scholarly journals Maternal mosaicism for a missense variant in the SMS gene that causes Snyder-Robinson syndrome

2021 ◽  
pp. mcs.a006122
Author(s):  
Mohammad Marhabaie ◽  
Scott E Hickey ◽  
Katherine E Miller ◽  
Olivia Grischow ◽  
Kathleen M Schieffer ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
De Novo ◽  
Genetic Disorders ◽  
Missense Variant ◽  
Hyperinsulinemic Hypoglycemia ◽  
Spermine Synthase ◽  
Genetic Mosaicism ◽  
The Family ◽  
Bilateral Sensorineural Hearing Loss

There is increasing recognition for the contribution of genetic mosaicism to human disease, particularly as high-throughput sequencing has enabled detection of sequence variants at very low allele frequencies. Here, we describe an infant male who presented at 9 months of age with hypotonia, dysmorphic features, congenital heart disease, hyperinsulinemic hypoglycemia, hypothyroidism, and bilateral sensorineural hearing loss. Whole-genome sequencing of the proband and the parents uncovered an apparent de novo mutation in the X-linked SMS gene. SMS encodes spermine synthase, which catalyzes the production of spermine from spermidine. Inactivation of the SMS gene disrupts the spermidine/spermine ratio, resulting in Snyder-Robinson syndrome. The variant in our patient is absent from the gnomAD and ExAC databases and causes a missense change (p.Arg130Cys) predicted to be damaging by most in silico tools. While Sanger sequencing confirmed the de novo status in our proband, PCR and deep targeted resequencing to ~84,000-175,000x depth revealed that the variant is present in blood from the unaffected mother at ~3% variant allele frequency. Our findings thus provided a long-sought diagnosis for the family while highlighting the role of parental mosaicism in severe genetic disorders.

scholarly journals A 2020 View on the Genetics of Developmental and Epileptic Encephalopathies

2020 ◽  
Vol 20 (2) ◽  
pp. 90-96 ◽  
Author(s):  
Hannah C. Happ ◽  
Gemma L. Carvill
Keyword(s):  
Molecular Diagnosis ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Autosomal Recessive Inheritance ◽  
Small Subset ◽  
Recessive Inheritance ◽  
Epileptic Encephalopathies ◽  
Pathogenic Variants ◽  
Genetic Mosaicism ◽  
Genetic Landscape

Developmental and epileptic encephalopathies (DEEs) can be primarily attributed to genetic causes. The genetic landscape of DEEs has been largely shaped by the rise of high-throughput sequencing, which led to the discovery of new DEE-associated genes and helped identify de novo pathogenic variants. We discuss briefly the contribution of de novo variants to DEE and also focus on alternative inheritance models that contribute to DEE. First, autosomal recessive inheritance in outbred populations may have a larger contribution than previously appreciated, accounting for up to 13% of DEEs. A small subset of genes that typically harbor de novo variants have been associated with recessive inheritance, and often these individuals have more severe clinical presentations. Additionally, pathogenic variants in X-linked genes have been identified in both affected males and females, possibly due to a lack of X-chromosome inactivation skewing. Collectively, exome sequencing has resulted in a molecular diagnosis for many individuals with DEE, but this still leaves many cases unsolved. Multiple factors contribute to the missing etiology, including nonexonic variants, mosaicism, epigenetics, and oligogenic inheritance. Here, we focus on the first 2 factors. We discuss the promises and challenges of genome sequencing, which allows for a more comprehensive analysis of the genome, including interpretation of structural and noncoding variants and also yields a high number of de novo variants for interpretation. We also consider the contribution of genetic mosaicism, both what it means for a molecular diagnosis in mosaic individuals and the important implications for genetic counseling.

scholarly journals Fluorinated Mannosides Inhibit Cellular Fucosylation.

