pairs). Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition in which a defective mismatch repair gene causes a microsatellite repeat replication error to go unfixed. Mismatch repair enzymes are most active in the G2 phase of the cell cycle.
Double strand DNA break repair
There are two methods of correcting double strand DNA breaks: homologous recombination (HR) and non-homologous end joining (NHEJ). HR results in accurate repair while NHEJ can cause significant errors because homology is not checked for when DNA fragments are joined. NHEJ is the predominant method of double-stranded break repair in mammals. Mutations genes that participate in non-homologous end joining lead to ataxia-telangiectasia and Fanconi anemia.
Nonhomologous end joining
Brings together two ends of DNA fragments to repair double stranded breaks. No requirement for homology. Some DNA may be lost. Mutated in ataxia telangiectasia and Fanconi anemia
DNA/ RNA/ protein synthesis direction
DNA and RNA are both synthesized from 5’ to 3’. The 5’ end of the incoming nucleotide bears the triphospate (energy source for bond). Protein synthesis is N-terminus to C-terminus. mRNA is read 5’ to 3’. The triphosphate bond is the target of the 3’ hydroxyl attack. Drugs blocking DNA replication often have modified 3’ OH, preventing addition of the next nucleotide (chain termination).
mRNA start codons
AUG (or rarely GUG). AUG inAUGurates protein synthesis. In eukaryotes, it codes for methionine, which may be removed before translation is completed. In prokaryotes, it codes for N-formylmethionine (fMet). fMet stimulates neutrophil chemotaxis.
mRNA stop codons
UGA, UAA, UAG. U Go Away, U Are Away, U Are Gone.
Promoters
Promoters are where RNA polymerase and transcription factors (TFs) bind to initiate transcription (often located 25 to 50 bases upstream of the gene, and often contains A-T rich sequences of TATA or CAAT boxes)
Enhancers
Enhancers also bind transcription factors, and can significantly ↑ the rate of transcription (can be located upstream, downstream, or a distance from the gene)
Silencers
Silencers repress transcription when repressors, a subset of transcription factors, bind to them (known as operators in prokaryotes)
Response elements
Response elements bind specific transcription factors (e.g. heat shock response element, estrogen response element) and modulate transcription
RNA polymerase I
RNAP I transcribes rRNA (most abundant). “Rampant, Massive, Tiny”: RNAP I transcribes the most abundant type rRNA, RNAP II transcribes the longest type mRNA, RNAP III transcribes the shortest type tRNA
RNA polymerase II
RNAP II transcribes mRNA
RNA polymerase III
RNAP III transcribes tRNA (shortest RNA)
alpha-amanitin
α-amanitin (deadly toxin found in certain mushrooms) inhibits RNAP II causing liver damage when ingested
Prokaryotic RNA polymerase
In contrast to eukaryotes (which use three different RNA polymerases), prokaryotic RNA Polymerase RNAP can synthesize all the three kinds of RNA (mRNA, rRNA, tRNA). RNA polymerases do not require primers. Prokaryotic RNAP binds directly to promoters
Transcription factors
Eukaryotic RNAP’s require transcription factors (pre-initiation complex) to direct transcription. Examples of transcription factors include TATA Binding Protein (TBP), which binds the TATA box in the promoter region, and Transcription Factors (TF) such as TFIIA.
RNA processing
The 3 primary modifications that occur in post-transcriptional processing include: 5’ capping, 3’ poly-adenylation, Splicing
5’ capping
5’ capping adds a 7-methylguanosine to the 5’ end of the transcript. The cap protects the transcript from ribonucleases and is involved in initiating translation of mRNA.
Poly (A) polymerase
Poly (A) polymerase adds the 3’ poly-A tail, as many as 200 adenines (does not require a template). The poly-A tail facilitates the mRNA’s exit from the nucleus and is also thought to protect the transcript from 3’ to 5’ exonuclease activity.
Splicing
Splicing removes introns (non-coding segments); the remaining exons are re-joined to form a single transcript. INtrons are INtervening segments and are removed; EXons are EXpressed. Splicing is catalyzed by the spliceosome and snRNPs (small nuclear ribonucleoproteins). Splicing occurs in the nucleus. Small nuclear ribonucleoproteins (snRNPs) include: U1, U2, U4, and U6. Antibodies directed against U1 RNP (ribonucleoprotein) are associated with mixed connective tissue disease (MCTD).
Alternative splicing
Alternative splicing allows multiple proteins to be translated from a single transcript (e.g. antibodies); though exons are usually expressed, in alternative splicing some exons may be discarded in a controlled fashion.
