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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
Point mutations are the simplest form of DNA alteration (Figure 2.9). In this case, a single nucleotide of the DNA sequence is affected. If a mutation affects the protein-coding sequence of a gene, it is termed silent if it does not alter the encoded amino acid. A missense mutation occurs when DNA alterations encode a different amino acid. Sometimes, the effects are more drastic; a mutation which introduces an early stop codon (nonsense mutation) will terminate protein translation and full-length protein will not be produced. Similarly, gain or loss of one or two nucleotides will alter the subsequent reading frame of the protein and the remainder of the correct sequence will be lost. Pathogenic mutations may also occur outside a protein-coding sequence; alterations to promoter regions or splice sites can have profound effects on gene expression.
Developmental Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James H. Tonsgard, Nikolas Mata-Machado
A variety of mutations have been demonstrated including missense mutations, nonsense, large deletions, splice-site mutations, point mutations, and small deletions. Missense mutations (which result in a complete protein product) and large deletions (with no protein product) are both associated with milder phenotype. Milder disease is also seen in patients with mutations in exons 9–15. Missense mutations are associated with longer survival than patients with nonsense and frameshift mutations. Patients with mosaicisms may have a milder course and lower risk of having offspring with NF-2. It is anticipated that treatment of NF-2 could ultimately be dictated by the genetic information.
Genetics of Uterine Leiomyomata
Published in John C. Petrozza, Uterine Fibroids, 2020
C. Scott Gallagher, Cynthia C. Morton
As described herein, inherited genomic variants, as well as constitutional and acquired genetic mutations, are associated with the biology of UL. Exactly how they may interact with one another remains to be determined. Shown in Figure 5.4, Knudson's classical two-hit hypothesis, in which an individual inherits a mutant allele and subsequently acquires a second mutation, or “hit,” in the wild-type allele, may explain both the late onset of UL and its well-demonstrated association with exposure to steroid hormones at puberty. This model can be applied to the rare familial cases of HLRCC and AS-DL and mutations in FH and COL4A5-COL4A6, respectively [65]. Alternatively, synergistic combinations of heterozygous loss-of-function mutations in tumor suppressor genes may be sufficient to drive tumorigenesis in the relevant biological context [119]. Under the former model, constitutional and acquired mutations act consecutively and additively in the pathobiology of UL. Under the latter, acquired point mutations and chromosomal abnormalities may be facilitators to advanced pathogenesis. In light of the exceptionally high frequency of UL and the comparatively very low frequency of uterine leiomyosarcoma, evaluating whether the observed somatic changes are harbingers of carcinogenesis or protection against malignant transformation will be valuable in gaining an understanding of the role of acquired genomic instability in UL [95,98,120].
The genetic background of Parkinson’s disease and novel therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2022
András Salamon, Dénes Zádori, László Szpisjak, Péter Klivényi, László Vécsei
The SNCA gene contains six exons which encode the 140 amino acid long α-synuclein protein. The protein has three domains: (1) amino-terminal region (1–60); (2) central hydrophobic domain (61–95); (3) carboxy-terminal domain (96–140) [5]. So far, a few recurrent genetic alterations have been described in the scientific literature: three missense mutations (p.A53T, p.A30P, p.E46K), duplications and triplications [5]. The three missense point mutations disrupt the amino-terminal region and modify the conformation of the protein (leading to the formation of more stable beta sheets), so they can be considered toxic gain of function mutations [5]. The Lewy bodies detected during neuropathological examinations are presumably remnants of the degenerative process, but the exact pathomechanism is still unknown [5].
Emerging FLT3 inhibitors for the treatment of acute myeloid leukemia
Published in Expert Opinion on Emerging Drugs, 2022
Antonio Solana-Altabella, Octavio Ballesta-López, Juan Eduardo Megías-Vericat, David Martínez-Cuadrón, Pau Montesinos
The FLT3 receptor kinase is highly expressed in acute leukemia, and activating FLT3 mutations occur often in AML. Constitutive activation of FLT3 is caused by internal tandem duplication (ITD) mutations within the juxtamembrane region (FLT3-ITD) with a prevalence of 17–22% in AML patients, or by point mutations in the second kinase domain (FLT3-TKD) with a prevalence of 4–6% [11], a substantial quantity of evidence suggests that FLT3-ITD mutations are related to leukocytosis and increased peripheral and bone marrow blasts, and play a crucial role within the development and survival of leukemia cells. Even though FLT3-ITD mutations might not clearly impact rates of CRc, substantial evidence suggests that FLT3-ITD mutations confer a worse prognosis, especially for patients with intermediate-risk cytogenetic [12]. Point mutations additionally occur most often in patients with normal cytogenetic and are related to proliferative illness, together with increased bone marrow and peripheral blasts, without clear impact on the relapse rate and survival.
CRISPR Cas9 based genome editing in inherited retinal dystrophies
Published in Ophthalmic Genetics, 2021
Mayank Bansal, Sundaram Acharya, Saumya Sharma, Rhythm Phutela, Riya Rauthan, Souvik Maiti, Debojyoti Chakraborty
CRISPR base editors are advantageous in several aspects. Most genetic disorders have point mutations, where the base editors can be very effective. However, recent reports of associated RNA editing events concomitant with base editing has triggered the need for more potent and safe base editors (5). Levy et al, reported in vivo base editing of retinal cells in mice models using AAV vectors. Specifically, they found an editing efficiency of 48%±5.9% using CBE, and 37 ± 22% using ABE (6). They reported this CRISPR base editing efficiency comparable to CRISPR with HDR for CEP290 gene preclinical studies (7). In another study, candidate genes were analysed for potential correction of mutations using base editing. In these genes causing IRDs gene therapy is not desirable due to the large size of the gene and therefore difficulty in AAV packaging of the gene. The analysis of ABCA4, CDH23, CEP290, EYS, MYO7A, and USH2A genes showed that most pathogenic variants can be corrected using CRISPR base editing (8)