International Journal of Molecular Sciences

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Open AccessEditorial

Biomarkers in Rare Diseases 2.0

by Bridget E. Bax

Int. J. Mol. Sci. 2022, 23(9), 4582; https://doi.org/10.3390/ijms23094582 - 21 Apr 2022

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Abstract

It is estimated that there are over 7000 rare diseases, collectively affecting more than 350 million individuals worldwide [...] Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

Research

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18 pages, 814 KiB

Open AccessArticle

Identification of Potential Muscle Biomarkers in McArdle Disease: Insights from Muscle Proteome Analysis

by Inés García-Consuegra, Sara Asensio-Peña, Rocío Garrido-Moraga, Tomàs Pinós, Cristina Domínguez-González, Alfredo Santalla, Gisela Nogales-Gadea, Pablo Serrano-Lorenzo, Antoni L. Andreu, Joaquín Arenas, José L. Zugaza, Alejandro Lucia and Miguel A. Martín

Int. J. Mol. Sci. 2022, 23(9), 4650; https://doi.org/10.3390/ijms23094650 - 22 Apr 2022

Viewed by 2059

Abstract

Glycogen storage disease type V (GSDV, McArdle disease) is a rare genetic myopathy caused by deficiency of the muscle isoform of glycogen phosphorylase (PYGM). This results in a block in the use of muscle glycogen as an energetic substrate, with subsequent exercise intolerance. [...] Read more.

Glycogen storage disease type V (GSDV, McArdle disease) is a rare genetic myopathy caused by deficiency of the muscle isoform of glycogen phosphorylase (PYGM). This results in a block in the use of muscle glycogen as an energetic substrate, with subsequent exercise intolerance. The pathobiology of GSDV is still not fully understood, especially with regard to some features such as persistent muscle damage (i.e., even without prior exercise). We aimed at identifying potential muscle protein biomarkers of GSDV by analyzing the muscle proteome and the molecular networks associated with muscle dysfunction in these patients. Muscle biopsies from eight patients and eight healthy controls showing none of the features of McArdle disease, such as frequent contractures and persistent muscle damage, were studied by quantitative protein expression using isobaric tags for relative and absolute quantitation (iTRAQ) followed by artificial neuronal networks (ANNs) and topology analysis. Protein candidate validation was performed by Western blot. Several proteins predominantly involved in the process of muscle contraction and/or calcium homeostasis, such as myosin, sarcoplasmic/endoplasmic reticulum calcium ATPase 1, tropomyosin alpha-1 chain, troponin isoforms, and alpha-actinin-3, showed significantly lower expression levels in the muscle of GSDV patients. These proteins could be potential biomarkers of the persistent muscle damage in the absence of prior exertion reported in GSDV patients. Further studies are needed to elucidate the molecular mechanisms by which PYGM controls the expression of these proteins. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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9 pages, 1207 KiB

Open AccessArticle

Laboratory Investigation of Hybrid IgG4 k/λ in MuSK Positive Myasthenia Gravis

by Umberto Basile, Cecilia Napodano, Francesca Gulli, Krizia Pocino, Riccardo Di Santo, Laura Todi, Valerio Basile, Carlo Provenzano, Gabriele Ciasca and Mariapaola Marino

Int. J. Mol. Sci. 2021, 22(17), 9142; https://doi.org/10.3390/ijms22179142 - 24 Aug 2021

Cited by 3 | Viewed by 1855

Abstract

Myasthenia gravis with antibodies (Abs) against the muscle-specific tyrosine kinase (MuSK) is a rare autoimmune disorder (AD) of the neuromuscular junction (NMJ) and represents a prototype of AD with proven IgG4-mediated pathogenicity. Thanks to the mechanism of Fab-arm exchange (FAE) occurring in vivo, [...] Read more.

