Biochem Night School II.1

• clonal DNA from mRNA reversetranscripted
• lacks introns

• manipulates genes after a point in development
• because for some genes if you mess with them too early you cause death

• injected into human cells promotes target mRNA degradation
• gene “knock down”

one gene contributes to multiple phenotypic effects

mutation after fertilization propagates a certain mutation in only some tissues

mutation occurred that affects germ cells of an individual, but is not present in the individual

• lethal if occurs before fertilization, only viable if somatic mosaicism
• G protein signaling issue leading to constituitive G protein function in some tissues causing autonomous hormone effects/production
• unilateral cafe au lait, polyostotic fibrous dysplasia (fibrous bone that is weak, poly meaning multiple affected bones), precocious puberty, hyperthyroidism, Cushing syndrome, growth

• 2 copies from one parent, none from the other
• AR disease when only one parent is carrier
• heterodisomy if meiosis I
• isodisomy if meiosis II

• p and q are allelic frequencies
• p² is homozygosity p
• 2pq is heterozygosity
• q² is homozygosity q
• if X linked frequency of disease in males is q and females is q²

• maternal imprinted and paternal deleted/mutated, on chrom 15
• hyperhpagia, obesity, intellectual disability, hypogonadism, hypotonia
• also maternal uniparental disomy

• paternal imprinted and maternal deleted/mutated, on chrom 15
• inappropriate laughter, seizures, ataxia, severe intellectual disability
• “happy puppet”
• also paternal uniparental disomys

• fathers to ALL daughters and no sons
• mothers to both 50/50 shot

• mothers to ALL children to some degree
• fathers to no one

• AD
• telangiectasias, epistaxis, skin discolorations, AVMs (death in brain), GI bleeding, hematuria

• AD
• SBLA cancer
• sarcoma, breast, leukemia, adrenal

• AD
• cystic medial necrosis of aorta
• lens sublux up and out
• floppy mitral

• NF1
• AD
• cafe au lait
• cutaneous neurofibromas, optic glioma, pheochromocytomas, Lisch nodules (iris hamartoma)

• AD
• bilateral acoustic schwannoma, juvenile cataracts, meningiomas, ependymomas

• AR
• chromosome 7, deletion of Phe508 is most common
• misfolded protein (#1), retained in RER Cl channel for lung/GI secretion and sweat reabsorption
• decreased Cl secretion in lungs/GI reduces Na secretion. H20 pulled back into cell causing less water in airway so more mucous by percent (thicker mucous)
• negative transepithelial potential difference
• Cl>60mEq/L in sweat
• contraction alkalosis and hypokalemia because losing Na through sweat so kidneys waste K and H
• new born screening of immunoreactive trypsinogen
• nasal polyps, nail clubbing

• XR with frameshift or nonsense truncating dystrophin links actin to transmembrane alpha and beta dystroglycan. lack causing myonecrosis
• first pelvic girdle then spread, calf pseudohypertrophy b/c first not affected and get used more, then replaced by fat
• use of upper extremities to stand (Gower maneuver)
• waddling gait
• dilated cardiomyopathy is fatal
• elevated CK and alkolase
• western blot confirms

• XR with non-frameshift insertions/deletions leading to partially functional dystrophin gene
• less sever with adolescence or early adulthood onset

• AD CTG trinucleotide repeat and expansion of DMPK (dystrophin myotonica protein kinase
• muscle wasting, myotonia (delayed relaxation), cataracts, testicular atrophy, frontal balding, arrhythmia
• mytonia, mytesticles, mytoupee, myticker

• XD CGG trinucleotide repeat in FMR1, methylating and reducing expression
• post pubertal macroorchidism, intellectual disability, long face, large jaw, large forward facing (everted) ears, autism, MV prolapse

• 95% meiotic nondisjunction, 4% unbalanced Robertsonian 14;21, 1% somatic mosaicism
• duodenal atresia, Hirschsprung, AV septal defect, Brushfield spots (white iris dots), early Alzheimers
• first trimester decreased serum PAPP-A, increased free beta hCG. Also nuchal translucency increased
• 2nd tri decreased alpha fetoprotein and estriol, increased beta hCG and inhibin A

