Enteroviruses
Avindra Nath, Joseph R. Berger in Clinical Neurovirology, 2020
The live oral vaccine offers many benefits. Even though it is given as a series of three doses, 50% of first-time vaccines have sufficient antibody (Ab) levels after just one dose and over 95% will have an adequate Ab response after the third dose [88]. It is believed that the protection is lifelong [88]. However, the oral vaccine has some drawbacks. When the live oral vaccine was used in the United States, 8–10 cases of vaccine-associated poliomyelitis were reported annually [88]. Some of these cases were due to the vaccination of immunodeficient children, and persistent disease of the vaccinee usually resulted in death. Other cases of vaccine-associated disease were due to a reversion of the vaccine strain to a more virulent strain during replication in the gut of the vaccinee [89]. The revertant strain could then infect unprotected caregivers. Because of the possible chance of getting polio from the live vaccine, in June 2000, the CDC issued a new vaccination policy. Now all children in the United States receive four doses of IPV.
Notes on Genetic and Radiation Control of Senescence
Nate F. Cardarelli in The Thymus in Health and Senescence, 2019
DNA, DNA repair, and the enzymes involved show little or no change with age; however, the histone content and binding activity do. In 1962 Benzer and Champe suggested that a “suppressor mutation”, a hereditary alteration of the genetic code, must exist to explain the mutations of phage T4 in several bacterial hosts.264 Ptashne summarized genetic experiments that indicated that a group of genes can be inactivated by a regulator gene or “supressor” gene.265 The postulated mechanism is that an isolated repressor binds with high affinity to DNA — and in doing so blocks transcription from DNA to RNA. A number of investigations indicate that histone binding is the effector of gene suppression.234,246,266–271 Von Hahn suggested that histone blocks DNA by cross-linking with it.246 The degree of histone binding increases with age.269 Supressed genes in normal cells may be active in neoplastic ones.272,273 Gene expression is readily reversible, indicating the existence of an “on-off” switch mechanism.271,273
Krev-1 and the Related Genes
Juan Carlos Lacal, Frank McCormick in The ras Superfamily of GTPases, 2017
There are seven divergent amino acids within the residues 18 to 40 between H-ras and Krev-1 (Table 3). To find which residue(s) among these seven divergent amino acids is important for the transformation-suppressor activity, we constructed a series of H-ras mutants. All or part of the divergent residues were substituted to the Krev-1 type, and the resulting mutants were transfected into DT and NIH 3T3 cells (Table 3). Some mutants (H3, H5, and possibly HI) acquired significant levels of revertant-inducing activity. Since common mutations among these positive mutants were Glu30 and Lys31, these residues seem to be important for the transformation-suppressor activity.
Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa
Published in Expert Opinion on Biological Therapy, 2020
Allison R. Keith, Kirk Twaroski, Christen L. Ebens, Jakub Tolar
Such successful autologous grafting relies on the availability of unaffected, healthy skin in patients with JEB (Figure 3). Revertant mosaicism, or ‘natural gene therapy,’ is a phenomenon in which the underlying cause of a genetic disease is corrected by somatic mutational events, usually during embryonic development [49]. One patient with generalized intermediate JEB (LM332-deficient) was treated with autologous transplant of punch biopsies from a revertant skin patch to multiple chronic ulcers [50]. Grafted sites did not form blisters 18 months post-transplant, and sequencing confirmed that the regenerated epidermis was comprised of revertant keratinocytes [50]. Although revertant skin grafts are capable of ameliorating blistering in the acceptor sites of LM332-deficient JEB patients, the utility of this approach does not seem to extend to other JEB etiologies. In one patient with generalized intermediate JEB (C17-deficient), a revertant skin patch was biopsied and cultured into epidermal sheets for subsequent transplant to an acceptor site prepared by epidermal stripping [51]. In contrast to LM332-deficient patients receiving revertant autografts, the graft site of the C17-deficient patient was fragile and blistered easily following mechanical manipulation. Notably, less than 3% of the graft was comprised of revertant keratinocytes [51]. In the absence of unaffected sites that give rise to viable grafts, genetic correction and subsequent transfer of autologous keratinocytes were successful in three patients [10–12].
Emerging drugs for the treatment of epidermolysis bullosa
Published in Expert Opinion on Emerging Drugs, 2020
Matthias Titeux, Mathilde Bonnet des Claustres, Araksya Izmiryan, Helene Ragot, Alain Hovnanian
Revertant mosaicism is an infrequent phenomenon that naturally occurs in genetic disorders. It is due to spontaneous, secondary somatic mutation in cells that compensate the inherited mutation and revert the phenotype by restoring the expression of a defective protein. The first evidence of revertant mosaicism in EB was demonstrated in JEB patients presenting with healthy skin patches due to somatic reversion occurring in keratinocyte stem cells [87]. Revertant mosaicism has since been further documented in keratinocytes from EBS, RDEB and KEB patients [88,89]. However, recently Twarovski et al. reported a patient with RDEB that presented with revertant somatic mosaicism as a result of genetic and transcriptional changes in dermal fibroblasts [90]. This natural gene therapy allows long-term correction without using genetic manipulation and could be a safer alternative to gene therapy when possible.
Genotoxic and mutagenic studies of teratogens in developing rat and mouse
Published in Drug and Chemical Toxicology, 2019
Eyyüp Rencüzoğulları, Muhsin Aydın
Ames test. In the method proposed by Ames in 1975 and later developed by Maron and Ames (1983), the mutagenic effects of chemicals were investigated on Salmonella typhimurium LT2 strains. This test is based on these strains, which cannot synthesize histidine but can synthesize histidine with mutation (revertant strains) in the presence of the chemical. Strains are grown as both frameshift mutant (TA98) and Base Exchange mutant (TA100). As a result of the treatment with chemicals, the number of revertant colonies gives an idea about the mutagenic effects (both frameshift and base substitution) of the chemical. The liver microsomal fraction (S9mix) can also be used in this test.
Related Knowledge Centers
- Frameshift Mutation
- Genetic Code
- Mutation
- Phenotype
- Reading Frame
- Synthetic Rescue
- Biological Pathway
- Gene
- Insertion
- Deletion