Transfer RNA (tRNA)
Transfer RNA (tRNA) is composed of 75-90 nucleotides. The secondary structure is “cloverleaf,”while the tertiary structure is “L-shaped”. The “bottom” of the cloverleaf houses the anti-codon, which pairs with mRNA codons when brought together in a ribosome. The 3’ end of tRNA has a CCA sequence that accepts the amino acid to be matched with it. Mnemonic: CCA “Can Carry Amino Acids”. The T-arm of tRNA facilitates binding of the tRNA to the ribosome for protein synthesis. The T-arm of tRNA contains the sequence TΨC, which stands for: Ribothymidine, Pseudouridine, Cytidine. The D-arm of tRNA contains dihydrouridine residues that act as a recognition site for for the corresponding aminoacyl-tRNA synthetase.
Aminoacylation
Aminoacylation (aka “charging”) covalently bonds an amino acid to the 3’ end of the tRNA. There is one aminoacyl-tRNA synthetase per amino acid. Because the genetic code is degenerate, some amino acids use multiple different tRNAs that recognize different codons that code for the same amino acid. Thus, each aminoacyl-tRNA synthetase may recognize multiple tRNAs but only one amino acid. Aminoacylation (aka “charging”) uses ATP. It gives a phosphate group (hence “charged”) that later provides energy for peptide bond formation; aminoacylation converts ATP to AMP (2 phosphate bonds).
Aminoacyl-tRNA synthetase
Aminoacyl-tRNA synthetases proofread both before and after charging a tRNA with an amino acid. If the wrong amino acid is on the tRNA, the covalent bond is hydrolyzed. In the event that an error in proofreading occurs, a mischarged tRNA is formed. Mischarged tRNAs insert the incorrect amino acid into a growing polypeptide chain because they retain the ability to read the codon corresponding to the amino acid they should have been matched to.
Wobble hypothesis
The 3rd position of the mRNA codon isn’t as critical to pairing and is allowed some “wobble” with respect to nucleotide base pairing with the tRNA. tRNAs that code for the same amino acid often differ in this “wobble” position.
Translation
The process of converting the mRNA message into protein is called translation. Translation has three steps: Initiation, Elongation, Termination. The “A” of A-site stands for “aminoacyl”; it’s where the aminoacyl-tRNA complexes (except initiation tRNA) enter. The “P” of P-site stands for “polypeptide”; it’s where the polypeptide chain sits. The “E” of E-site stands for “exit” and holds the empty tRNA as it is exiting the ribosome.
Initiation step of protein synthesis
Initiation: Using GTP, the small ribosomal subunit binds upstream on the 5’ end, then proceeds downstream (5’ to 3’) until AUG (start codon) is encountered. Prokaryotic small subunit: 30S. Eukaryotic small subunit: 40S. Mnemonic:”prOkaryotic=Odd=30S (small), 50S (large), 70S (whole ribosome complex), Eukaryotic=Even=40S (small), 60S (large), 80S (whole ribosome complex)”. The small ribosomal subunit is joint by the large subunit, initiation factors, and the initiator tRNA. The initiator tRNA (Met or fMet) enters the P-site. The initiation factors dissociate from the ribosome-mRNA complex once initiation is complete. Prokaryotic large subunit: 50S. Eukaryotic large subunit: 60S. Mnemonic:”prOkaryotic=Odd=30S (small), 50S (large), 70S (whole ribosome complex), Eukaryotic=Even=40S (small), 60S (large), 80S (whole ribosome complex)”. Initiator tRNA is the only tRNA that can bind to the P-site; all others bind to A-site.
Elongation step of protein synthesis
Elongation begins when a tRNA enters the A-site. Binding of the aminoacyl tRNA to the A-site requires GTP hydrolysis (think “G” for Gripping, i.e. binding) and elongation factors (EFs). Ribosomal peptidyl transferase catalyzes formation of a peptide bond between the amino acids in the A and P sites. The prior tRNA is released from the P-site. As peptidyl transferase catalyzes the new peptide bond, the ribosome translocates one codon downstream, moving the latest tRNA and the newly elongated polypeptide chain into the P-site and emptying the A-site. Translocation consumes 1 GTP (think “G” for Going places, i.e. translocation). So, two GTP are used per cycle, one for binding (“Gripping”) of the aminoacyl tRNA and one for translocation (“Going places”) of the ribosome along the mRNA.
Termination step of protein synthesis
Stop codons are recognized by protein release factors, which release the polypeptide from the ribosome and cause the ribosomal subunits to dissociate. In all, translation uses 4 high-energy phosphate bonds per amino acid: 2 during aminoacylation (tRNA charging): ATP to AMP (A for Activation). 1 during tRNA “loading” into the A-site: GTP to GDP (G for Gripping). 1 during translocation: GTP → GDP (G for Going places)
Posttranslational trimming
Removal of N or C-termininal propeptides from zymogen to generate mature protein (eg trypsinogen to trypsin).