2020 ◽  
Author(s):  
Johan Pijnenborg ◽  
Emiel Rossing ◽  
Marek Noga ◽  
Willem Titulaer ◽  
Raisa Veizaj ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
De Novo ◽  
Genetic Disorders ◽  
Living Cells ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Inflammation ◽  
Mannose Derivatives ◽  
Potential Therapeutics

Fucose sugars are expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a novel class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis. We demonstrate that cell permeable fluorinated mannoside 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

scholarly journals Critical Role of E1623 Residue in S3-S4 Loop of Nav1.1 Channel and Correlation Between Nature of Substitution and Functional Alteration

2022 ◽  
Vol 14 ◽  
Author(s):  
Tao Su ◽  
Meng-Long Chen ◽  
Li-Hong Liu ◽  
Hen Meng ◽  
Bin Tang ◽  
...  
Keyword(s):  
Current Density ◽  
Genetic Disorders ◽  
Critical Role ◽  
Missense Variant ◽  
Loss Of Function ◽  
Channel Conductance ◽  
Peak Current Density ◽  
Functional Changes ◽  
Functional Alteration

Objective: An overwhelming majority of the genetic variants associated with genetic disorders are missense. The association between the nature of substitution and the functional alteration, which is critical in determining the pathogenicity of variants, remains largely unknown. With a novel missense variant (E1623A) identified from two epileptic cases, which occurs in the extracellular S3-S4 loop of Nav1.1, we studied functional changes of all latent mutations at residue E1623, aiming to understand the relationship between substitution nature and functional alteration.Methods: Six latent mutants with amino acid substitutions at E1623 were generated, followed by measurements of their electrophysiological alterations. Different computational analyses were used to parameterize the residue alterations.Results: Structural modeling indicated that the E1623 was located in the peripheral region far from the central pore, and contributed to the tight turn of the S3-S4 loop. The E1623 residue exhibited low functional tolerance to the substitutions with the most remarkable loss-of-function found in E1623A, including reduced current density, less steady-state availability of activation and inactivation, and slower recovery from fast inactivation. Correlation analysis between electrophysiological parameters and the parameterized physicochemical properties of different residues suggested that hydrophilicity of side-chain at E1623 might be a crucial contributor for voltage-dependent kinetics. However, none of the established algorithms on the physicochemical variations of residues could well predict changes in the channel conductance property indicated by peak current density.Significance: The results established the important role of the extracellular S3-S4 loop in Nav1.1 channel gating and proposed a possible effect of local conformational loop flexibility on channel conductance and kinetics. Site-specific knowledge of protein will be a fundamental task for future bioinformatics.

scholarly journals Die Ontwikkeling Van Genetiese Dienste Van Die Departement Van Gesondheid — 1978

Curationis ◽  
1979 ◽  
Vol 1 (4) ◽  
Author(s):  
J. Hof
Keyword(s):  
Genetic Factors ◽  
Genetic Disorders ◽  
Community Health Services ◽  
Organisational Structure ◽  
Functional Activities ◽  
The Family ◽  
Hereditary Disorders ◽  
And Training ◽  
Diagnostic Investigations

Genetic Services may be regarded as a new addition to community health services, and are currently in the process of institutionalisation. The provision of this “ advanced” health service is long overdue, considering the widespread prevalence of genetic disorders, the role of genetic factors in disease in general, the possibilities of prevention, and the devastating implications of congenital and hereditary disorders for the family and community. The functional activities of the service are based on detection of high-risk and affected individuals, which includes diagnostic investigations and surveillance, genetic counselling and education and training. The nature of the service is outlined with particular reference to the genetics nurse. Designing a suitable organisational structure and providing essential facilities hallmarked the first phase in the process of institutionalising the service. In the next phase, commencing in 1979, the service will be implemented more formally with emphasis on evaluation and improvement of the service.

