Term
| Beta-galactosidase deficiency |
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Definition
Lysosomal storage disease. Problem with breakdown of Gangliosides (type of sphingolipid) in lysosomes. Gangliosides commonly present in grey matter neurons. (Gangliosides are a type of sphingolipid that contains branched sugar head groups attached to ceramide)
Symptoms: in child 6 months of age, first loss of vision, then startle response, cerebellar ataxia, muscle contractions, thrombocytopenia, immune system problems.
Can see thinning of grey matter in outer cell layer of cortex where cell bodies are. |
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Term
| Nephrogenic diabetes insipidus |
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Definition
| defect in aquaporins channels. unable to save water from the urine--the patients excrete large unregulated volume of dilute urine |
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Term
Cystic fibrosis (specialized domain)
(regulation of ENaC)
(most common deletion) |
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Definition
has a PDZ-binding domain that restricts lateral diffusion of the CFTR, holding the ion channel in the apical face of the cell membrane, and regulating endocytosis for CFTR turnover.
12 transmembrane domains, one regulatory domain where Protein Kinase A phosphorylates, and two nucleotide binding domains where ATP binds.
The chloride channel normally functions to inhibit ENaC function in most cells and activate ENaC in sweat glands. Thus, in cystic fibrosis, a defect in CFTR leads to activation of ENaC/uptake of Na+ and water into airway epithelial cells, drying out the surface layer coating mucosal cells. In sweat glands, loss of function of CFTR leads to decreased Na+ and Cl- influx into epithelial cells, causing salty sweat.
Most common mutation is F508del (deletion of phenylalanine), leading to disruption of trafficking and its accumulation in the ER and degradation via ERAD pathway. |
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Term
| HIV Virus (sphingolipids) |
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Definition
| gp120 surface protein of HIV binds sphingomyelin lipid rafts. Sphingomyelin induces structural changes in gp120 that are essential for subsequent viral fusion. HIV then preferentially buds from lipid rafts enriched in spingomyelin. The HIV membrane is enriched in spingomyelin which gives it resistance to detergent disruption. |
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Term
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Definition
Kidney disease due to defect in Na+/glucose/amino acid transporters. Disease of proximal tubules: aa, glucose, phosphate, HCO3 all pass into urine and are not absorbed.
Causes ricket's in children: phosphate is necessary for bone development. patients have deformities or fractures, growth failures, acidosis, hypokalemia.
Causes osteomalacia in adults: body pains, muscle weakness, fragile bones.
absorption requires efficient recycling of megalin
Can be caused by:
-defects in the receptor megalin
-defects in associated receptor cubilin
-machinery associated with endocytosis recycling |
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Term
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Definition
| Block Na+/K+ATPase, causing intracellular Na+ to rise and the loss of the Na+ gradient that drives the 3Na+/Ca2+ antiporter in cardiac muscle. Thus, Ca2+ will stick around longer and prolong cardiac muscle contractions--used clinically in treatment of heart failure. |
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Term
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Definition
| non-competitive inhibitor of the H/K ATPase pump to block acid secretion in the stomach. |
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Term
| Hyperinsulinemia of infancy |
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Definition
inappropriate oversecretion of insulin despite low glucose levels.
caused by inactivating mutations in SUR1 and KIR6.2, which are the two subunits of the K+ATP channel of pancreatic beta cells. Binding of ATP ro KIR6.2 or binding of sulfonylurea drugs to SUR1 causes K+ATP channels to close, depolarizing the membrane and thus opening voltage dependant Ca2+ channels. The influx of intracellular Ca2+ is what drives the release of insulin from stored vesicles. Thus, mutations in the SUR1 and KIR6.2 subunits caused oversecretion of insulin. |
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Term
| Permanent neonatal diabetes mellitus |
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Definition
can be caused by inactivating mutations of KIR6.2, a subunit of the K+ATP channel on pancreatic beta cells.
characterized by reduced insulin secretion, hyperglycemia, and low birth weight. |
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Term
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Definition
Mutation in amiloride-sensitive ENaC which prevents its interaction with Nedd4 (an E3 ubiquitin ligase). Thus, ENaC has decreased degradation and turnover, stays on the apical surface of cells in the collecting tubule, and causes excessive Na+ reabsorption.
Called "pseudohyperaldosteronism" because there's not an actual increase in aldosterone.
