scholarly journals Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Zayed Al-Zayed ◽  
Roua A. Al-Rijjal ◽  
Lamya Al-Ghofaili ◽  
Huda A. BinEssa ◽  
Rajeev Pant ◽  
...  
Keyword(s):  
Mutation Rate ◽  
De Novo ◽  
Mutation Spectrum ◽  
Sequencing Analysis ◽  
De Novo Mutations ◽  
Novel Mutations ◽  
Hereditary Multiple Exostoses ◽  
Multiple Osteochondromas ◽  
Multiple Exostoses ◽  
Saudi Patients

Abstract Background Hereditary Multiple Exostoses (HME), also known as Multiple Osteochondromas (MO) is a rare genetic disorder characterized by multiple benign cartilaginous bone tumors, which are caused by mutations in the genes for exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2). The genetic defects have not been studied in the Saudi patients. Aim of study We investigated mutation spectrum of EXT1 and EXT2 in 22 patients from 17 unrelated families. Methods Genomic DNA was extracted from peripheral leucocytes. The coding regions and intron–exon boundaries of both EXT1 and EXT2 genes were screened for mutations by PCR-sequencing analysis. Gross deletions were analyzed by MLPA analysis. Results EXT1 mutations were detected in 6 families (35%) and 3 were novel mutations: c.739G > T (p. E247*), c.1319delG (p.R440Lfs*4), and c.1786delA (p.S596Afs*25). EXT2 mutations were detected in 7 families (41%) and 3 were novel mutations: c.541delG (p.D181Ifs*89), c.583delG (p.G195Vfs*75), and a gross deletion of approximately 10 kb including promoter and exon 1. Five patients from different families had no family history and carried de novo mutations (29%, 5/17). No EXT1 and EXT2 mutations were found in the remaining four families. In total, EXT1 and EXT2 mutations were found in 77% (13/17) of Saudi HME patients. Conclusion EXT1 and EXT2 mutations contribute significantly to the pathogenesis of HME in the Saudi population. In contrast to high mutation rate in EXT 1 (65%) and low mutation rate in EXT2 (25%) in other populations, the frequency of EXT2 mutations are much higher (41%) and comparable to that of EXT1 among Saudi patients. De novo mutations are also common and the six novel EXT1/EXT2 mutations further expands the mutation spectrum of HME.

scholarly journals Identification of a Novel EXT Mutation in A Kindred With Hereditary Multiple Exostoses Using Whole-Exome Sequencing and Overview of Mutation Spectrum

2021 ◽  
Author(s):  
yanhan deng ◽  
yujian liu ◽  
wei tu ◽  
liu yang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mutation Spectrum ◽  
Loss Of Function ◽  
Site Mutation ◽  
Hereditary Multiple Exostoses ◽  
Multiple Osteochondromas ◽  
Online Databases ◽  
Whole Exome ◽  
Multiple Exostoses

Abstract Background: Hereditary Multiple Osteochondromas(HMO) is a rare genetic musculoskeletal disorder characterized by multiple osteochondromas that form near to the growth plates of many bones. Loss-of-function mutations in EXT1 or EXT2 that encode glycosyltrasferases are the causal mutations for most HMO patients.Methods: After collecting the family history and clinical information, we used Whole-Exome Sequencing to find the pathogenic mutations in one Chinese Hereditary Multiple Exostoses pedigree. Sanger sequencing and relevant online databases were used to validate the screened variants. Lollipop plots were drew to map the reported mutations from online databases (Multiple Osteochondroma Mutation Database and clinvar)on a linear protein domains by MutationMapper.Results: A novel heterozygous splicing-site mutation in gene EXT1 (NM_000127:exon5:c.1417+1G>C，chr8:118834703) was found in this pedigree and mutation spectrum of genes EXT1 and EXT2 were demonstrated.Conclusions: Our results help this pedigree to identify the pathogenic variant and guide the prenatal diagnosis, also expand the mutation spectrum in Hereditary Multiple Osteochondromas.

scholarly journals Mutation spectrum in Australian pedigrees with hereditary hyperferritinaemia-cataract syndrome reveals novel and de novo mutations

