Some New Concepts Derived from Inborn Errors in Human Metabolism

A dynamic multi-tissue model to study human metabolism

npj Systems Biology and Applications ◽

10.1038/s41540-020-00159-1 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Patricia Martins Conde ◽

Thomas Pfau ◽

Maria Pires Pacheco ◽

Thomas Sauter

Keyword(s):

Drug Targets ◽

Metabolic Diseases ◽

Human Metabolism ◽

Inborn Errors ◽

Predictive Capacity ◽

Physiological Level ◽

Urine Metabolites ◽

Tissue Model ◽

Novel Approach ◽

New Biomarkers

AbstractMetabolic modeling enables the study of human metabolism in healthy and in diseased conditions, e.g., the prediction of new drug targets and biomarkers for metabolic diseases. To accurately describe blood and urine metabolite dynamics, the integration of multiple metabolically active tissues is necessary. We developed a dynamic multi-tissue model, which recapitulates key properties of human metabolism at the molecular and physiological level based on the integration of transcriptomics data. It enables the simulation of the dynamics of intra-cellular and extra-cellular metabolites at the genome scale. The predictive capacity of the model is shown through the accurate simulation of different healthy conditions (i.e., during fasting, while consuming meals or during exercise), and the prediction of biomarkers for a set of Inborn Errors of Metabolism with a precision of 83%. This novel approach is useful to prioritize new biomarkers for many metabolic diseases, as well as for the integration of various types of personal omics data, towards the personalized analysis of blood and urine metabolites.

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From rodent heart to inborn errors of human metabolism

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2018.02.001 ◽

2018 ◽

Vol 123 (3) ◽

pp. 287-288

Author(s):

Jörn Oliver Sass ◽

Sema Kalkan Uçar ◽

Clara D.M. van Karnebeek

Keyword(s):

Human Metabolism ◽

Inborn Errors

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Natural variation in a glucuronosyltransferase modulates propionate sensitivity in a C. elegans propionic acidemia model

10.1101/2020.03.02.973206 ◽

2020 ◽

Author(s):

Huimin Na ◽

Stefan Zdraljevic ◽

Robyn E. Tanny ◽

Albertha J.M. Walhout ◽

Erik C. Andersen

Keyword(s):

Rare Diseases ◽

Genetic Background ◽

Statistical Power ◽

Natural Variation ◽

Propionic Acidemia ◽

Human Metabolism ◽

Loss Of Function ◽

Inborn Errors ◽

C Elegans ◽

Metabolic Genes

ABSTRACTMutations in human metabolic genes can lead to rare diseases known as inborn errors of human metabolism. For instance, patients with loss-of-function mutations in either subunit of propionyl-CoA carboxylase suffer from propionic acidemia because they cannot catabolize propionate, leading to its harmful accumulation. Interestingly, both the penetrance and expressivity of metabolic disorders can be modulated by genetic background. However, modifiers of these diseases are difficult to identify because of the lack of statistical power for rare diseases in human genetics. Here, we use a model of propionic acidemia in the nematode Caenorhabditis elegans to identify genetic modifiers of propionate sensitivity. By genome-wide association mapping across wild strains exposed to excess propionate we identify several genomic regions correlated with reduced propionate sensitivity. We find that natural variation in the putative glucuronosyltransferase GLCT-3, a homolog of human B3GAT, partly explains differences in propionate sensitivity in one of these genomic intervals. Using genome-editing, we demonstrate that loss-of-function alleles in glct-3 render the animals less sensitive to propionate. Additionally, we find that C. elegans has an expansion of the glct gene family, suggesting that the number of members of this family could influence sensitivity to excess propionate. Our findings demonstrate that natural variation in metabolic genes that are not directly associated with propionate breakdown can modulate propionate sensitivity. Our study provides a framework for using C. elegans to characterize the contributions of genetic background to inborn errors in human metabolism.