Patients have severe hypertension that often begins in infancy. |
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Term
| Charcot Marie Tooth's Disease |
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Definition
Neuropathy. Symptoms include: foot drop, high arch, claw toe, muscle wasting in legs, weakness in arms, loss of sensation, painful nuscle contractions, variable neuropathic pain
Caused by gain of function mutation in peripheral myelin protein, resulting in accumulation in the ER and activation of the unfolded protein response. Ultimately--> toxicity in Schwann cells.
OR Ubiquiotus trafficking components MTMR2, MTMR13, FIG4, SH3TC2 affected. |
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Term
| Inclusion Cell disease (mucolipidosis II) |
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Definition
| caused by defect in Golgi enzyme that phosphorylates a specific mannose on lysosomal hydrolase such that they are not targeted to lysosomes. Almost all hydrolases missing from lysosomes. |
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Term
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Definition
| Lysosomal Storage Disease. Mutation in a structural gene for a single hydrolytic enzyme (deficiency of alpha-L iduronidase) |
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Term
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Definition
caused by mutations in lamin A/C. Exhibit a wide variety of skeletal muscle and cardiac defects as well as premature aging (hair loss, diminished subcutaneous fat). Fibroblasts cultured have abnormally shaped nuclei. Cardiomyocytes have disorganized cytoskeletal desmin filaments and detachment of these filaments from the nuclear surface.
Other laminopathies include
-limb girdle muscular dystrophy
-charcot-marie-tooth disorder type 2 |
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Term
| Hutchinson-Gilford Progeria Syndrome |
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Definition
A laminopathy tat leads to precocious aging. Symptoms appear within 1 year, include hair loss, diminished subcutaneous fat, cardiovascular disease, skeletal abnormalities.
Lamin A mutations lead to truncated protein called progerin, which is inappropriately processed and retains a C-terminal farnesyl group (whose addition is catalyzed by farnesyl transferase). This causes mislocalization of progerin to the nuclear envelope and changes in nuclear structure and function. Farnesyltransferase inhibitors can rescue altered nuclear morphology. |
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Term
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Definition
Leigh's syndrome: caused by >95% heteroplasmic point mutation in ATP6 gene (a subunit of ATP Synthase), or mutations in various mitochondira DNA genes in addition to ATP6.
NARP: Neurogenic muscular weakness, ataxia, and retinitis pigmentoasa. Caused by <75% heteroplasmic point mutation in ATP6 gene |
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Term
Peroxisomal Diseases
(i.e. Zellweger syndrome, Neonatal Adrenoleukodystropy) |
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Definition
accumulation of very long chain fatty acids (VLCFA) causes membrane disfunction in RBCs, and demylination/intense inflammation in the brain.
Zellweger Syndrome: dysmorphic facial features, flat nose bridge, wide-set eyes, low set ears, deformed limbs, diseased liver and kidneys, malformation of brain, hypomyelination, eye disease, hearing loss, hypotonic, seizures, fatal within first year of life.
Neonatal adrenoleukodystropy: X-linked, lack enzyme in peroxisome to esterify fatty acids to acetyl coA. VLCFAs accumulate, fatal within first 10 years. |
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Term
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Definition
| a partial agonist for dopamine used in schizophrenia. acts as antagonist for overactive dopamine pathways and acts as agonist for underactive dopamine pathways. |
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Term
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Definition
| injected into intestinal epithelial cells, causes ADP-ribosylation of Galpha s subunit locking it into AT-bound on state. cAMP goes way up and causes the efflux of Cl- and H2O from the CFTR channel, shuts down ENaC. |
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Term
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Definition
| ADP-ribosylateds Galpha i such that it is stuck in the GDP-bound off state. Due to lack of inhibition of adenylyl cyclase, cAMP is decreased. Causes whooping cough. |
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Term
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Definition
Characterized by progressive peripheral vision loss, night vision difficulties, and eventually central vision loss.