2002 ◽  
Vol 118 (4) ◽  
pp. 1179-1182 ◽  
Author(s):  
Janet L. McLeod ◽  
Jamie Craig ◽  
Sarah Gumley ◽  
Sarah Roberts ◽  
Mark A. Kirkland
Keyword(s):  
De Novo ◽  
Mutation Spectrum ◽  
De Novo Mutations

scholarly journals Spontaneous rate of clonal mutations in Daphnia galeata

2020 ◽  
Author(s):  
Markus Pfenninger ◽  
Halina Binde Doria ◽  
Jana Nickel ◽  
Anne Thielsch ◽  
Klaus Schwenk ◽  
...  
Keyword(s):  
Mutation Rate ◽  
De Novo ◽  
Mutation Accumulation ◽  
Parental Genotype ◽  
De Novo Mutations ◽  
Daphnia Galeata ◽  
Short Term ◽  
Heritable Variation ◽  
Nucleotide Mutation ◽  
Ultimate Source

AbstractMutations are the ultimate source of heritable variation and therefore the fuel for evolution, but direct estimates exist only for few species. We estimated the spontaneous nucleotide mutation rate among clonal generations in the waterflea Daphnia galeata with a short term mutation accumulation approach. Individuals from eighteen mutation accumulation lines over five generations were deep genome sequenced to count de novo mutations that were not present in a pool of F1 individuals, representing the parental genotype. We identified 12 new nucleotide mutations in 90 clonal generational passages. This resulted in an estimated haploid mutation rate of 0.745 x 10-9 (95% c.f. 0.39 x 10-9 − 1.26 x 10-9), which is slightly lower than recent estimates for other Daphnia species. We discuss the implications for the population genetics of Cladocerans.

Empirical investigation of mutation rate for herbicide resistance

Weed Science ◽  
2019 ◽  
Vol 67 (4) ◽  
pp. 361-368 ◽  
Author(s):  
Federico A. Casale ◽  
Darci A. Giacomini ◽  
Patrick J. Tranel
Keyword(s):  
Mutation Rate ◽  
Herbicide Resistance ◽  
De Novo ◽  
Selection Process ◽  
Theoretical Calculations ◽  
Acetolactate Synthase ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Sources Of Resistance ◽  
Resistant Mutants

AbstractIn a predictable natural selection process, herbicides select for adaptive alleles that allow weed populations to survive. These resistance alleles may be available immediately from the standing genetic variation within the population or may arise from immigration via pollen or seeds from other populations. Moreover, because all populations are constantly generating new mutant genotypes by de novo mutations, resistant mutants may arise spontaneously in any herbicide-sensitive weed population. Recognizing that the relative contribution of each of these three sources of resistance alleles influences what strategies should be applied to counteract herbicide-resistance evolution, we aimed to add experimental information to the resistance evolutionary framework. Specifically, the objectives of this experiment were to determine the de novo mutation rate conferring herbicide resistance in a natural plant population and to test the hypothesis that the mutation rate increases when plants are stressed by sublethal herbicide exposure. We used grain amaranth (Amaranthus hypochondriacus L.) and resistance to acetolactate synthase (ALS)-inhibiting herbicides as a model system to discover spontaneous herbicide-resistant mutants. After screening 70.8 million plants, however, we detected no spontaneous resistant genotypes, indicating the probability of finding a spontaneous ALS-resistant mutant in a given sensitive population is lower than 1.4 × 10−8. This empirically determined upper limit is lower than expected from theoretical calculations based on previous studies. We found no evidence that herbicide stress increased the mutation rate, but were not able to robustly test this hypothesis. The results found in this study indicate that de novo mutations conferring herbicide resistance might occur at lower frequencies than previously expected.

scholarly journals Extensivede novomutation rate variation between individuals and across the genome ofChlamydomonas reinhardtii

2015 ◽  
Author(s):  
Rob W Ness ◽  
Andrew D Morgan ◽  
Radhakrishnan B Vasanthakrishnan ◽  
Nick Colegrave ◽  
Peter D Keightley
Keyword(s):  
Mutation Rate ◽  
Evolutionary Biology ◽  
De Novo ◽  
Spontaneous Mutation ◽  
Gc Content ◽  
Rate Variation ◽  
De Novo Mutations ◽  
Local Sequence ◽  
Wild Strains ◽  
Genomic Regions

