Nearly 70 inherited human glycosylation disorders span a breathtaking clinical spectrum, impacting nearly every organ system and launching a family-driven diagnostic odyssey. Advances in genetics, ...especially next generation sequencing, propelled discovery of many glycosylation disorders in single and multiple pathways. Interpretation of whole exome sequencing results, insights into pathological mechanisms, and possible therapies will hinge on biochemical analysis of patient-derived materials and animal models. Biochemical diagnostic markers and readouts offer a physiological context to confirm candidate genes. Recent discoveries suggest novel perspectives for textbook biochemistry and novel research opportunities. Basic science and patients are the immediate beneficiaries of this bidirectional collaboration.
Congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic disorders that result from abnormal protein or lipid glycosylation. They are often difficult to clinically ...diagnose because they broadly affect many organs and functions and lack clinical uniformity. However, recent technological advances in next-generation sequencing have revealed a treasure trove of new genetic disorders, expanded the knowledge of known disorders, and showed a critical role in infectious diseases. More comprehensive genetic tools specifically tailored for mammalian cell-based models have revealed a critical role for glycosylation in pathogen–host interactions, while also identifying new CDG susceptibility genes. We highlight recent advancements that have resulted in a better understanding of human glycosylation disorders, perspectives for potential future therapies, and mysteries for which we continue to seek new insights and solutions.
Over 125 congenital disorders of glycosylation (CDG) are clinically diverse and cover all major glycosylation pathways.
Next-generation sequencing (NGS) enabled discovery of over 51 novel glycosylation disorders and identified de novo mutations in several disorders.
Complex genetic screening of human cells shows glycosylation is critical for many pathogens, especially viruses. Targeting glycosylation pathways could become a short-term treatment.
Simple monosaccharide therapies and novel chemical approaches offer treatments for several glycosylation disorders.
Over 100 human genetic disorders result from mutations in glycosylation-related genes. In 2013, a new glycosylation disorder was reported every 17 days. This trend will probably continue given that ...at least 2% of the human genome encodes glycan-biosynthesis and -recognition proteins. Established biosynthetic pathways provide many candidate genes, but finding unanticipated mutated genes will offer new insights into glycosylation. Simple glycobiomarkers can be used in narrowing the candidates identified by exome and genome sequencing, and those can be validated by glycosylation analysis of serum or cells from affected individuals. Model organisms will expand the understanding of these mutations’ impact on glycosylation and pathology. Here, we highlight some recently discovered glycosylation disorders and the barriers, breakthroughs, and surprises they presented. We predict that some glycosylation disorders might occur with greater frequency than current estimates of their prevalence. Moreover, the prevalence of some disorders differs substantially between European and African Americans.
The impulsive phase of a solar flare marks the epoch of rapid conversion of energy stored in the preflare coronal magnetic field. Hard X-ray observations imply that a substantial fraction of flare ...energy released during the impulsive phase is converted to the kinetic energy of mildly relativistic electrons (10-100 keV). The liberation of the magnetic free energy can occur as the coronal magnetic field reconfigures and relaxes following reconnection. We investigate a scenario in which products of the reconfiguration-large-scale Alfven wave pulses-transport the energy and the magnetic field changes rapidly through the corona to the lower atmosphere. This offers two possibilities for electron acceleration. First, in a coronal plasma with image, the waves propagate as inertial Alfven waves. In the presence of strong spatial gradients, these generate field-aligned electric fields that can accelerate electrons to energies on the order of 10 keV and above, including by repeated interactions between electrons and wave fronts. Second, when they reflect and mode-convert in the chromosphere, a cascade to high wavenumbers may develop. This will also accelerate electrons by turbulence, in a medium with a locally high electron number density. This concept, which bridges MHD-based and particle-based views of a flare, provides an interpretation of the recently observed rapid variations of the line-of-sight component of the photospheric magnetic field across the flare impulsive phase, and offers solutions to some perplexing flare problems, such as the flare 'number problem' of finding and resupplying sufficient electrons to explain the impulsive-phase hard X-ray emission.
Mannose metabolism: More than meets the eye Sharma, Vandana; Ichikawa, Mie; Freeze, Hudson H.
