NDFS 333 Exam 2, 2023 with with complete solution

factors that lead to incomplete penetrance age-related cumulative frequency, environmental modifiers, genetic modifiers, epigenetic regulation example of incomplete penetrance "carriers" of autosomal dominant diseases must have incomplete penetrance vitamin A absorption absorbed through passive and facilitated diffusion, dependent on structure carotenoid metabolism converted into retinal by oxidative cleavage by BCO1 BCO1 vs BCO2 BCO1 is the enzyme primarily responsible for oxidative cleavage of carotenoids, but forms several products besides retinal. BCO2 also cleaves carotenoids, but at a much lower level Vitamin A transported by transported in lipoproteins (non-specific transportation) or specialized proteins(specifically deliver vit A to cells that need it) retinol binding protein - beta barrel, retinol is loaded to the center of the beta barrel - Stra6 is a receptor that binds to holo-RBP CRBP/CRABP CRBP - binds retinol in the cytol, makes it retinaldehyde CRABP - binds retinoic acid in the cytosol, relocates it to nucleus A57T and A55T mutations that prevent retinol from loading How do genes become autosomal dominant? mutant RBP does not bind to retinol, mutant RBP binds more tightly to STRA6 vitamin A storage stored in stellate cells of liver as retinol ester (retinol is esterified with a fatty acid by LRAT) vitamin A function: genetics binds to nuclear receptors (RAR and RXR), which form homo/heterodimers and act as transcription factors vitamin A function: vision light converts 11-cis retinal into all-trans retinal, which is then hydrolyzed off of rhodopsin. retinal is reduced to retinol and shipped to the retinal pigment epithelium by IRBP, where it is then esterified with a fatty acid, isomerized, hydrolyzed, and oxidized back to retinal, then IRBP brings 11-cis retinal back to the photoreceptor to form rhodopsin vitamin D absorption and metabolism in the skin 7-DCH (precursor to cholesterol) is converted to vitamin D3 by UV light vitamin D: liver CYP2R1 (MAJ) and CYP27A1 (min) hydroxylate vit D at carbon 25 how kidney activates vit D vit D BP binds to CUBN in proximal renal tubules, where it is then hydroxylated at carbon 1 to form calcitriol by CYP27B1 to activate it how kidney inactivates already active vit D hydroxylates on caron 24 by CYP24A1 - leads to degradation and excretion two main dietary forms of vit D ergocalciferol (D2) and cholecalciferol (D3), naturally found in fatty fish and shiitake mushrooms, selected food are fortified conversion of 7DHC to D3 DHCR7 reduces 7DHC to frm cholesterol Smith-Lemli-Opitz Syndrome mutations in DHCR7 lead to a decrease in cholesterol and an increase in 7DHC and vit D; linkage to disequilibrium with NADSYN1 most polymorphic gene known vitamin D binding protein vit D increases calcium absorption increases expression of TRPv6, calbindin D9k, and PMCA heritable rickets when VDR does not function correctly it leads to VDR deficiency diseases which can be reversed through high doses of vitamin D folic acid oxidized form found in fortified foods or supplements folate reduced form found naturally in foods and tissues digestion of folate polyglutamate folate is hydrolyzed to become monoglutamate form, which is then reduced to THF in the enterocytes found as monoglutamate folate in the blood dihydrofolate reductase (DHFR) mutation 19 BP deletion in first intron, 20% DEL homozygosity in US. leads to increased folic acid in blood, increased breast cancer risk for multivitamin users, increased risk of retinoblastoma for babies with moms that use multivitamins natural v supplemental folate natural folate has higher absorption, increases RBC and serum supplemental can mask B12 deficiency, can lead to cancer, epigenetic changes, and high serum folic acid, reduces NTD folate functions amino acid and choline metabolism (serine/glycine degradation, His degradation, choline degradation, methionine and SAM synthesis), gene expression, purine and pyrimidine synthesis/nucleotide metabolism, serine hydroxymethyltransferase (SHMT) uses folate as carbon acceptor and B6 for catalysis of serine to glycine; 70% of glycine in the body comes from this reaction as opposed to from the diet. L474F mutation of SHMT 12% inhibits sumolyation and nuclear transport, decreased risk for cancer cobalaim (b12) primarily found in animal products and supplements vitamin B12 digestion binds R protein in the stomach, which is hydrolyzed in the duodenum so B12 can bind to intrinsic factor, where it is later absorbed in the ileum by cubilins. TCII for transport vitamin B12 transport TCII main protein TCI and TCIII exact functions unknown P259R TCII mutation decreases delivery, unclear change in homocysteine, increase in methylmalonyl-CoA S348F TCII mutation higher homocysteine levels, higher methylmalonyl-C0A I23V TCII mutation pernicious anemia G220R TCII mutation higher serum cobalamin levels, linked to SNP in corresponding receptor functions of b12 conversion of homocysteine to methionine, conversion of L-methylmalonyl CoA to succinyl CoA P1173L MS mutation severe, megaloblastic anemia, SAM binding site mutation A919G MS mutation mild phenotype, MTRR binding site mutation, required every 200-1000 reactions I22M MS mutation FMN binding, increased NTD risk folate trap accumulating lots of 5-methyl-THF because there is not enough B12 to convert it into THF and it can't go back to 10,5THF cystathionine beta-synthase converts homocysteine to cysteine (only way to synthesize cysteine). over 100 mutations in this enzyme, some of which can lead to increased activity. 68ins polymorphisms of CBS associated with decreased schizophrenia risk vitamin C deficiency: 4Hs hemorrhagic signs, hyperkeratosis of hair follicles, hypochondriasis, hematologic abnormalities GLO gene codes for enzyme in the last step of vit C synthesis; primates have remnants of the gene, but 7 of 12 exons are missing SVCT 1 absorbs vit C on the apical side of enterocytes; has low affinity and fast kinetics (which works well with high concentrations) expressed in epithelial tissue, mutant alleles lead to decreased serum VC levels SVCT2 absorbs vit C on the basolateral side, high affinity but slow kinetics (grabs any vit C it can), expression in cells is tightly controlled haptoglobin binds free hemoglobin; oxidative damage occurs in its absence HP1-1 vs HP2-1 and 2-2 1-1 forms a dimer that efficiently binds free Hgb, 2-1 and 2-2 form polymers that have minimal affinity for Hgb vit C functions antioxidant, DNA demethylation, cosubstrate for enzyme acitivity, collagen synthesis, carnitine synthesis, tyrosine catabolism, neurotransmitter synthesis VC dependent DNA demethylation mice: decreased fecundity, unsuccessful matings, oocytes have abnormal DNA methylation, resemel TET KO mice