Regulating the level of intracellular hydrogen peroxide: the role of peroxiredoxin IV

2014 ◽  
Vol 42 (1) ◽  
pp. 42-46 ◽  
Author(s):  
Rachel E. Martin ◽  
Zhenbo Cao ◽  
Neil J. Bulleid
Keyword(s):  
Hydrogen Peroxide ◽  
De Novo ◽  
Protein Tyrosine Phosphatases ◽  
Disulfide Formation ◽  
Signalling Molecule ◽  
Protein Thiols ◽  
The Family ◽  
Rapid Removal ◽  
And Function

Hydrogen peroxide (H2O2) can act as a signalling molecule affecting the cell cycle as well as contributing towards the oxidative stress response. The primary target of this molecule is oxidation-sensitive cysteine residues in proteins such as protein tyrosine phosphatases. The cell has robust mechanisms to remove H2O2 that need to be regulated for H2O2 to react with and modify protein thiols. In particular, the family of peroxiredoxins are capable of the rapid removal of even trace amounts of this molecule. It has been suggested that the inactivation of peroxiredoxins by hyperoxidation may allow H2O2 levels to increase in cells and thereby modify critical thiol groups in proteins. We have been studying how the H2O2 produced during disulfide formation in the ER (endoplasmic reticulum) is metabolized and have shown that ER-resident peroxiredoxin IV not only can remove H2O2, but also contributes to de novo disulfide formation. In the present article, we review recent data on the structure and function of this enzyme as well as its sensitivity to hyperoxidation.

scholarly journals Fluorinated rhamnosides inhibit cellular fucosylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Johan F. A. Pijnenborg ◽  
Emiel Rossing ◽  
Jona Merx ◽  
Marek J. Noga ◽  
Willem H. C. Titulaer ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
De Novo ◽  
Genetic Disorders ◽  
Living Cells ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Inflammation ◽  
Mannose Derivatives ◽  
Potential Therapeutics

AbstractThe sugar fucose is expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis via competitive GMDS inhibition. We demonstrate that cell permeable fluorinated rhamnose 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

scholarly journals Identification and Characterization of a Novel Emaravirus From Grapevine Showing Chlorotic Mottling Symptoms

2021 ◽  
Vol 12 ◽  
Author(s):  
Xudong Fan ◽  
Chen Li ◽  
Zunping Zhang ◽  
Fang Ren ◽  
Guojun Hu ◽  
...  
Keyword(s):  
Phylogenetic Trees ◽  
High Throughput Sequencing ◽  
Rna Virus ◽  
Reading Frame ◽  
A Genome ◽  
The Family ◽  
Pcr Products ◽  
Chlorotic Mottling

A novel negative-sense, single-stranded (ss) RNA virus was identified in a “Shennong Jinhuanghou” (SJ) grapevine showing severe chlorotic mottling symptoms by integrating high-throughput sequencing (HTS) and conventional Sanger sequencing of reverse transcription polymerase chain reaction (RT-PCR) products. The virus was provisionally named as “grapevine emaravirus A” (GEVA). GEVA had a genome comprising five genomic RNA segments, each containing a single open reading frame on the viral complementary strand and two untranslated regions with complementary 13- nt stretches at the 5′ and 3′ terminal ends. RNA1 (7,090 nt), RNA2 (2,097 nt), RNA3 (1,615 nt), and RNA4 (1,640 nt) encoded putative proteins P1–P4 that, based on their conserved motifs, were identified as the RNA-dependent RNA polymerase, glycoprotein, nucleocapsid protein, and movement protein, respectively. However, the functional role of protein P5 encoded by RNA5 (1,308 nt) could not be determined. Phylogenetic trees constructed based on amino acids of P1 to P4, allocated GEVA in clade I, together with other species-related emaraviruses. These data support the proposal that GEVA is a representative member of a novel species in the genus Emaravirus of the family Fimoviridae. Moreover, when GEVA was graft-transmitted to SJ and “Beta” grapevines, all grafted plants showed the same symptoms, similar to those observed in the source of the inoculum. This is the first report to our knowledge of an emaravirus infecting grapevine and its possible association with chlorotic mottling symptoms.

scholarly journals Fluorinated Mannosides Inhibit Cellular Fucosylation.