Posttranslational covalent alterations
Phosyphorylation, glycosylation, hydroxylation, methylation, acetylation, and ubiquitnation
Chaperone protein
Intracellular protein involved in facilitating and/ or maintaining protein folding. For example, in yeast, heat shock proteins (eg Hsp60) are expressed at high temperatures to prevent protein denaturing/ misfolding.
Cell cycle phases
Checkpoints control transitions between phases of cell cycle. This process is regulated by cyclins. This process is regulated by cyclins, cyclin dependent kinases (CDKs), and tumor suppressors. M phase (the shortest phase of cell cycle) includes mitosis (prophase, prometaphase, metaphase, anaphase, telophase) and cytokinesis (cytoplasm splits in two). G1 and G0 are of variable duration.
CDKs
Constitutive and inactive.
Cyclins
Regulatory proteins that control cell cycle events. It is phase specific. It activates CDKs.
Cyclin- CDK complexes
Phosphorylate other proteins to coordinate cell cycle progression. It must be activated and inactivated at appropriate times for cell cycle to progress.
Tumor supressor genes
p53 and hypophosphorylated Rb normally inhibits G1 to S progression. Mutations in these genes result in unrestrained cell division (eg Li- Fraumeni syndrome).
Permanent cells
Remain in G0, regenerate from stem cells. For example, neurons, skeletal and cardiac muscle, RBCs.
Stable (quiescent) cells
Enter G1 from G0 when stimulated. For example, hepatocytes and lymphocytes.
Labile cells
It never goes to G0, divide rapidly with a short G1. They are the most affected by chemotherapy. For example, bone marrow, gut epithelium, skin, hair follicles, and germ cells.
Rough endoplasmic reticulum
It is the site of synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins.
Nissl bodies
Nissl bodies (RER in neurons) and synthesize peptide neurotransmitters for secretion.
Free ribosomes
They are unattached to any membrane and is the site of synthesis of cytosolic and organellar proteins. Mucus secreting goblet cells of the small intestine and antibody secreting plasma cells are rich in RER.
Smooth endoplasmic reticulum
I is the site of steroid synthesis and detoxification of drugs and poisons. Lacks surface ribosomes. Liver hepatocytes and steroid hormone-producing cells of the adrenal cortex and gonads are rich in SER.
Cell trafficking
The golgi is the distribution center for proteins and lipids from the ER to the vesicles and plasma membrane. It modifies N-oligosacharides on asparagine and adds O-oligosaccharides on serine and threonine. It adds mannose-6-phosphate to proteins for trafficking lysosomes.
Endosomes
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.
I-cell disease
Also called inclusion cell disease. It is an inherited lysosomal storage disorder with a defect in N-acetylglucosaminyl-phosphotransferase, which causes there to be a failure of the Golgi to phosphorylate mannose residues (ie a decrease in mannose-6-phosphate) on glycoproteins, which causes proteins to be secreted extracellularly rather than delivered to lysosomes. It results in coarse facial features, clouded corneas, restricted joint movement, and high plasma levels of lysosomal enzymes. It is often fatal in childhood.
Signal recognition particle (SRP)
Abundant, cytosolic ribonucleoprotein that traffics proteins from the ribosome to the RER. If it is absent or dysfunctional, than proteins accumulate in the cytosol.
COPI
A vesicular trafficking proteins. Transports vesicles retrograde in the Golgi, to cis Golgi, to ER.
COPII
A vesicular trafficking proteins. Transport vesicles anterograde from ER to cis-ER.
Clathrin
A vesicular trafficking proteins. Transports vesicles from trans-golgi to lysosomes and plasma membrane to endosomes (receptor mediated endocytosis [eg LDL receptor activity]).
Peroxisome
Membrane enclosed organelle involved in catabolism of very-long chain fatty acids, branched chain fatty acids, and amino acids.
Proteasome
Barrel shaped protein complex that degrades damaged or ubiquitin-tagged proteins. Defects in the ubiquitin- proteasome system have been implicated in some cases of Parkinson disease.
Cytoskeletal elements
A network of protein fibers within the cytoplasm that supports cell structure, cell and organelle movement, and cell division. Includes microfilaments, intermediate filaments, and microtubules.
Microfilaments
Involved in muscle contraction and cytokinesis. An example is actin.
Intermediate filaments
Involved in maintaining cell structure. Examples include vimentin, desmin, cytokeratin, lamins, glial fibrillary acid proteins (GFAP), neurofilaments.
Microtubules
Involved in movement and cell division. Examples include cilia, flagella, mitotic spindle, axonal trafficking centrioles. They are of cylindrical structure composed of a helical array of polymerized heterodimers of alpha and beta tubulin, which create protofilaments, which combine to create microtubule. Each dimer has two GTP bound. Incorporated into flagella, cilia, mitotic spindles. They grow slowly, collapses quickly. It is also involved in slow axoplasmic transport in neurons.
Vimentin
located within connective tissue.