• chromosome 18 trisomy
• rocker bottom feet, small jaw, low ears, clenched hands overlapping fingers,prominent occiput, congenital heart disease
• first trimester decreased serum PAPP-A and beta hCG
• 2nd tri decreased alpha fetoprotein, beta hCG, estriol, and decreased/normal inhibin A

• trisomy 13
• rocker bottom feet, small eye(s), small head, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease, cutis aplasia
• first trimester decreased PAPP-A and beta hCG

• 2 acrocentric chromosome long arms (q) get together and leave the little p bits
• balanced don’t cause any problems, but then you can give your kid an unbalanced and that causes chromosomal abnormalities

• microdeletion of short arm of 5
• microcephaly, intellectual disability, high pitched cry/mew, epicanthal folds, ventral septal defect

• microdeletion of long arm 7 (includes elastin gene)
• elfin face, intellectual disability, hypercalcemia (increased VIT D sensitivity), friendly with strangers, supravalvular aortic stenosis

• microdeletion of 22q11 (chrom 22 long arm that is)
• cleft palate, abnormal face, thymic aplasia, T cell lack, tet of fallot, truncus arteriosus, hypocalcemia (lack PTH)
• velocardiofacial syndrome is same but just palate, facial, and cardiac

• retinol
• visual pigments, epithelial specialization (pancreatic, mucin secreting), prevents squamous metaplasia
• nigh blindness, dry scaly skin, corneal degeneration, bitot spots on conj (chunky fat looking stuff), immunosuppression
• isotretinoin is a teratogen, requires pregnancy test and 2 forms of contraception

• thiamine
• thiamine pyrophosphate (TPP) is a cofactor for pyruvate dehydrogenase (glycolysis to TCA), alhpa ketoglutarate dehydrogenase (alphaKG to succinyl CoA in TCA), transketolase (HMP shunt)
• impaired glucose breakdown worsened by glucose xfusion so low ATP and highly aerobic tissues first affected (brain and heart)
• dilated high output heart failure, edema (wet beriberi)
• polyneuritis, symmetrical muscle wasting (dry beriberi)
• Wernicke-Korsakoff is confusion, ophthalmoplegia, ataxia
• think ATP for alpha ketoglutarate, transketolase, and pyruvate dehydrogenase

• riboflavin
• FAD and FMN (oxidizer flavins) for redox reactions, succinate dehydrogenase in TCA (succinate to fumarate)
• cracked lips at the corners (cheilosis) and corneal vascularization
• 2Cs

• niacin aka nicotinic acid
• NAD and NADP oxidizers derived from tryptophan where synthesis needs B2 and B6. dyslipidemia treatment lowering VLDL and raising HDL
• glossitis, pellagra if severe caused by malignant carcinoid syndrome (decreased tryptophans b/c they're used to synth serotonin and dopamine instead), Hartnup disease (decreased tryptophan absorption), INH (by decreasing B6)
• pellagra is diarrhea, dementia, dermatitis (hyperpigmentation of sun exposed)

• AR reducing tryptophan absorption lowering melatonin, serotonin, and niacin levels
• pellagra
• treat with high protein diet and nicotinic acid (niacin)

• pantothenic acid
• component of CoA, fatty acid synthase, acne, enteritis, alopecia, adrenal insuf
• coA, acne, abdominal pain, alopecia, adrenal insuf

• pyridoxine
• converted to pyridoxal phosphate used in transamination, decarboxylation, glycogen phosphorylase, synthesis of heme, cystathionine, niacin, histamine, serotonin, epinephrine, NE, dopamine, GABA
• INH and OCPs: convulsions, hyperirritability, peripheral neuropathy, sideroblastic anemia

• biotin
• cofactor for carboxylation that adds a carbon like pyruvate carboxylase (pyruvate to oxaloacetate), acetyl CoA carboxylase (acetyl CoA to malonyl CoA), propionyl CoA carboxylase (propionyl CoA [3C] to methylmalonyl CoA
• dermatitis, alopecia, enteritis, rare but antibiotics and raw egg white ingestion
• avidin in egg whites avidly binds biotin