Some cases (15%) are caused by a mutation in rhodopsin, a GPCR. Rhodopsin aggregates and accumulates in the ER. Normally, when light activates rhodopsin, Galpha-Transducin is activated by GTP and activates cGMP phosphodiesterase. cGMP phosphodiesterase cleaves and inactivates cGMP, cause closure of cGMP depending Na+ channels. Closure of the Na+ channels causes hyperpolarization of the bipolar cells. |
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Term
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Definition
a beta2-adrenergic receptor agonist that is used in asthma to increase broncodilation.
demonstrates the concept of spare receptors because the effectors last much longer than receptor occupancy. |
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Term
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Definition
| noncompetitive antagonist of nicotinic Acl receptor |
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Term
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Definition
| competitive antagonist of muscarinic GPCR Ach receptor |
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Term
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Definition
| competitive antagonist against mineralocorticoid receptors. is a K-sparing diuretic that is used to treat hypertension associated with Liddle's syndrome. Note that antagonistic effects can be overcome with increased generation of endogenous ligand (aldosterone) for example in tumors. |
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Term
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Definition
| inverse agonist for nonselective beta-adrenergic receptor used to prevent migraines in children. changes signalling pathway by changing conformation of the receptor. |
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Term
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Definition
| have tails containing the activating ligand. overexpressed in cancers which use proteases to cut through cells/migrate. can lead to pathways that increase proliferation and growth |
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Term
| Dwarfism (i.e. Achondroplasia, Thanatophoric Dysplasia, hypochondroplasia) |
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Definition
mutations in FGF receptors cause receptors to be activated prematurely. (FGF instruct chondrocytes in the epiphyseal growth plates to stop proliferation and begin differentiation)
Achondroplasia: a dominant mutation in the transmembrane domain of FGFR3. Is the most common type of dwarfism.
Hypochondroplasia: substitution in the split tyrosine kinase domain of FGFR3. Similar to achondroplasia but milder, bowed legs, mental retardation.
Thanatophoric Dysplasia: lethal form of dwarfism caused by mutation int he extracellular domain or tyrosine kinase domain. Respiratory insufficiency due to compression of rib cage and compression of brain stem usually leads to death before the baby comes to term. |
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Term
| Pfeiffer vs. Crouzon Syndrome |
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Definition
Pfeiffer syndrome: caused by mutations in the extracellular domain of FGFR-1. Broad thumbs and big toes.
Crouzon syndrome: caused by mutation in the extracellular domain of FGFR-2. Normal hands and feet.
Limb defects, premature fusion of cranial sutures (craniosynostosis), abnormal head shape and midface underdevelopment. |
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Term
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Definition
| antibody that binds overexpressed HER2 receptors and inhibit their activity. Initially good treatment for more aggressive forms of breast cancer with overexpression of HER2 (ErbB2), which is a type of EGFR/member of the tyrosine kinase family. |
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Term
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Definition
| a monoclonal antibody that inhibits the extracellular domain of tyrosine kinase of HER and other EGFR upregulated in cancer. |
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Term
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Definition
| inhibits the kinase activity of HER/EGFR by acting as ATP analogues. Anti-cancer drugs. |
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Term
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Definition
| binds to and inhibits non-receptor tyrosine kinase abl (ex. jak/stat pathway). patients to can become resistant to Gleevac after a period of remission because of activation of other pathways. |
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Term
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Definition
| a phosphatase and tumor supressor that inhibits AKT signalling and inhibits growth/proliferation. PTEN deficiency found in advanced cancer stages and associated with resistance to anticancer drugs. |
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Term
| Rubinstein-Taybi Syndrome |
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Definition
Caused by mutation in CBP (CREB binding protein). CBP is a transcriptional co-activator of CREB that has histone actyltransferase activity, which helps loosen the grip of histones on DNA.
Characterized by mental retardation, congenital heart defect, broad thumb and toes, down-slanting eyes, beak nose, developmental delay,feeding difficulties. |
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Term
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Definition
| CAG Repeat. activity of CREB is decreased and depletion of CBP. PDE inhibitor Rolipram may have a protective effect. |
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Term
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Definition
| cGMP PDE inhibitor used for erectile dysfunction. NO activates guanylyl cyclase to increase cGMP signalling and ultimately produce vasodilation necessary for an erection. Inhibiting PDE can prevent degradation of cGMP and prolong its effects. |
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Term
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Definition
| in 14% of sudden unexplained death, mutations in RYR are found. They are clinically relevant in the heart. |
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Term
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Definition
| prevents graft rejection by blocking the IP3/DAG-->PKC pathway. |
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Term
| thiazolidinediones (Avandia) |
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Definition
| Synthetic ligand for PPARs (peroxisome proliferaor-activated receptor gamma)twas approved for treatment of Type II diabetes b/c of insulin sensitizing effects, but was withdrawn due to increased risk fo adverse cardiovascular events. |
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Term
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Definition
| is a selective estrogen receptor modulator. antagonistic in breat but partial agonist in uterus, bone, and liver. |
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Term
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Definition
mutation in the RET receptor that responds to GDNF (glial cell derived neurotrophic factor). causes enteric neural crest cells to fail to migrate to a portion of the bowel--> results in lack of auerbach's plexus.
