China
Africa
Explore chapters and articles related to this topic
Genetic Disorders
Published in Jeremy R. Jass, Understanding Pathology, 2020
Whereas DNA is made of only four bases, proteins are built of 20 amino acids. The DNA code works through a series of three bases serving as a template for one amino acid. Three such adjacent bases are known as a codon. Mutations frequently involve a single base within a codon. For example, one base may be substituted by an inappropriate base, such as a C instead of a T. This tiny change may then send out the wrong message (a missense mutation). Typically, the altered codon may code for a different amino acid, which may in turn alter the structure and function of the protein. Alternatively, the mutation could order the synthesis of the protein to stop prematurely (by becoming a specific stop signal, or as a nonsense mutation), resulting in the production of a ‘truncated protein’. A nucleotide may be added or deleted resulting in a frameshift mutation (disrupting downstream coding completely and again causing protein truncation). It is also possible that the mutation could have no significant consequences (silent mutation). Given that each chromosome has many millions of bases, an error in only one (called a point mutation) will be extremely difficult to find. It is like being asked to find a single misprinted letter in a dictionary. The technology for detecting such a small error certainly exists, but the task is onerous and there are many pitfalls. Larger mutations, for example the deletion of a long run of bases, may be equally difficult to detect.
Lipoprotein lipase deficiency/type I hyperlipoproteinemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
In apoC-II deficiency, biochemical data are consistent with pedigree information and an autosomal recessive mode of transmission [63]. The gene for apoC-II has been mapped to chromosome 19 [64] and contains four exons spanning 3.3 kb [66]. Patients to date have been homozygous for a single mutation and are often products of a consanguineous mating. The nature of mutation has been defined in many of the small number of kindreds so far described [51]. In four, single-base change has led to a stop-codon [66–70], and in one there was a single-base substitution in the methionine initiation codon [70]. A donor splice mutation intron 2 [71] rounds out this group, none of whom had demonstrable apoC-II protein on immunoassay. Four frameshift mutations would be expected to lead to truncated proteins; two of them had no detectable protein [72–77]. In a patient with the homozygous C1118A change in the APOC2 gene, which resulted in a Y63X, the patient had lipid encephalopathy, fatty deposits on cranial MRI, neurologic impairment, and impaired mental development [78].
Genetic and genomic investigations
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Frameshift mutations, as well as nonsense mutations that terminate translation, often have more severe effects than missense mutations. However, the complete absence of some proteins may cause fewer problems than a simple amino acid substitution, especially in protein molecules that are subunits contributing to large, macromolecular assemblies that can be disrupted more by a missense mutation in one component than by a heterozygous deletion.
In vitro screening of genotoxicity and mutagenicity of pyriproxyfen in human lymphocytes and Salmonella typhimurium TA98 and TA100 strains
Published in Drug and Chemical Toxicology, 2023
Havva Bugda, Banu Guven Ezer, Eyyup Rencuzogullari
Pyriproxyfen showed a clear mutagenic effect in the presence of the used metabolic activator (S9mix). However, in the absence of metabolic activator, it showed a mutagenic effect only at the highest dose and only in TA98 strain. This indicates that the metabolites of PPX have a greater risk than the PPX, since PPX is metabolized in in vitro by metabolic activators. These chemicals, called indirect mutagens, only show their mutagenic effects when they are metabolized in the body. It has been reported that PPX is metabolized to 16 different metabolites in zebrafish of which two of them (−)-pyriproxyfen and 4′-OH-PPX showed a twofold higher toxicity than the PPX (Wei et al.2021). The same results were reported for rat hepatocytes (Liu et al.2020). In this study, PPX caused both frameshift and base substitution type mutations at all doses in the presence of a metabolic activator. Frameshift mutation is clearly known that the most dangerous mutation type among gene mutations.
What’s next in cancer immunotherapy? - The promise and challenges of neoantigen vaccination
Published in OncoImmunology, 2022
Alec J. Redwood, Ian M. Dick, Jenette Creaney, Bruce W. S. Robinson
For some cancers, for example, clear-cell renal-cell carcinoma (ccRCC), the number of SNV mutations is low and SNV burden is not linked to successful ICI.25 Vaccines targeting SNV neoantigen are unlikely to be useful in this patient cohort. However, ccRCC’s, as well as DNA mismatch repair deficient, microsatellite instability-high (MSI-H) tumors, are rich in indel-induced frameshift mutations.26 Frameshift mutations generate an entirely novel amino acid sequence. Neoantigens derived from frameshift mutations appear to be highly immunogenic because indel burden is associated with elevated and activated TILs26–31 and because MSI-H tumors have high response rates to ICI immunotherapy.32,33 Frameshift derived neoantigens are therefore likely to be highly effective vaccine targets.
Identification of two AMH gene variants in two unrelated patients with persistent Müllerian duct syndrome: one novel variant
Published in Gynecological Endocrinology, 2021
Sezer Acar, Özlem Nalbantoğlu, Semra Gürsoy, Beyhan Özkaya, Özge Köprülü, Gülçin Arslan, Filiz Hazan, Behzat Özkan
Serum AMH level is a guiding marker in determining the genetic cause (AMH or AMHRII) in cases with PMDS. As it is known, serum AMH level is high in male cases until the first two years of age and remains at a measurable level until puberty and decreases to undetectable level at the puberty [9]. While low or undetectable levels of serum AMH indicate AMH gene mutations, normal or high AMH levels suggest AMHRII mutations in cases with PMDS [9–11]. However, it has been reported that AMH mutation was also detected in some cases of PMDS despite normal AMH levels. It has been shown in functional studies that these variants in either the C- or the N- terminal domain that may impact on protein stability and folding cause lack of biological activity of AMH [12]. In Case 1, in which single amino acid changes were detected in the 5th exon of the AMH gene (at the coding N-terminal region), low serum AMH level was found in accordance with the literature data [10–12]. In Case 2, a frameshift mutation generating downstream stop codon, resulting in a truncated protein, was detected. Frameshift mutations are considered as harmful and are often lead to loss-of-function. The frameshift variant we detected in our patient was previously described in 5 cases with PMDS by Picard et al., but serum AMH levels of these patients were not noted. In addition, undetectable AMH level has been reported in cases with PMDS, in which variant was found to cause frameshift in the AMH gene, as in our case [12,13].