Desmin
Located within muscle (Muscle=desMin).
Cytokeratin
Located within epithelial cells
GFAP
Located within neuroGlia
Neurofilaments
Located within neurons
Dynein
Dynein acts retrograde to microtubule (from positive to negative). They transport cellular cargo toward opposite ends of microtubule tracks.
Kinesin
Acts anterograde to microtubule (from negative to positive)
Drugs that act on microtubule
Mebendazole (antihelminthic), Griseofluvin (antifungal), Colchicine (antigout), Vincristine/Vinblastine (anticancer), Paclitaxel (anticancer). Microtubules Get Constructed Very Poorly.
Cilia structure
9+2 arrangement of microtubule doublets.
Axonemal dynein
ATPase that links peripheral 9 doublets and causes bending of celium by differential sliding of doublets.
Kartagener syndrome
Also called primary ciliary dyskinesia. It causes there to be immotile cilia due to a dynein arm defect. It results in male and female infertility due to immotile sperm and dysfunctional fallopian cube cilia, respectively. It increases the risk of ectopic pregnancy. It can cause bronchiectasis, recurrent sinusitis, and situs inversus (eg dextrocardia on CXR).
Plasma membrane composition
Asymmetric lipid bilayer. It contains cholesterol, phospholipids, sphingolipids, glycolipids, and proteins. Fungal membranes contain ergosterol.
Sodium potassium pump
Na-K ATPase is located in the plasma membrane ATP site on cytosolic side. For each ATP consumed, 3 Na go out of the cell (pump phosphorylated) and 2 K come into the cell (pump dephosphorylated). Ouabain inhibits the pump by binding to K site. Cardiac glcosides (digoxin and digitoxin) directly inhibit the Na-K ATPase, which leads to indirect inhibition of Na/Ca exchange, causing there to be a higher intracellular [Ca], increasing cardiac contractility.
Collagen
It is the most abundant protein in the human body. It is extensively modified by posttranslational modification. It organizes and strengthens extracellular matrix. Be (So Totally) [type I] Cool [type II] Read [type III] Books [type IV]. Bone (Skin, Tendon), Cartilage, Reticulin, and Basement membrane.
Type I collagen
It is the most common (90%). Located within bone (made by osteoblasts), skin, tendon, dentin, fascia, cornea, late wound repair. There is decrease production in osteogenesis imperfecta type I. (Type I= bONE).
Type II collagen
Located within cartilage (including hyaline), vitreous body, nucleus pulposus. (Type II= carTWOlage)
Type III collagen
Located with reticulin, including skin, blood vessels, uterus, fetal tissue, and granulation tissue. This is deficiency in the uncommon, vascular type of Ehlers-Danlos syndrome.
Type IV collagen
Located within basement membrane, basal lamina, and lens. It is defective in Alport syndrome and is the target of autoantibodies in Goodpasture syndrome. (Type IV, under the floor).
Collagen synthesis
Occurs within the RER of fibroblasts. Translation of collagen alpha chains (preprocollagen), usually Gly-X-Y (X and Y are proline or lysine). Glycine content best reflects collagen synthesis (collagen is 1/3 glycine).
Hydroxylation of collagen
Occurs within the RER of fibroblasts. Hydroxylation of specific proline and lysine residues, which requires vitamin C (deficiency causes scurvy).
Gycosylation of collagen
Occurs within the RER of fibroblasts. Glycosylation of pro-alpha-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen alpha chains). Problems forming triple helix causes osteogenesis imperfecta.
Exocytosis of collagen
Exocytosis of procollagen from fibroblasts into extracellular space.
Proteolytic processing of collagen
Cleavage of disulfide-rich terminal regions of procollagen, transforming it into insoluble tropocollagen. Occurs outside of the fibroblasts.
Cross-linking of collagen
Reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by copper-containing lysyl oxidase) to make collagen fibrils. Problems with cross-linking causes Ehlers Danlos syndrome, Menkes disease.
Osteogenesis imperfecta
A genetic bone disorder (brittle bone disease) caused by a variety of gene defects. The most common form in autosomal dominant with a decrease production of otherwise normal type I collagen. Manifestations can include 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 ossicles), dental imperfections due to a lack of dentin.
Polymerase chain reaction (PCR)
Polymerase chain reaction (PCR) is a laboratory technique that can be used to amplify a specific DNA segment. One cycle of the polymerase chain reaction (PCR) is as follows. In a PCR tube, the following are placed: DNA sample of interest. Two different known primers (one for each strand of the double-stranded DNA). Taq polymerase. Nucleotides. DNA is heated (95ºC) to denature and separate the strands. The sample is cooled (50ºC) to anneal the primer to the sample. The primer sequence must be known, usually ~20 nucleotides long. DNA primers are in molar excess so that upon cooling it is the primer that anneals to the strand. The sample is heated to 72ºC and Taq DNA polymerase (or another heat stable DNAP) elongates the primer, generating a new copy of the desired DNA fragment. The process is repeated; every cycle doubles the number of copies (8 cycles = 2^8 copies = 256 copies).