Pigmentation and hearing loss is associated with some mutations. |
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Term
| Kartagener Syndrome or Primary ciliary Dyskinesia |
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Definition
mutations in motile cilia
-situs inversus and cardiac malformations (cilia at embryonic node)
-infertility (cilia in oviduct)
-hydrocephalus (cilia in brain ventricles)
-respiratory tract and ear infections and impaired mucociliary clearance |
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Term
| Polycystic Kidney Diseases and Bardet Biedl Syndrome |
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Definition
Mutations in proteins localized to primary non-motile cilia.
Symptoms include:
-urogenital abnormalities
-vision loss
-anosmia (detection of smells dependent on primary cilia)
-hearing loss
-mental retardation and obesity
-postaxial poldactyly (disruptions in hedgehog signalling) |
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Term
| Food Poisoning by Clostridium perfringens |
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Definition
| bacterium produces endotoxin that binds claudins 3 and 4 and occludin (recall claudins/occludins are transmembrane components of tight junctions), induces their degradation, and lead to major increases in permeability and secretory diarrhea |
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Term
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Definition
| association with Hereditary Deafness. Loss of claudin 14 thought to lead to incorrect tight junction formation, local changes in K+ distribution, and ultimately death of hair cells. |
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Term
| Relation between E-Cadherin and Cancer? |
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Definition
abnormal E-Cadherin expression often present in advanced cancers.
One possible explanation: beta-catenin is a transcriptional coactivator in Wnt signalling, which is known to preferentially influence the expansion of epithelial stem cell populations and possibly a key early event in some cancers.
E-Cadherein may serve as a sink for beta-catenin, keeping it associated with adhesion complexes, thus dampening the effects of Wnt signalling. E-cadherin may also modulate factors that promote an epithelial to mesenchymal transition. |
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Term
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Definition
| autoimmune response against desmogleins 1 and 3. disruption of cell-cell adhesion causes formation of blisters on the skin and mucous membranes. |
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Term
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Definition
| An easily treated staphylococcus aureus infection that causes blisters. Desmoglein 1 is the proteolytic target of the bacterial toxin. |
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Term
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Definition
(Recall that 6 connexin subunits make up a gap junction)
Causes death of cells in the organ of corti and deafness |
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Term
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Definition
linked to peripheral neuropathy of Charcot Marie Tooth Disease
(6 connexin subunits = gap junction) |
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Term
| Congenital Muscular Dystropy |
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Definition
| caused by mutations in laminin alpha 2 chain. |
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Term
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Definition
| mutation in gly-x-y, can't form functional collagen |
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Term
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Definition
| Vitamin C deficiency. Vitamin C is necessary for the actions of Proline hydroxylase and Lysyl oxidase, enzymes important for collagen synthesis and crosslinking. |
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Term
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Definition
| bone instability, synthesized and rapid turnover. Can see increased number of cement lines and no real organized haversian systems |
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Term
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Definition
| increased degradation and decreased synthesis of proteoglycans in articular cartilage--results in loss of compressibility. associated with aging and joints subject to wear and tear |
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Term
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Definition
| infection of bone via blood vessels |
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Term
| bisphosphonates (i.e.Boniva) |
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Definition
anti-resorbative drugs used in osteoporosis. blocks protein prenylation only in newly forming bone matrix. osteoclasts eat up the drug and is killed.
downside is that bisphosphonates stay in the bone matrix for a long long time and inhibit normal bone turnover. causes spontaneous and traumatic fractures |
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Term
| SERMS in osteoporosis (i.e. raloxifene mechanism) |
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Definition
Selective Estrogen Receptor Modulator. Mimicks the effects of estrogen in bone and decreases IL-6 and IL-11 and blocks osteoclast differentiation. used post menopausally. Good for decreasing spine fractures, not for hip fractures.
Downside: risk for thromboembolisms |
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Term
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Definition
is an osteroprotegerin analogue. Binds Rank ligand and blocks formation of osteoclasts. used for osteoporosis. postmenopausal
Downside: risk for more infections |
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Definition
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