2020 ◽  
Author(s):  
Johan Pijnenborg ◽  
Emiel Rossing ◽  
Marek Noga ◽  
Willem Titulaer ◽  
Raisa Veizaj ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
De Novo ◽  
Genetic Disorders ◽  
Living Cells ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Inflammation ◽  
Mannose Derivatives ◽  
Potential Therapeutics

Fucose sugars are expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a novel class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis. We demonstrate that cell permeable fluorinated mannoside 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

scholarly journals A De Novo Mutation in COL1A1 in a Holstein Calf with Osteogenesis Imperfecta Type II

Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 561
Author(s):  
Joana G. P. Jacinto ◽  
Irene M. Häfliger ◽  
Fintan J. McEvoy ◽  
Cord Drögemüller ◽  
Jørgen S. Agerholm
Keyword(s):  
Osteogenesis Imperfecta ◽  
De Novo ◽  
Perinatal Death ◽  
Genetic Disorders ◽  
Missense Variant ◽  
Connective Tissue Disorder ◽  
De Novo Mutation ◽  
Osteogenesis Imperfecta Type ◽  
Fibrillar Collagen ◽  
Type Ii

Osteogenesis imperfecta (OI) type II is a genetic connective tissue disorder characterized by bone fragility, severe skeletal deformities and shortened limbs. OI usually causes perinatal death of affected individuals. OI type II diagnosis in humans is established by the identification of heterozygous mutations in genes coding for collagens. The purpose of this study was to characterize the pathological phenotype of an OI type II-affected neonatal Holstein calf and to identify the causative genetic variant by whole-genome sequencing (WGS). The calf had acute as well as intrauterine fractures, abnormally shaped long bones and localized arthrogryposis. Genetic analysis revealed a private heterozygous missense variant in COL1A1 (c.3917T>A) located in the fibrillar collagen NC1 domain (p.Val1306Glu) that most likely occurred de novo. This confirmed the diagnosis of OI type II and represents the first report of a pathogenic variant in the fibrillar collagen NC domain of COL1A1 associated to OI type II in domestic animals. Furthermore, this study highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for rare lethal genetic disorders in cattle.

scholarly journals Unravelling the virome in birch: RNA-Seq reveals a complex of known and novel viruses

2019 ◽  
Author(s):  
Artemis Rumbou ◽  
Thierry Candresse ◽  
Armelle Marais ◽  
Laurence Svanella-Dumas ◽  
Maria Landgraf ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
De Novo ◽  
Leaf Roll ◽  
Viral Population ◽  
Comprehensive Overview ◽  
Dna And Rna ◽  
Birch Trees ◽  
Viral Communities ◽  
The Impact

AbstractHigh-throughput sequencing (HTS), combined with bioinformatics for de novo discovery and assembly of plant virus or viroid genome reads, has promoted the discovery of abundant novel DNA and RNA viruses and viroids. However, the elucidation of a viral population in a single plant is rarely reported. In five birch trees of German and Finnish origin exhibiting symptoms of birch leaf-roll disease (BRLD), we identified in total five viruses, among which three are novel. The number of identified virus variants in each transcriptome ranged from one to five. The novel species are genetically - fully or partially - characterized, they belong to the genera Carlavirus, Idaeovirus and Capillovirus and they are tentatively named birch carlavirus, birch idaeovirus, and birch capillovirus, respectively. The only virus systematically detected by HTS in symptomatic trees affected by the BRLD was the recently discovered birch leafroll-associated virus. The role of the new carlavirus in BLRD etiology seems at best weak, as it was detected only in one of three symptomatic trees. Continuing studies have to clarify the impact of the carlavirus to the BLRD. The role of the Capillovirus and the Idaeovirus within the BLRD complex and whether they influence plant vitality need to be investigated. Our study reveals the viral population in single birch trees and provides a comprehensive overview for the diversities of the viral communities they harbor.

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