Elher-Danlos syndrome
Faulty collagen synthesis causing hyperextensible skin, tendency to bleed (easy bruising), and hypermobile joints. There are multiple types. Inheritance and severity vary. It can be autosomal dominant or recessive. It may be associated with joint dislocation, berry and aortic aneurysms, and organ rupture. Hypermobility type (joint instability) is the most common type. The classical type (joint and skin symptoms) is caused by a mutation in type V collage. Vascular type (vascular and organ rupture) is caused by a deficiency in type III collagen.
Menkes disease
X-linked recessive connective tissue disease caused by impaired copper absorption and transport due to defective Menkes protein (ATP7A). This leads to a decrease in activity of lysyl oxidase (copper is a necessary cofactor). this results in brittle, kinky hair, growth retardation, and hypotonia.
Elastin
It is the stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connect vertebrae in either relaxed or stretched conformations). It is rich in nonhydroxylated proline, glycine, and lysine residues. Synthesis of elastin involves cross-linking multiple tropoelastin molecules on a fibrillin (encoded by the FBN1 gene) framework. Cross-linking takes place extracellularly and gives elastin its elastic properties. It is broken down by elastase, which is produced by neutrophils and some other cell types such as macrophages. Elastin is normally inhibited by alpha 1-antitrypsin.
Marfan syndrome
It is caused by a defect in fibrillin, a glycoprotein that forms a sheath around elastin.
Alpha 1-antitrypsin deficiency
α1-antitrypsin is a protein that inhibits excess elastase (thereby protecting elastin proteins). A deficiency in α1-antitrypsin causes emphysema as elastase destroys pulmonary elastin. α1-antitrypsin deficiency also causes cirrhosis due to accumulation of misfolded α1-antitrypsin proteins in the liver. These accumulations can be seen by PAS stain on histological section. Wrinkles of aging are due to a decrease in collagen and elastin production.
Blotting
Blotting is a molecular biology technique that checks for the presence of a specific sequence of nucleotides or protein in a sample (usually encased in a gel). SNoW DRoP: Southern=DNA, Northern=RNA, Western=Protein.
Southern blot
Southern blot detects DNA. The process involves the following steps: 1. DNA samples are separated (via electrophoresis) on a gel. 2. Separated DNA is transferred to a filter. 3. DNA is exposed to a labeled DNA probe that anneals to its complement. 4. Labeled probe is visualized, locating the DNA sample of interest
Northern blot
Northern blot detects RNA. The process is the same as Southern blot, except the sample is RNA, not DNA. Note that the probe remains DNA.
Western blots
Western blots detect protein. The process involves: 1. Proteins are electrophoretically separated and transferred to a filter. 2. A primary antibody (specific to the protein of interest) is applied. 3. Excess primary antibody is washed off, and secondary antibody (enzyme-linked, e.g. horseradish peroxidase) is applied. Secondary antibody recognizes and binds to the primary antibody. 4. An appropriate substrate is added to visualize the bands of interest. The western blot is the confirmatory test in a presumed HIV infection. (ELISA is the screening test).
Southwestern blot
Southwestern blot detects interactions between DNA and proteins. Southwestern blots are used to study the interaction of DNA with DNA-binding proteins, such as proteins that regulate transcription. The steps of a southwestern blot are as follows: 1. Proteins are separated (via electrophoresis) on a gel. 2. Proteins are transferred to a filter. 3. Proteins are exposed to radiolabeled known DNA sequences. 4. Proteins that bind that sequence will bind the DNA, which can then be visualized on a film
Microarrays
DNA microarray is a glass chip that contains an arrangement of thousands of sample genes. They are used to measure gene expression in any given cell by taking advantage of the fact that mRNA (and cDNA) binds to its parent DNA. DNA oligonucleotides with known sequences are synthesized by machines and immobilized on the grid. mRNA from the cell of interest is isolated and used to construct a cDNA library, which contains fluorescent tags. This forms the “mobile probe”. The “mobile probe” can consist of cDNA, mRNA or DNA. The fluorescent probe is then incubated on the immobilized sequences and allowed to hybridize. The more sample that binds, the greater the degree of fluorescence, which represents higher gene expression. Used to simultaneously profile gene expression of different tissues and diseases.
Enzyme-linked immunosorbent assay
Enzyme linked immuno-sorbent assay (ELISA) is a biochemical technique used to detect the presence of antigens or antibodies in blood. Direct ELISA detects antigen presence in a patient sample by applying an antibody conjugated to a color generating or fluorescent enzyme. If the antigen is present, the antibody will bind it and the enzyme will change color or fluoresce. Indirect ELISA can detect antigens or antibodies. The steps are: 1. A test antigen is applied to detect an antibody in a patient sample, or an antibody is applied to detect an antigen in a patient sample. 2. A second antibody conjugated to a color generating or fluorescent enzyme is then applied. 3. The second antibody binds the antigen-antibody complex and changes color or fluoresces. ELISA has both high sensitivity and high specificity.