Myasthenia gravis with antibodies (Abs) against the muscle-specific tyrosine kinase (MuSK) is a rare autoimmune disorder (AD) of the neuromuscular junction (NMJ) and represents a prototype of AD with proven IgG4-mediated pathogenicity. Thanks to the mechanism of Fab-arm exchange (FAE) occurring in vivo, resulting MuSK IgG4 k/λ Abs increase their interference on NMJ and pathogenicity. The characterization of hybrid MuSK IgG4 as a biomarker for MG management is poorly investigated. Here, we evaluated total IgG4, hybrid IgG4 k/λ, and the hybrid/total ratio in 14 MuSK-MG sera in comparison with 24 from MG with Abs against acetylcholine receptor (AChR) that represents the not IgG4-mediated MG form. In both subtypes of MG, we found that the hybrid/total ratio reflects distribution reported in normal individuals; instead, when we correlated the hybrid/total ratio with specific immune-reactivity we found a positive correlation only with anti-MuSK titer, with a progressive increase of hybrid/total mean values with increasing disease severity, indirectly confirming that most part of hybrid IgG4 molecules are engaged in the anti-MuSK pathogenetic immune-reactivity. Further analysis is necessary to strengthen the significance of this less unknown biomarker, but we retain it is full of a diagnostic-prognostic powerful potential for the management of MuSK-MG. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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17 pages, 3176 KiB

Open AccessArticle

Plasma Gelsolin Reinforces the Diagnostic Value of FGF-21 and GDF-15 for Mitochondrial Disorders

by Ana Peñas, Miguel Fernández-De la Torre, Sara Laine-Menéndez, David Lora, María Illescas, Alberto García-Bartolomé, Montserrat Morales-Conejo, Joaquín Arenas, Miguel A. Martín, María Morán, Cristina Domínguez-González and Cristina Ugalde

Int. J. Mol. Sci. 2021, 22(12), 6396; https://doi.org/10.3390/ijms22126396 - 15 Jun 2021

Cited by 9 | Viewed by 2530

Abstract

Mitochondrial disorders (MD) comprise a group of heterogeneous clinical disorders for which non-invasive diagnosis remains a challenge. Two protein biomarkers have so far emerged for MD detection, FGF-21 and GDF-15, but the identification of additional biomarkers capable of improving their diagnostic accuracy is [...] Read more.

Mitochondrial disorders (MD) comprise a group of heterogeneous clinical disorders for which non-invasive diagnosis remains a challenge. Two protein biomarkers have so far emerged for MD detection, FGF-21 and GDF-15, but the identification of additional biomarkers capable of improving their diagnostic accuracy is highly relevant. Previous studies identified Gelsolin as a regulator of cell survival adaptations triggered by mitochondrial defects. Gelsolin presents a circulating plasma isoform (pGSN), whose altered levels could be a hallmark of mitochondrial dysfunction. Therefore, we investigated the diagnostic performance of pGSN for MD relative to FGF-21 and GDF-15. Using ELISA assays, we quantified plasma levels of pGSN, FGF-21, and GDF-15 in three age- and gender-matched adult cohorts: 60 genetically diagnosed MD patients, 56 healthy donors, and 41 patients with unrelated neuromuscular pathologies (non-MD). Clinical variables and biomarkers’ plasma levels were compared between groups. Discrimination ability was calculated using the area under the ROC curve (AUC). Optimal cut-offs and the following diagnostic parameters were determined: sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and efficiency. Comprehensive statistical analyses revealed significant discrimination ability for the three biomarkers to classify between MD and healthy individuals, with the best diagnostic performance for the GDF-15/pGSN combination. pGSN and GDF-15 preferentially discriminated between MD and non-MD patients under 50 years, whereas FGF-21 best classified older subjects. Conclusion: pGSN improves the diagnosis accuracy for MD provided by FGF-21 and GDF-15. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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13 pages, 29460 KiB

Open AccessArticle

Mesenchymal and Proneural Subtypes of Glioblastoma Disclose Branching Based on GSC Associated Signature

by Giedrius Steponaitis and Arimantas Tamasauskas

Int. J. Mol. Sci. 2021, 22(9), 4964; https://doi.org/10.3390/ijms22094964 - 7 May 2021

Cited by 15 | Viewed by 3804

Abstract

Glioblastomas (GBM)—the most common, therapy-resistant, and lethal tumors driven by populations of glioma stem cells (GSCs) are still on the list of the most complicated pathologies. Thus, deeper understanding and characterization of GSCs is indispensable to find suitable targets and develop more effective [...] Read more.