• folate
• converted to THF a coenzyme for methylation, synthesis of nitrogenous bases in DNA and RNA
• megaloblastic anemia, glossitis
• icnreased homocysteine, normal methylmalonic acid
• alcoholism, pregnancy, phenytoin, sulfonamides, methotrexate
• neural tube defects in children

• cobalamin
• cofactor for methionine syntahse and methylmalonyl CoA mutase
• megaloblastic anemia, paresthesias (subacute combined degeneration [dorsal columns, lateral corticospinal, spinocerebellar] prolonged is irreversible) by low myelin
• elevated homocysteine and methylmalonic acid
• gastic bypass, long malabsorption, absence of terminal ileum (Chron), veganism, pernicious anemia (anti intrinsic factor Ab for dx)

• ascorbic acid
• antioxidant, keeps iron reduced to Fe²⁺ for absorption, hydroxylation of proline and lysine, dopamine beta hydroxylase (dopamine to NE)
• part of methemoglobinemia treatment
• scurvy (gum bleed, petechiae, hemarthrosis, anemia, poor wound healing, corkscrew hair, weak immunity)

• D₂ from plants converted to D₃ by sun, D₃ from milk, 25-OH D₃ is storage form, 1,25(OH)₂ D₃ is active
• absorption of Ca and PO
• bone pain and deformity rickets/osteomalacia, hypocalemic tetany
• supplement infant if breast feeding
• granulomatous diseases (sarcoid) activate epithelioid macrophages to cause excess leading to hypercalcemia, hypercalciuria, loss of appetite, stupor

• tocopherol/tocotrienol
• antixoidant protecting RBCs from ROS, can enhance warfarin anticoag
• hemolytic anemia, acathocytosis, muscle weakness, posterior column and spinocerebellar tract demyleiantion
• similar to B12 but without megaloblastic anemia or increased methylmalonic acid

• phytomenadione, phylloquinone, phytonadione
• cofactor of gamma carboxylation of glutamic acids on clotting factor proteins (2, 7, 9, 10, C, S), synthed by gut flora
• seen in neonatal hemorrhage (lack gut flora), prolonged use of broad spectrum antibiotics
• not in breast milk, given as injection

• zinc fingers (transcription), zinc for wound healing, a million enzymes
• delayed wound healing, hypogonadism, less pubertal hair (facial, axillary, pubic), can’t taste (dysgeusia), anosmia, acrodermatitis enteropathica, may predispose to alcoholic cirrhosis

• protein malnutrition leading to edema (low oncotic pressure), fatty liver change, anemia
• MEAL (malnutrition, edema, anemia, liver)

total caloric malnutrition resulting in emaciation, maybe edema

• NADH formed with breakdown, increases NADH/NAD ratio making pyruvate go to lactic acid (lactic acidosis)
• oxaloacetate to malate (preventing gluconeogenesis, causing fasting hypoglycemia)
• dihydroxyacetone phosphate to glycerol-3-phosphate (combines with FA to make triglyceride, causing hepatosteatosis)
• decreasing TCA cycle so acetyl CoA is used for ketogenesis (ketoacidosis) and lipogenesis instead (hepatosteatosis)

fatty acid oxidation (beta ox), ketogenesis

• mito disease
• failure of oxidative phospohrylation, leading to mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (migraine, strokes, cortical blindness)
• ragged red fibers on muscle biopsy, Gomori trichome shows mitochondrial proliferation

• mito disease
• myoclonic epilepsy with ragged-red fibers, you get epilepsy triggered by things and muscle weakness
• Gomori trichrome for mitochondria

• mito disease, NADH dehydrogenase
• leber hereditary optic neruopathy
• young adult onset blindness in one eye then the next weeks-months apart, retinal ganglion degeneration
• edematous nerve with telangiectasisas

fatty acid synth, cholesterol synth, nucleotide synth

• phenotypic variant of FAP with fibromas aka desmoid tumors (usually peritoneal from colon surgery) and osteomas (usually facial)
• also thyroid

• FAP with glial cancers and meduloblastomas
• the genes are actually biallelic mismatch repair genes