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Electron Microscopy of Fibroblasts from Myotonic Muscular Dystrophy Patients

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100098976 ◽

1981 ◽

Vol 39 ◽

pp. 498-499

Author(s):

S. E. Miller ◽

G. B. Hartwig ◽

R. A. Nielsen ◽

A. P. Frost ◽

A. D. Roses

Keyword(s):

Electron Microscopy ◽

Muscular Dystrophy ◽

Genetic Diseases ◽

Skin Fibroblasts ◽

Inborn Errors ◽

Cytoplasmic Inclusions ◽

Cultured Skin ◽

Myotonic Muscular Dystrophy ◽

Glycosaminoglycan Metabolism

Many genetic diseases can be demonstrated in skin cells cultured in vitro from patients with inborn errors of metabolism. Since myotonic muscular dystrophy (MMD) affects many organs other than muscle, it seems likely that this defect also might be expressed in fibroblasts. Detection of an alteration in cultured skin fibroblasts from patients would provide a valuable tool in the study of the disease as it would present a readily accessible and controllable system for examination. Furthermore, fibroblast expression would allow diagnosis of fetal and presumptomatic cases. An unusual staining pattern of MMD cultured skin fibroblasts as seen by light microscopy, namely, an increase in alcianophilia and metachromasia, has been reported; both these techniques suggest an altered glycosaminoglycan metabolism An altered growth pattern has also been described. One reference on cultured skin fibroblasts from a different dystrophy (Duchenne Muscular Dystrophy) reports increased cytoplasmic inclusions seen by electron microscopy. Also, ultrastructural alterations have been reported in muscle and thalamus biopsies from MMD patients, but no electron microscopical data is available on MMD cultured skin fibroblasts.

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Fine Structure of Type IV Glycogenosis

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100098812 ◽

1981 ◽

Vol 39 ◽

pp. 464-465

Author(s):

P.K. Simons

Keyword(s):

Needle Biopsy ◽

Tissue Concentration ◽

Inborn Errors ◽

Rare Type ◽

Type Iv ◽

Iron Copper ◽

Proper Diagnosis ◽

Type Iv Glycogenosis ◽

Loss Of Appetite ◽

Enzymatic Defect

Glycogenosis is defined as any condition in which the tissue concentration of glycogen is increased. There are currently ten recognized variants of glycogenosis that are heritable inborn errors of metabolism. The specific enzymatic defect in each of the variants is known or at least suspected. In all cases, the enzymatic defect prevents the proper metabolism or formation of the glycogen molecule. The clinical and histologic differences between the types of glycogenosis is important to a proper diagnosis after the presence of such a condition is realized. This study was initiated to examine the ultrastructure of the rare Type IV Glycogenosis (Amylopectinosis) of which there is very little morphologic characterization in the literature.Liver tissue was obtained by needle biopsy from a 12-month-old Oriental female who was originally admitted to the hospital after observation of poor development, loss of appetite, and hepatomegaly. The majority of the tissue was fixed for light microscopy in neutral buffered formalin and processed using routine and special staining procedures (reticulin, trichrome, iron, copper, PAS, PAS-diastase and PAS-pectinase.

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Novel Approaches to Low-Voltage Scanning Electron Microscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100180586 ◽

1990 ◽

Vol 48 (1) ◽

pp. 366-367

Author(s):

Arthur V. Jones

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Low Voltage ◽

Electron Optics ◽

Current Interest ◽

New Concepts ◽

Opportune Time ◽

Novel Approaches ◽

Voltage Scanning ◽

Scanning Electron

In comparison with the developers of other forms of instrumentation, scanning electron microscope manufacturers are among the most conservative of people. New concepts usually must wait many years before being exploited commercially. The field emission gun, developed by Albert Crewe and his coworkers in 1968 is only now becoming widely available in commercial instruments, while the innovative lens designs of Mulvey are still waiting to be commercially exploited. The associated electronics is still in general based on operating procedures which have changed little since the original microscopes of Oatley and his co-workers.The current interest in low-voltage scanning electron microscopy will, if sub-nanometer resolution is to be obtained in a useable instrument, lead to fundamental changes in the design of the electron optics. Perhaps this is an opportune time to consider other fundamental changes in scanning electron microscopy instrumentation.

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