Karyotyping
A process in which metaphase chromosomes are stained, ordered, and numbered according to morphology, size, arm-length ratio, and banding pattern. It can be performed on a sample of blood, bone marrow, amniotic fluid, or placental tissue. It is used to diagnose chromosomal imbalances (eg autosomal trisomies and sex chromosome disorders).
Fluorescence in situ hybridization
Fluorescent in situ hybridization (FISH) is a cytogenetic technique that allows scientists to detect the presence and location of a specific sequence of DNA or RNA. The process for performing a basic FISH are as follows: The DNA double helix is separated by heating or chemicals. A fluorescent DNA probe hybridizes to its complementary DNA. The sample is washed to remove excess probe and visualized under a microscope. Though the steps for a DNA FISH are described above, this process can be used to probe for both specific DNA and RNA sequences. FISH can be used to detect deletions, translocations, and duplications that are too small to be detected by karyotype. Another advantage of FISH over karyotype is that FISH can be used on non-mitotic cells (i.e. FISH can be used on cells in interphase).
Cloning
Cloning is a recombinant DNA technique in which specific cDNA is incorporated into a cloning vector, which then is inserted into cultured host cells. The cDNA can then be expressed in large amounts. The steps for using a plasmid as a vector for cloning are as follows: 1. Eukaryotic mRNA is isolated and reverse transcriptase is used to generate cDNA without intron and exon regions (this is necessary because prokaryotes don’t have the necessary machinery to process the introns and exons of eukaryotic genes). 2. Restriction enzymes are used to insert the cDNA into the plasmid which also contains antibiotic resistance. 3. Competent cells (e.g. E. coli) are then used to take up the plasmid. This process is known as transformation. The bacteria are then grown in antibiotic medium and only the cells containing the plasmid (and thus gene of interest and antibiotic resistance) will proliferate.
Vector
Carrier for the recombinant DNA of interest. Commonly used vectors includes plasmids, BAC (bacterial artificial chromosomes), and viruses (e.g. λ phage).
Gene expression modifications
Strategies for the modulation of gene expression include: Knock-down, which is the inactivation or removal of mRNA encoding a particular gene. Knock-out, which is the inactivation or removal of DNA encoding a particular gene. Knock-in, which is the addition of DNA encoding a particular gene. Transgenic mice can be generated by both nonhomologous (random) or homologous (targeted) recombination in mouse embryonic stem cells.
Cre-lox system
The Cre-lox system is used to inducibly delete a gene at particular developmental timepoint or in a particular tissue. This is a particularly useful strategy for studying genes whose deletion is embryonic lethal or for studying the tissue-specific role of a gene.
RNA interference
RNA interference is commonly used to knock-down a gene of interest. RNA interference uses synthetic dsRNA that is complementary to the targeted mRNA sequence. After transfection, the synthetic dsRNA is: Separated into ssRNA; The complementary ssRNA sequence binds the targeted mRNA sequence; The newly-formed dsRNA complex is degraded, knocking-down gene expression
Allelic heterogeneity
Allelic heterogeneity is exhibited when different mutations in the same gene (at the same locus) cause similar phenotype. Example: Duchenne and Becker muscular dystrophy have a similar phenotype and both are caused by dystrophin mutations. However, Duchenne muscular dystrophy is a frameshift mutation resulting in nonfunctional protein, while Becker muscular dystrophy is another mutation (usually a point mutation) that retains some dystrophin function.
Anticipation
Anticipation is the phenomenon in which a disease exhibits increased severity or an earlier age of onset with each succeeding generation. Example: Trinucleotide repeat diseases such as Huntington disease or myotonic dystrophy classically exhibit anticipation.
Codominance
Codominance describes genes whose alleles are both expressed simultaneously (i.e. dominance is shared). Example: The ABO blood group exhibit codominance, such that both the A and B antigen alleles may be expressed individually or simultaneously (type AB blood).
Dominant negative mutation
Dominant negative mutations occur when the product of the mutant allele actually inactivates the product of the normal gene. Thus, the mutation exerts a dominant effect. Example: Mutant forms of fibrillin-1 in Marfan syndrome interfere with the utilization of the normal protein from the normal allele.
Heteroplasmy
Heteroplasmy is a condition in which there is a mixture of normal and mutant mitochondrial DNA within a cell or individual. As such, there is inconsistent expression (variable expressivity) of the disease among patients. Example: Heteroplasmy is classically tested as the genetic mechanism observed in mitochrondrial myopathies (recall the “ragged red fiber” appearance of these myopathies on muscle biopsy).