Describing the process of spontaneous mutation is fundamental for understanding the genetic basis of disease, the threat posed by declining population size in conservation biology, and in much evolutionary biology. However, directly studying spontaneous mutation is difficult because of the rarity of de novo mutations. Mutation accumulation (MA) experiments overcome this by allowing mutations to build up over many generations in the near absence of natural selection. In this study, we sequenced the genomes of 85 MA lines derived from six genetically diverse wild strains of the green algaChlamydomonas reinhardtii. We identified 6,843 spontaneous mutations, more than any other study of spontaneous mutation. We observed seven-fold variation in the mutation rate among strains and that mutator genotypes arose, increasing the mutation rate dramatically in some replicates. We also found evidence for fine-scale heterogeneity in the mutation rate, driven largely by the sequence flanking mutated sites, and by clusters of multiple mutations at closely linked sites. There was little evidence, however, for mutation rate heterogeneity between chromosomes or over large genomic regions of 200Kbp. Using logistic regression, we generated a predictive model of the mutability of sites based on their genomic properties, including local GC content, gene expression level and local sequence context. Our model accurately predicted the average mutation rate and natural levels of genetic diversity of sites across the genome. Notably, trinucleotides vary 17-fold in rate between the most mutable and least mutable sites. Our results uncover a rich heterogeneity in the process of spontaneous mutation both among individuals and across the genome.

scholarly journals Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families

2017 ◽  
Vol 118 (2-3) ◽  
pp. 87-94
Author(s):  
Karel Medek ◽  
Jiří Zeman ◽  
Tomáš Honzík ◽  
Hana Hansíková ◽  
Štěpánka Švecová ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
De Novo ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Gene Mutations ◽  
Nonsense Mutations ◽  
Hereditary Multiple Exostoses ◽  
Multiple Exostoses ◽  
The Mean

Hereditary multiple exostoses (HME) represents a heterogeneous group of diseases often associated with progressive skeletal deformities. Most frequently, mutations inEXT1andEXT2genes with autosomal dominant inheritance are responsible for HME. In our group of 9 families with HME we evaluated the clinical course of the disease and analysed molecular background using Sanger sequencing and MLPA inEXT1andEXT2genes. The mean age in our group of patients, when the first exostosis was recognised was 4.5 years (range 2–10 years) and the number of exostoses per one patient documented on X-ray ranged from 2 to 54. Most of the exostoses developed before the growth was completed and they were dominantly localised in the distal femurs, proximal tibia, proximal humerus and distal radius. In all patients, at least one to 8 surgeries were necessary due to complaints and local complications, but neither patient developed malignant transformation. In half of the patients, the disease resulted in short stature. DNA analyses were positive in 7 families. In five probands, differentEXT1gene mutations resulting in premature stop-codon (p.Gly124Argfs*65, p.Leu191*, p.Trp364Lysfs*11, p.Val371Glyfs*10, p.Leu490Profs*31) were found. In two probands, nonsense mutations were found inEXT2gene (p.Val187Profs*115, p.Cys319fs*46). Five mutations have been novel and two mutations have occurredde novoin probands. Although the risk for malignant transformation is usually low, especially in patients with low number of exostoses, early diagnostics and longitudinal follow up of patients is of a big importance, because early surgery can prevent progression of secondary bone deformities.

scholarly journals A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals

2016 ◽  
Author(s):  
Vagheesh M Narasimhan ◽  
Raheleh Rahbari ◽  
Aylwyn Scally ◽  
Arthur Wuster ◽  
Dan Mason ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Base Pair ◽  
De Novo ◽  
Recent Common Ancestor ◽  
Human Populations ◽  
De Novo Mutations ◽  
Pakistani Population ◽  
Human Mutation ◽  
C To T Mutations ◽  
Mutational Processes

AbstractHeterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations (DNMs) across multiple generations. Using exome sequences from 3,222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1. 45 ± 0.05 × 10−8 per base pair per generation in autosomal coding sequence, with a corresponding noncrossover gene conversion rate of 8.75 ± 0.05 × 10−6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germline mutation rate. We found frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5’ CCG 3’ → 5’ CTG 3’ context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

scholarly journals Higher Germline Mutagenesis of Genes with Stronger Testis Expressions Refutes the Transcriptional Scanning Hypothesis

2020 ◽  
Vol 37 (11) ◽  
pp. 3225-3231
Author(s):  
Haoxuan Liu ◽  
Jianzhi Zhang
Keyword(s):  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
Expression Level ◽  
Human Testis ◽  
Confounding Factors ◽  
De Novo Mutations ◽  
Gene Expressions ◽  
Specific Manner ◽  
Mammalian Testis

