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Cancer Informatics
Published in Trevor F. Cox, Medical Statistics for Cancer Studies, 2022
In our last analysis, we look at mutations in the genes. The mutation data is stored in MAF files (Mutation Annotation Format) which are downloaded in like manner to the expression data. The Bioconductor package maftools is used to analyse the data. The functions getGeneSummary() and getSampleSummary() summarise the mutations. There are five types of mutation recorded: Missense mutation: a change in a base pair that leads to a different amino acid being used in the resulting protein.Nonsense mutation: a change in a base pair that leads to a premature stop codon.Nonstop mutation: a change in a base pair in a stop codon leading to further inappropriate translation.Splice site: an alteration at the boundary af an exon and an intron.Translation start site: an alteration of the start site of translation of a gene.
Adenylosuccinate lyase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The cDNA for the gene contains 1452 nucleotides and codes for a protein of 484 amino acids [27]. Molecular analysis in the first reported Moroccan family with four affected children [1, 2, 4] indicated homozygosity for a point mutation in the ASL gene resulting in a serine to proline change originally placed at amino acid 413, but now called S438P in the 484 amino acid protein. This might be expected to increase the flexibility of the peptide backbone of the enzyme, which might account for decreased stability. Analysis of genomic polymerase chain reaction (PCR) products from the parents of the patients revealed both a normal and a mutant allele, documenting heterozygosity [2]. The mutation p.R426A remains the most common mutation in a variety of unrelated patients [3]. Another, p.Y114H, has also been found in more than one unrelated family [3]. Most mutations continue to be private. Another mutation identified [30] in a gypsy patient without known consanguinity, G1279A, converted a well-conserved arginine at 401 to histidine. Other missense mutations identified have indicated a high degree of molecular heterogeneity [30–32]. A 39-bp deletion in the cDNA was caused by a C to A change in exon 5 creating a consensus 59 donor splice site [33]. One nonsense mutation has been observed [27].
Genetics of Endocrine Disorders and Diabetes Mellitus
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Bess Adkins Marshall, Abby Solomon Hollander
Although most glucokinase mutations have been found in patients with MODY, a few have been described in families with typical late-onset NIDDM. One such family carried a nonsense mutation,108 another a missense mutation.103 Likewise, nonsense and missense mutations in glucokinase have been identified in patients with gestational diabetes who have a family history of diabetes.109
Genetic and clinical variations of developmental epileptic encephalopathies
Published in Neurological Research, 2023
Gül Demet Kaya Özçora, Elif Söbü, Uğur Gümüş
Refractory seizures were observed in DEE type 2 (p.1 and 2), DEE 7 (p. 6, 7 and 9) and DEE 42 (p.17). DEE2 is characterised by polytherapy-resistant seizures that mostly occur in the first two months of life. Females are most often affected while males are rarely but severely affected. Dysmorphic facial features are subtle; we observed that our patients with DEE type 2 exhibited deep-set eyes, anteverted nares, broad forehead and dysmorphic features such as microcephaly and hypotony. It has been reported that nonsense mutations may have milder phenotypic features. In our study, patient 2 had the nonsense mutation and a more severe phenotype, and a decrease in seizures was observed in patient 1 after the fifth month. Patients 1 and 2 showed phenotypic features consistent with the literature [16–18] and both had de-novo mutations, refractory seizures, microcephaly and hypotonia. In our study, DEE type 2 had severe phenotypic features.
Bilateral cranial nerve 6 palsy in a patient with multiple sclerosis and vitamin D-dependent rickets
Published in Neuro-Ophthalmology, 2022
Aishwarya Sriram, Devon Joiner, Kevin Hsu, Cheng Zhang
Type 2A, commonly known as vitamin D-resistant rickets, is due to a defect in the vitamin D receptor gene, thus causing resistance to 1,25-dihydroxyvitamin D (vitamin D 1,25-[OH]). It is similarly autosomal recessive; however, these patients tend to have severe, early-onset rickets, and supplementation may not improve the condition, particularly in patients with nonsense mutations in the DNA-binding domain. Type 2B, whose inheritance pattern is unknown, is clinically similar to type 2A but is due to abnormal expression of a hormone response element-binding protein, which interferes with the vitamin D receptor function. In these patients, there are low levels of 25-hydroxyvitamin D (vitamin D 25-OH) with compensatory elevated levels of vitamin D 1,25(OH). Types 2A and 2B can only be distinguished by genetic testing.5,6
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
As CF is a genetic disease, gene therapy has been the field of intense research since the cloning of the CFTR gene. It consists in the delivery of deoxyribonucleic acid (DNA) encoding the normal CFTR protein into cells resulting in normal CFTR protein synthesis in addition to the constitutive abnormal CFTR protein. More recently, gene editing has become a very active field in CF research. It is another DNA-based therapy exploiting the ability of cellular DNA repair pathways. It uses a donor DNA molecule as a template to correct the genomic DNA sequence [33]. With the ongoing extensive research and knowledge about RNA biology and RNA therapy, several RNA-based therapies are studied that could benefit distinct subsets of patients with CF either by using messenger RNA (mRNA), transfer RNA (tRNA) and small antisense RNA molecules called antisense oligonucleotides. Another approach uses readthrough agents for nonsense mutations: they are small molecules binding to the ribosome and stimulating the PTC readthrough and the incorporation of an aminoacyl. In the more distant future, cell-based therapies might also be applied to CF. The status of these four therapeutic strategies, DNA-based, RNA-based, readthrough of PTCs and cell-based strategy will be discussed in the next sections (Table 1).