Glioblastomas (GBM)—the most common, therapy-resistant, and lethal tumors driven by populations of glioma stem cells (GSCs) are still on the list of the most complicated pathologies. Thus, deeper understanding and characterization of GSCs is indispensable to find suitable targets and develop more effective therapies. In the present study, we applied native glioblastoma cells and GSCs sequencing, screened for GSC-specific targets and checked if the signature is related to GBM patient pathological, clinical data as well as molecular subtypes applying TCGA cohort. Data analysis revealed that tumors of proneural and mesenchymal subtypes are branching in separate clusters based on screened gene expression. Samples of the same subtype revealed significantly different patient survival prognosis as well as recurrence chance between the clusters. Recently, different subpopulations of mesenchymal GSC demonstrating different properties were shown, which indicates possible internal heterogeneity of GBM subtypes as well. Current findings also revealed branching of molecular GBM subtypes that were significantly linked to patient outcome and that might be decided by distinct GSC subpopulations. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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50 pages, 26154 KiB

Open AccessArticle

Circulating miRNAs as Biomarkers for Mitochondrial Neuro-Gastrointestinal Encephalomyopathy

by Mark Mencias, Michelle Levene, Kevin Blighe, Bridget E. Bax and on behalf of the Project Group

Int. J. Mol. Sci. 2021, 22(7), 3681; https://doi.org/10.3390/ijms22073681 - 1 Apr 2021

Cited by 4 | Viewed by 3172

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease for which there are currently no validated outcome measures for assessing therapeutic intervention efficacy. The aim of this study was to identify a plasma and/or serum microRNA (miRNA) biomarker panel for MNGIE. Sixty-five patients and [...] Read more.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease for which there are currently no validated outcome measures for assessing therapeutic intervention efficacy. The aim of this study was to identify a plasma and/or serum microRNA (miRNA) biomarker panel for MNGIE. Sixty-five patients and 65 age and sex matched healthy controls were recruited and assigned to one of four study phases: (i) discovery for sample size determination; (ii) candidate screening; (iii) candidate validation; and (iv) verifying the performance of the validated miRNA panel in four patients treated with erythrocyte-encapsulated thymidine phosphorylase (EE-TP), an enzyme replacement under development for MNGIE. Quantitative PCR (qPCR) was used to profile miRNAs in serum and/or plasma samples collected for the discovery, validation and performance phases, and next generation sequencing (NGS) analysis was applied to serum samples assigned to the candidate screening phase. Forty-one differentially expressed candidate miRNAs were identified in the sera of patients (p < 0.05, log₂ fold change > 1). The validation cohort revealed that of those, 27 miRNAs were upregulated in plasma and three miRNAs were upregulated in sera (p < 0.05). Through binary logistic regression analyses, five plasma miRNAs (miR-192-5p, miR-193a-5p, miR-194-5p, miR-215-5p and miR-34a-5p) and three serum miRNAs (miR-192-5p, miR-194-5p and miR-34a-5p) were shown to robustly distinguish MNGIE from healthy controls. Reduced longitudinal miRNA expression of miR-34a-5p was observed in all four patients treated with EE-TP and coincided with biochemical and clinical improvements. We recommend the inclusion of the plasma exploratory miRNA biomarker panel in future clinical trials of investigational therapies for MNGIE; it may have prognostic value for assessing clinical status. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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Review

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16 pages, 3346 KiB

Open AccessReview

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

by Nicolás Lundahl Ciano-Petersen, Pablo Cabezudo-García, Sergio Muñiz-Castrillo, Jérôme Honnorat, Pedro Jesús Serrano-Castro and Begoña Oliver-Martos

Int. J. Mol. Sci. 2021, 22(23), 13127; https://doi.org/10.3390/ijms222313127 - 4 Dec 2021

Cited by 23 | Viewed by 5676

Abstract

The discovery of biomarkers in rare diseases is of paramount importance to allow a better diagnosis, improve predictions of outcomes, and prompt the development of new treatments. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder associated with the presence of antibodies targeting [...] Read more.