Imprinting
Imprinting is an allele inactivation process (via methylation) that results in the presence of only one active allele at some gene loci. While this occurs physiologically in some genes without consequence, it produces pathology when the active allele is mutated. Example: Classically, Prader-Willi and Angelman syndromes are two disorders that may result from mutation of an active allele when the other allele is imprinted. In Prader-Willi syndrome, a paternal gene is deleted at a loci where the maternal allele is imprinted. In Angelman syndrome, a maternal gene is deleted at a loci where the paternal allele is imprinted.
Incomplete penetrance
Incomplete penetrance refers to a mutant phenotype that is not expressed in all individuals containing the mutation. Example: Familial cancer syndromes such as hereditary nonpolyposis colorectal cancer. While multiple members of a family may have the mutant gene, not all will develop cancer.
Linkage
Linkage refers to the possibility of two different genes on the same chromosome segregating together during recombination. This produces a disequilibrium in gene occurrence, such that certain linked alleles may occur more often than chance would dictate. Example: HLA alleles HLA-A1 and HLA-B8 occur together more frequently in European populations than random chance would suggest.
Locus heterogeneity
Locus heterogeneity describes the phenomenon in which mutations at different loci can produce a similar phenotype. Example: Severe combined immunodeficiency (SCID) exhibits locus heterogeneity because it can be caused by an adenosine deaminase mutation, interleukin receptor mutations, as well as mutations at other loci.
Loss of heterozygosity (LOH)
Loss of heterozygosity (LOH) is a term used to describe a mutation in the single normal allele at a locus where there is only one functioning allele (the other allele is most commonly inherited as non-functional). Example: Classically, tumor suppressor genes such as retinoblastoma-1 (RB1) are said to exhibit loss of heterozygosity when the second allele becomes mutated, after the individual inherited the first defective RB1 allele. This references the Knudson “two-hit hypothesis of tumorigenesis.”
Mosaicism
Mosaicism refers to mutations that are not reflected throughout the entire patient’s cell line (typically due to a mutation early in embryogenesis). This may allow for less severe phenotypes of mutations, or allow for the sparing of a patient with an otherwise fatal mutation. Example: Patients with Turner syndrome may have a less severe phenotype if their 45, XO mutation is mosaic. Germline mosaicism is the presence of two or more genetically distinct cell lines limited to the egg and sperm cells. It should be considered when there is a mutation present in the offspring that is not present in the parents.
Pleiotropy
Pleiotropy refers to a single gene causing several, sometimes seemingly unrelated phenotypic effects. Example: The CFTR gene mutation in cystic fibrosis contributes to pancreatic, pulmonary, and other systemic manifestations.
Uniparental disomy
Uniparental disomy is a genetic error in which a child receives 2 copies of a chromosome from one parent and none from the other. Note that uniparental disomy results in a euploid child, unlike most cases of nondisjunction. Example: Uniparental disomy is a cause of Prader-Willi and Angelman syndromes, in which one parent donates two copies of normally imprinted (inactivated) genes.
Variable expressivity
Variable expressivity describes a disease that can have different manifestations in people with the same genetic condition. Example: Two people with Marfan syndrome (same mutation in the fibrillin-1 gene) may have a different spectrum of disease manifestations; both may have physical manifestations, but only one may develop an acute aortic dissection.
McCune-Albright syndrome
Occurs due to mutation affecting G-protein signaling. It presents with unilateral cafe-au-lait spots, polysototic fibrous dysplasia (the replacement of multiple areas of bone by fibrous tissue, which may cause fractures and deformity), precocious puberty, multiple endocrine abnormalities. It is lethal if mutation occurs before fertilization (affecting all cells), but survivable in patients with mosaicism.
Hardy Weinberg law assumptions
Both allele and genotype frequencies in a population remain constant if 5 conditions are met: No mutations. No natural selection. The population is large. Random mating. No migration
Hardy Weinberg population genetics
Allele prevalence: p+q=1. p is the frequency for allele A. q is the frequency for allele B. Genotype prevalence: p2 + 2pq + q2 = 1. p2 = frequency of AA genotype (homozygote). 2pq = frequency of AB genotype (heterozygote). q2 = frequency of BB genotype (homozygote). If allele A is X-linked recessive: If males inherit one A allele, they have the A phenotype. The frequency of A = p. Females must inherit two A alleles in order to have the A phenotype since the disease is X linked recessive. If the frequency of A = p, then the odds of having two A alleles can be calculated by multiplying p by p, which is equal to p2.
Prader Willi syndrome
Maternal imprinting on this region of chromosome 15 makes gene from mom silent and Paternal gene is deleted/ mutated. It results in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia. 25% of cases occurs due to maternal uniparental disomy (two maternally imprinted genes are received), no paternal gene received.