Abstract Why are more genes expressed in the testis than in any other organ in mammals? The recently proposed transcriptional scanning hypothesis posits that transcription alleviates mutagenesis through transcription-coupled repair so has been selected in the testis to modulate the germline mutation rate in a gene-specific manner. Here, we show that this hypothesis is theoretically untenable because the selection would be too weak to have an effect in mammals. Furthermore, the analysis purported to support the hypothesis did not control known confounding factors and inappropriately excluded genes with no observed de novo mutations. After remedying these problems, we find the human germline mutation rate of a gene to rise with its testis expression level. This trend also exists for inferred coding strand-originated mutations, suggesting that it arises from transcription-associated mutagenesis. Furthermore, the testis expression level of a gene robustly correlates with its overall expression in other organs, nullifying the need to explain the testis silencing of a minority of genes by adaptive germline mutagenesis. Taken together, our results demonstrate that human testis transcription increases the germline mutation rate, rejecting the transcriptional scanning hypothesis of extensive gene expressions in the mammalian testis.

scholarly journals Rapid Accumulation of Mutations in Growing Mycelia of a Hypervariable Fungus Schizophyllum commune

2020 ◽  
Vol 37 (8) ◽  
pp. 2279-2286
Author(s):  
Aleksandra V Bezmenova ◽  
Elena A Zvyagina ◽  
Anna V Fedotova ◽  
Artem S Kasianov ◽  
Tatiana V Neretina ◽  
...  
Keyword(s):  
Cell Division ◽  
Mutation Rate ◽  
De Novo ◽  
Schizophyllum Commune ◽  
Natural Populations ◽  
De Novo Mutations ◽  
Rapid Accumulation ◽  
Living Organisms ◽  
Very High ◽  
Rate Of Accumulation

Abstract The basidiomycete Schizophyllum commune has the highest level of genetic polymorphism known among living organisms. In a previous study, it was also found to have a moderately high per-generation mutation rate of 2×10−8, likely contributing to its high polymorphism. However, this rate has been measured only in an experiment on Petri dishes, and it is unclear how it translates to natural populations. Here, we used an experimental design that measures the rate of accumulation of de novo mutations in a linearly growing mycelium. We show that S. commune accumulates mutations at a rate of 1.24×10−7 substitutions per nucleotide per meter of growth, or ∼2.04×10−11 per nucleotide per cell division. In contrast to what has been observed in a number of species with extensive vegetative growth, this rate does not decline in the course of propagation of a mycelium. As a result, even a moderate per-cell-division mutation rate in S. commune can translate into a very high per-generation mutation rate when the number of cell divisions between consecutive meiosis is large.

scholarly journals Foramen magnum osteochondroma causing myelopathy in a patient with hereditary multiple exostoses

2020 ◽  
Vol 11 ◽  
pp. 296
Author(s):  
Siddharth Sinha ◽  
Venkat Iyer ◽  
K. Joshi George
Keyword(s):  
Cervical Myelopathy ◽  
Bone Tumors ◽  
Cervical Spinal Cord ◽  
Foramen Magnum ◽  
Solitary Lesion ◽  
Hereditary Multiple Exostoses ◽  
Multiple Osteochondromas ◽  
Multiple Exostoses ◽  
Intracranial Lesions ◽  
History Of

Background: Osteochondromas are commonly occurring benign bone tumors which may be either a solitary lesion or occur due to association with hereditary multiple exostoses (HMEs). There have been several reported cases of spinal osteochondromas, but intracranial lesions are rare. Case Description: A 51-year-old male with a history of multiple osteochondromas presented with myelopathy. He had an exostosis arising from the foramen magnum causing compression of the cervical spinal cord that was successfully removed. Genetic testing revealed that he had HMEs. Conclusion: Osteochondromas of the skull are extremely rare. However, parts of the foramen magnum ossify in cartilage and can give rise to an osteochondroma. Here, we present a patient with HMEs who developed cervical myelopathy due to an osteochondroma arising from the foramen magnum. Due to the cartilaginous ossification of the foramen magnum, clinicians should be aware that osteochondromas can occur in this location and potentially give rise to cervical myelopathy.

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