Biochemical and biophysical research communications,
10/2014, Letnik:
453, Številka:
2
Journal Article
Recenzirano
Odprti dostop
•Mammalian plasma contains 50–100μM mannose and dietary mannose supplements raise it 3–5-fold.•Mutations in mannose-metabolizing enzymes cause Congenital Disorders of Glycosylation (CDG).•Mannose ...supplements treat phosphomannose isomerase (MPI) deficient CDG patients.•Mannose supplements kill Mpi-hypomorphic mouse embryos and blind survivors.•Mannose is a routine remedy for urinary tract infections. Caution, especially during pregnancy.
Mannose is a simple sugar with a complex life. It is a welcome therapy for genetic and acquired human diseases, but it kills honeybees and blinds baby mice. It could cause diabetic complications. Mannose chemistry, metabolism, and metabolomics in cells, tissues and mammals can help explain these multiple systemic effects. Mannose has good, bad or ugly outcomes depending on its steady state levels and metabolic flux. This review describes the role of mannose at cellular level and its impact on organisms.
The spectrum of all glycan structures--the glycome--is immense. In humans, its size is orders of magnitude greater than the number of proteins that are encoded by the genome, one percent of which ...encodes proteins that make, modify, localize or bind sugar chains, which are known as glycans. In the past decade, over 30 genetic diseases have been identified that alter glycan synthesis and structure, and ultimately the function of nearly all organ systems. Many of the causal mutations affect key biosynthetic enzymes, but more recent discoveries point to defects in chaperones and Golgi-trafficking complexes that impair several glycosylation pathways. As more glycosylation disorders and patients with these disorders are identified, the functions of the glycome are starting to be revealed.
This review presents principles of glycosylation, describes the relevant glycosylation pathways and their related disorders, and highlights some of the neurological aspects and issues that continue ...to challenge researchers. More than 100 rare human genetic disorders that result from deficiencies in the different glycosylation pathways are known today. Most of these disorders impact the central and or peripheral nervous systems. Patients typically have developmental delays intellectual disabilities, hypotonia, seizures, neuropathy, and metabolic abnormalities in multiple organ systems. Among these disorders there is great clinical diversity because all cell types differentially glycosylate proteins and lipids. The patients have hundreds of misglycosylated products, which afflict a myriad of processes, including cell signaling, cell-cell interaction, and cell migration. This vast complexity in glycan composition and function, along with the limited availability of analytic tools, has impeded the identification of key glycosylated molecules that cause pathologies. To date, few critical target proteins have been pinpointed.
Inflammatory mediators play important roles in the development and progression of cancer. Cellular stress, damage, inflammation, and necrotic cell death cause release of endogenous damage-associated ...molecular pattern (DAMP) molecules or alarmins, which alert the host of danger by triggering immune responses and activating repair mechanisms through their interaction with pattern recognition receptors. Recent studies show that abnormal persistence of these molecules in chronic inflammation and in tumor microenvironments underlies carcinogenesis and tumor progression, indicating that DAMP molecules and their receptors could provide novel targets for therapy. This review focuses on the role of DAMP molecules high-mobility group box 1 and S100 proteins in inflammation, tumor growth, and early metastatic events.
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus of significant public health concern. ZIKV shares a high degree of sequence and structural homology compared with other flaviviruses, ...including dengue virus (DENV), resulting in immunological cross-reactivity. Improving our current understanding of the extent and characteristics of this immunological cross-reactivity is important, as ZIKV is presently circulating in areas that are highly endemic for dengue. To assess the magnitude and functional quality of cross-reactive immune responses between these closely related viruses, we tested acute and convalescent sera from nine Thai patients with PCR-confirmed DENV infection against ZIKV. All of the sera tested were cross-reactive with ZIKV, both in binding and in neutralization. To deconstruct the observed serum cross-reactivity in depth, we also characterized a panel of DENV-specific plasmablast-derived monoclonal antibodies (mAbs) for activity against ZIKV. Nearly half of the 47 DENV-reactive mAbs studied bound to both whole ZIKV virion and ZIKV lysate, of which a subset also neutralized ZIKV. In addition, both sera and mAbs from the dengue-infected patients enhanced ZIKV infection of Fc gamma receptor (FcγR)-bearing cells in vitro. Taken together, these findings suggest that preexisting immunity to DENV may impact protective immune responses against ZIKV. In addition, the extensive cross-reactivity may have implications for ZIKV virulence and disease severity in DENV-experienced populations.
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