Branched chain keto acid dehydrogenase kinase (BCKDK) deficiency
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
Mutations reported to date in the gene on chromosome 16 have included the null mutation R174G and a missense mutation p.L389P [2]. A C to T change in exon 4 led to a premature stop at position 156 [1], prior to the kinase domain. A single-base deletion c.G222 del in exon 2 led to a frameshift that terminated the protein at position 74 of R412 amino acids [1]. A missense mutation G671C led to a change from a highly conserved arginine at 224 to a proline. Levels of mRNA were shown to be reduced in two families studied [1], suggesting nonsense mediated decay, and enzyme protein was undetectable by western blot [1]. Mice with deficiency of BCKDK have increased basal activity of the BCKDH complex [3]. These mice developed neurologic abnormalities including seizures; histology of the brain was normal.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow in Fetal and Perinatal Skeletal Dysplasias, 2012
Genetics: autosomal recessive; many affected individuals present nonsense mutations in exon 1 of MESP2, which are predicted to result in nonsense-mediated decay. In some cases compound heterozygosity for a nonsense mutation and a missense mutation has been found. STD is frequent in Spanish Puerto Ricans, presumably as a result of the MESP2 founder mutation, p.Glu103X (E103X). Studies in the mouse demonstrate that Mesp2 is expressed in the anterior somitic compartment and is essential in the somite-boundary formation, a crucial step for the formation of vertebrae, which occur through a process called resegmentation, in which the caudal half of one somite fuses to the rostral half of the next somite in a rostrocaudal order. MESP2 mutations also cause SCD2.
Precision medicine in ovarian carcinoma
Debmalya Barh in Precision Medicine in Cancers and Non-Communicable Diseases, 2018
For proper functioning of our biological system, genes expression is needed in precise quality and quantity so that smooth processing of all activities could be maintained. Modification or change may happen in the controlling region of the particular gene so the product of that gene may be abnormal in quantity, thus deregulation of governing function may occur. Commonly this abrupt regulation may manifest in two ways—nonsense-mediated decay (NMD) or ubiquitin-mediated decay—and may cause carcinogenesis. A few studies suggested that this upregulation of gene expression may advance the stage of the cancer (Dwivedi et al., 2015; Dwivedi et al., 2015; Dwivedi, Singh, et al., 2015)
Novel DNAH17 mutations associated with fertilization failures after ICSI
Published in Gynecological Endocrinology, 2021
Miaomiao Jia, Rong Shi, Xia Xue
The variant c.1048C > T was located in the N-terminal stem domain of DNAH family of genes. This variant introduces a premature stop codon in position 350, which is predicted to result in a truncated and nonfunctional protein (p.Arg350*) that lacks all six ATPase domains (AAA1, AAA2, AAA3, AAA4, AAA5 and AAA6) and a microtubule binding region (Stalk). This variant may also prevent protein production by causing mRNA degradation through nonsense-mediated decay. The variant c.3390G > A was also located in the stem domain of DNAH family of genes and is absent in the East Asian population of ExAC, gnomAD, and 1000 Genomes Project. Sequence alignment indicated that the amino acids affected by the mutation sites (p.Met1130) in human DNAH17 were highly conserved in other species, suggesting that these sites play important roles in protein function (Figure 1(D)).
Genetic Study of Hereditary Angioedema Type I and Type II (First Report from Iranian Patients: Describing Three New Mutations)
Published in Immunological Investigations, 2022
Susan Nabilou, Fatemeh Pak, Zahra Alizadeh, Mohammad Reza Fazlollahi, Masoud Houshmand, Maryam Ayazi, Iraj Mohammadzadeh, Mohammad Hasan Bemanian, Abbas Fayezi, Mohammad Nabavi, Shiva Saghafi, Sajedeh Mohammadian, Parviz Kokhaei, Mostafa Moin, Zahra Pourpak
Furthermore, p.G217Vfs* (in P13) as a new frameshift mutation is located on upstream of RCL (R466-W467), leading to truncated protein. Additionally, four other reported frameshifts found in this study including p.S422Lfs*9, p.V454Gfs*18 in exon 8, p.S36Ffs*21 in exon 3, and p.L243Cfsx*9 in exon 5 failed to cover the RCL region. Moreover, p.R494* in exon 8, as a nonsense mutation within a hot spot mutated CpG dinucleotide, is responsible for early termination of mRNA translation and creating premature stop codon leading to rapid protein degradation (Amrani et al. 2006; Verpy et al. 1995). Early nonsense or frameshift mutations lead to premature stop codon and truncation protein, which result in synthesizing defective protein and generating transitory transcription via nonsense mediated mRNA decay (NMD) (Amrani et al. 2006).
Slowly progressive retinitis pigmentosa caused by two novel mutations in the MAK gene
Published in Ophthalmic Genetics, 2018
Joanna Monika Gray, Harry Otway Orlans, Morag Shanks, Penny Clouston, Robert Elvis MacLaren
The two compound heterozygous mutations identified in our patient (marked in Figure 1 by red arrows) have not been previously reported in the literature, nor are they in any population frequency database. The first of the two mutations described here is a two base-pair deletion (AC) within the 9th exon of the MAK gene. This is predicted to result in a frame-shift causing the introduction of a premature stop codon six amino acids downstream with resultant nonsense-mediated decay of the mutated transcript. The second is of interest as it disrupts the 3ʹ splice acceptor consensus sequence (21,22), with the result that exon 4 is likely to be skipped by the spliceosome. Since exon 4 comprises 80 bp, its loss would likewise be expected to induce a frame-shift. Further genetic analysis of the patient’s daughter (indicated in Figure 4), was undertaken. She was found to be heterozygous for the AC deletion but lacked the splice site mutation. This segregation analysis confirmed that the two mutations described above are in trans on the MAK gene in the proband.
Related Knowledge Centers
- Eukaryote
- Exon Junction Complex
- NONsense Mutation
- Ribosome
- Messenger Rna
- Phosphorylation
- Mrna Surveillance
- Stop Codon
- Trans-Acting
- Translation