AngelMan syndrome
Paternal imprinting on this region of chromosome 15 makes gene from dad is normally silent and Maternal gene is deleted/mutated. This results in inappropriate laughter (happy puppet), seizures, ataxia, and severe intellectual disability. 5% of cases occurs due to paternal uniparental disomy (two paternally imprinted genes are received; no maternal gene received).
Autosomal dominant
Autosomal dominant disorders result from mutations of genes on autosomal chromosomes. Development of an autosomal dominant disorder requires inheritance of one mutation to develop the disease. The mutation often affects structural genes. Homozygous dominant phenotypes are typically lethal, while heterozygous phenotypes are typically less severe than autosomal recessive diseases. Phenotypes are often pleiotropic. Men and women are affected equally, and have an equal likelihood of passing the gene to offspring, since the mutations occur on autosomal chromosomes. When analyzing a pedigree, look for affected people in each generation.
Autosomal recessive
Two alleles (homozygote) are required for expression of the phenotype. A common feature of an autosomal recessive pedigree is that the phenotype skips generations. Males and and females are equally affected.
X-linked recessive
No father-to-son transmission; sons of heterozygous mothers have a 50% chance of being affected. In women, X chromosomes are randomly inactivated in each cell (this takes place early in embryogenesis). Female carriers are rarely symptomatic, however they can be. This would be due to inactivation of the normal allele. X-linked recessive traits are much more common in males.
X-linked dominant
All daughters of an affected father (only one X chromosome) are affected. No father-to-son transmission.
Mitochondrial inheritance
It is only transmitted via mother. No children of an affected father will inherit a mitochondrial disease (assuming a normal mother). Mitochondrial inheritance affects male and female offspring of an affected mother equally.
Hypophosphatemic rickets
It is formely known as vitamin D resistant rickets. It is inherited disorder resulting in an increase in phosphate wasting at the proximal tubules. It is X-linked dominant. It results in a rickets like presentation.
Mitochondrial myopathies
A group of mitochondrial inherited rare disorders that often present with myopathy, lactic acidosis and CNS disease. It occurs secondarily to failure in oxidative phosphorylation. Muscle biopsy often shows ragged red fibber.
Autosomal dominant polycystic kidney disease (ADPKD)
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 are due to mutation in PKD2 (chromosome 4).
Familial adenomatous polyposis
Autosomal dominant. Colon becomes covered with adenomatous polyps after puberty. Progresses to colon cancer unless colon is resected. Mutations on chromosome 5q (APC gene); 5 letters in polyp.
Familial hypercholesterolemia
Autosomal dominant. Elevated LDL due to defective or absent LDL receptor. It leads to severe atherosclerotic disease early in life, corneal arcus, tendon xanthomas (classically seen in the Achilles tendon).
Hereditary hemorrhagic telangiectasia
Autosomal dominant. Inherited disorder of blood vessels. Findings include branching skin lesions (telangiectasia), recurrent epistaxis, skin discoloration, arteriovenous malformations (AVMs), GI bleeding, hematuria. It is also known as Osler-Weber-Rendu syndrome.
Hereditary spherocytosis
Autosomal dominant. Spheroid erythrocytes due to spectrin or ankyrin defect. It causes hemolytic anemia, an increase in mean corpuscular hemoglobin concentration (MCHC), an increase in RDW. Treatment is splenectomy.
Huntington disease
Autosomal dominant. Findings include depression, progressive dementia, choreiform movements, and caudate atrophy. There is an increase in dopamine, a decrease in GABA, a decrease in ACh in the brain. Gene is on chromosome 4; a trinucleotide repeat disorder (CAG)n. Demonstrates anticipation: an increase in repeats leads to an earlier age of onset. Hunting 4 food.
Li-Fraumeni syndrome
Autosomal dominant. Abnormalities in TP53 leads to multiple malignancies at an early age. It is also known as SBLA cancer syndrome (sarcoma, breast, leukemia, and adrenal gland).
Marfan syndrome
Autosomal dominant. FBN1 gene mutation on chromosome 15 creates a defective fibrin (scaffold for elastin), leading to a connective tissue disorder affecting skeleton, heart, and eyes. Findings include being tall with long extremities, pectus excavatum, hypermobile joints, and long tapering fingers and toes (arachnodactyly). There is cystic medial necrosis of the aorta causes aortic incompetence and dissecting aortic aneurysms. There is also a floppy mitral valve. Subluxation of the lens is typically upward and temporally.
Multiple endocrine neoplasias (MEN)
Autosomal dominant. They are several distinct syndromes (1, 2A, and 2B) characterized by familial tumors of endocrine glands, including those of the pancreas parathyroid, pituitary, thyroid, and adrenal medulla. Men 1 is associated with MEN1 gene, MEN 2A and 2B are associated with the RET gene.
