Mutation Information and Courses from MediaLab, Inc.

Genetic mutations in HIV are well known and are very likely, considering the presence of two RNA molecules per virus. Either or both RNA molecules can mutate. These mutations potentially lead to drug resistance or encourage the virus to evade the body's immune response. Mutations have created three major groups of HIV - M, N, and O. M is found in 99% of all the HIV cases in the world. N and O are primarily found in West African countries. N, though, infects only a very small number of individuals. The M group has subgroups lettered A to J. Subgroup B predominates in North America.

Specialists in cytogenetics detect chromosome abnormalities and genetic disorders. Cytogenetics counseling may only be performed by an individual licenses in the cytogenetics specialty at the director level. Specialists in molecular genetics analyze DNA and RNA to find disease-related genotypes, mutations, and phenotypes in order to detect or predict disease and identify carriers. Specialists in histocompatibility test to determine tissue compatibility, prevent infections, and investigate and post-transplant problems. Techniques include blood typing, HLA typing, HLA antibody screening, disease markers, flow cytometry, crossmatching, HLA antibody identification, lymphocyte immunophenotyping, immunosuppressive drug assays, allogenic, isogeneic and autologous bone marrow processing and storage, mixed lymphocyte culture, stem cell culture, cell mediated assays, and assays for the presence of cytokines. Specialists in andrology and embryology examine gametes and embryos, including production, morphology, number, and motility, to address issues of fertility and infertility.

In addition to protein availability, other factors may affect drug absorption and distribution in the body as a whole or at specific sites within the body. The following table highlights some of these other factors. Factor Discussion Regional blood flow Reduced area blood flow can be seen in diabetics and enhanced blood flow can be seen in tumors. Lipid solubility of the drug The more lipophilic a drug is, the more likely it will enter the central nervous system. The integrity of the GI tract In a diseased gut, an orally-administered drug may not be absorbed as expected. Age Drug kinetics and dispositions change throughout life. In general, metabolism of drugs is reduced in the elderly. Genetics Mutations or deletions in drug metabolizing enzymes can greatly affect a drug's disposition.

The following is a list of enzymes for which known mutations have been associated with clinical effects. Enzymes Substrates (Drugs) Acetylaldehyde dehydrogenase Alcohol Acetylcholinesterase Succinylcholine Alcohol dehydrogenase Alcohol Dihydropyrimidine dehydrogenase Fluorouracil CYP2C9 Warfarin, phenytoin, losartan CYP2C19 Diazepam, omeprazole (Prilosec) CYP2D6 Many antidepressants, opioids, antiarrhythmics Glucose-6-phosphate dehydrogenase Aspirin, quinidine N-acetyltransferase Procainamide, isoniazid Thioprine methyltransferase 6-mercaptopurine UDP-glucuronosyl transferase Acetaminophen, tolbutamide, irinotecan

Variables other than mutations also affect CYP450 enzymes. Many drugs are able to induce CYP450 enzymes, and CYP450s can be inhibited by a variety of substances. For example, CYP2D6 can be inhibited by the common medications cimetidine (Tagamet) and fluoxetine (Prozac). Since many patients are on multiple medications and since dietary and environmental factors can change, CYP450 expression levels cannot be solely predicted based on their genotype. Some CYP450 inducers and inhibitors are listed in the table on the following page.

Hemoblobin H disease follows deletions of 3 of the 4 alpha globulin chains. Beta chains, unable to bind with insufficient numbers of alpha chains, form beta chain tetramers, or HbH.These beta chain tetramers appear as numerous dot size inclusions in erythrocyte cytoplasm, best seen in supravital brilliant cresyl blue stains (lower photograph).The most common molecular defect in alpha thalassemia is DELETION, not MUTATION; whereas, in beta thalassemia, the molecular defect is MUTATION.Leptocytes, as illustrated in the upper photograph,(lepto, derived from a Greek word meaning thin, fine, or slight), are characteristic of HbH disease. They have thinner cell membranes than the cells we recognize as target cells. They stain more lightly than normal erythrocytes and their centers are almost colorless.Subtle changes perhaps, but worth keeping in mind

Chediak-Higashi syndrome is a rare autosomal recessive disorder. It results from a mutation of the gene LYST which encodes a protein with multiple phosphorylation sites. This defect causes a cellular abnormality involving the fusion of cytoplasmic granules. Early in neutrophil maturation normal azurophilic granules form, but they fuse together to form megagranules. Later during the myelocyte stage, normal specific granules form. The mature neutrophils contain both normal specific granules and abnormal azurophilic granules. These large abnormal granules can be seen in the cytoplasm of neutrophils, eosinophils, basophils, monocytes and lymphocytes. These abnormal granules are able to kill bacteria in neutrophils and monocytes; however, the process is much less effective than in normal cells in part, because these neutrophils have impaired locomotion. For these reasons, individuals with Chediak-Higashi have recurrent infections. An accelerated lymphoma-like phase occurs, with lymphadenopathy, hepatosplenomegaly, and pancytopenia. Death often occurs at an early age.