The discovery of biomarkers in rare diseases is of paramount importance to allow a better diagnosis, improve predictions of outcomes, and prompt the development of new treatments. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder associated with the presence of antibodies targeting the GluN1 subunit of the NMDAR. Since it was discovered in 2007, large efforts have been made towards the identification of clinical, paraclinical, and molecular biomarkers to better understand the immune mechanisms that govern the course of the disease as well as to define predictors of treatment response and long-term outcomes. However, most of these biomarkers are still in an exploratory phase, with only a few candidates reaching the final phases of the always-complex process of biomarker development, mainly due to the low incidence of the disease and its recent description. Clinical and paraclinical markers are probably the most widely explored in anti-NMDAR encephalitis, five of them combined in a clinical score to predict 1 year outcome. On the contrary, soluble molecules, such as persistent antibody positivity, antibody titers, cytokines, and other inflammatory mediators, have been proposed as biomarkers of clinical activity, inflammation, prognosis, and treatment response, but further studies are required for their clinical validation including larger and more homogenous cohorts of patients. Similarly, genetic susceptibility biomarkers are still in the exploratory phase and, therefore, weak conclusions can for now only be achieved. Thus, further studies are warranted to define biomarkers and unravel the underlying mechanisms driving rare diseases such as anti-NMDAR encephalitis. Future international collaborative studies with prospective designs that enable the enrollment of large cohorts will allow for the identification and validation of novel biomarkers for clinical decision-making. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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21 pages, 348 KiB

Open AccessReview

Biomarkers in AL Amyloidosis

by Despina Fotiou, Foteini Theodorakakou and Efstathios Kastritis

Int. J. Mol. Sci. 2021, 22(20), 10916; https://doi.org/10.3390/ijms222010916 - 9 Oct 2021

Cited by 8 | Viewed by 3259

Abstract

Systemic AL amyloidosis is a rare complex hematological disorder caused by clonal plasma cells which produce amyloidogenic immunoglobulins. Outcome and prognosis is the combinatory result of the extent and pattern of organ involvement secondary to amyloid fibril deposition and the biology and burden [...] Read more.

Systemic AL amyloidosis is a rare complex hematological disorder caused by clonal plasma cells which produce amyloidogenic immunoglobulins. Outcome and prognosis is the combinatory result of the extent and pattern of organ involvement secondary to amyloid fibril deposition and the biology and burden of the underlying plasma cell clone. Prognosis, as assessed by overall survival, and early outcomes is determined by degree of cardiac dysfunction and current staging systems are based on biomarkers that reflect the degree of cardiac damage. The risk of progression to end-stage renal disease requiring dialysis is assessed by renal staging systems. Longer-term survival and response to treatment is affected by markers of the underlying plasma cell clone; the genetic background of the clonal disease as evaluated by interphase fluorescence in situ hybridization in particular has predictive value and may guide treatment selection. Free light chain assessment forms the basis of hematological response criteria and minimal residual disease as assessed by sensitive methods is gradually being incorporated into clinical practice. However, sensitive biomarkers that could aid in the early diagnosis and that could reflect all aspects of organ damage and disease biology are needed and efforts to identify them are continuous. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

17 pages, 533 KiB

Open AccessReview

Biomarkers for Ehlers-Danlos Syndromes: There Is a Role?

by Laura Caliogna, Viviana Guerrieri, Salvatore Annunziata, Valentina Bina, Alice Maria Brancato, Alberto Castelli, Eugenio Jannelli, Alessandro Ivone, Federico Alberto Grassi, Mario Mosconi and Gianluigi Pasta

Int. J. Mol. Sci. 2021, 22(18), 10149; https://doi.org/10.3390/ijms221810149 - 20 Sep 2021

Cited by 9 | Viewed by 5262

Abstract

Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described [...] Read more.

Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described first by Hippocrates in 400 BC. In the last years, multiple gene variants involved in the pathogenesis of specific EDS subtypes have been identified; moreover, new clinical diagnostic criteria have been established. New classification models have also been studied in order to differentiate overlapping conditions. Moreover, EDS shares many characteristics with other similar disorders. Although distinguishing between these seemingly identical conditions is difficult, it is essential in ensuring proper patient care. Currently, there are many genetic and molecular studies underway to clarify the etiology of some variants of EDS. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. In this review, we focused on the study of two of the most common forms of EDS—classic and hypermobile—by trying to identify possible biomarkers that could be of great help to confirm patients’ diagnosis and their follow up. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

16 pages, 670 KiB

Open AccessReview

Biomolecular Markers of Recurrent Implantation Failure—A Review

by Aleksandra E. Mrozikiewicz, Marcin Ożarowski and Piotr Jędrzejczak

Int. J. Mol. Sci. 2021, 22(18), 10082; https://doi.org/10.3390/ijms221810082 - 18 Sep 2021

Cited by 46 | Viewed by 9494

Abstract

Currently, infertility affects 8–12% of reproductive age couples worldwide, a problem that also affects women suffering from recurrent implantation failure (RIF). RIF is a complex condition resulting from many physiological and molecular mechanisms involving dynamic endometrium–blastocyst interaction. The most important are the endometrial [...] Read more.

Currently, infertility affects 8–12% of reproductive age couples worldwide, a problem that also affects women suffering from recurrent implantation failure (RIF). RIF is a complex condition resulting from many physiological and molecular mechanisms involving dynamic endometrium–blastocyst interaction. The most important are the endometrial receptivity process, decidualization, trophoblast invasion, and blastocyst nesting. Although the exact multifactorial pathogenesis of RIF remains unclear, many studies have suggested the association between hormone level imbalance, disturbances of angiogenic and immunomodulatory factors, certain genetic polymorphisms, and occurrence of RIF. These studies were performed in quite small groups. Additionally, the results are inconsistent between ethnicities. The present review briefly summarizes the importance of factors involved in RIF development that could also serve as diagnostic determinants. Moreover, our review could constitute part of a new platform for discovery of novel diagnostic and therapeutic solutions for RIF. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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19 pages, 891 KiB

Open AccessReview

by Karina Maciak, Sylwia Pietrasik, Angela Dziedzic, Justyna Redlicka, Joanna Saluk-Bijak, Michał Bijak, Tomasz Włodarczyk and Elzbieta Miller

Int. J. Mol. Sci. 2021, 22(16), 8946; https://doi.org/10.3390/ijms22168946 - 20 Aug 2021

Cited by 22 | Viewed by 3212

Abstract

Multiple sclerosis (MS) and Devic’s disease (NMO; neuromyelitis optica) are autoimmune, inflammatory diseases of the central nervous system (CNS), the etiology of which remains unclear. It is a serious limitation in the treatment of these diseases. The resemblance of the clinical pictures of [...] Read more.

Multiple sclerosis (MS) and Devic’s disease (NMO; neuromyelitis optica) are autoimmune, inflammatory diseases of the central nervous system (CNS), the etiology of which remains unclear. It is a serious limitation in the treatment of these diseases. The resemblance of the clinical pictures of these two conditions generates a partial possibility of introducing similar treatment, but on the other hand, a high risk of misdiagnosis. Therefore, a better understanding and comparative characterization of the immunopathogenic mechanisms of each of these diseases are essential to improve their discriminatory diagnosis and more effective treatment. In this review, special attention is given to Th17 cells and Th17-related cytokines in the context of their potential usefulness as discriminatory markers for MS and NMO. The discussed results emphasize the role of Th17 immune response in both MS and NMO pathogenesis, which, however, cannot be considered without taking into account the broader perspective of immune response mechanisms. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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30 pages, 1194 KiB

Open AccessReview

Objective and Measurable Biomarkers in Chronic Subjective Tinnitus

by Dae-Woong Kang, Sung-Soo Kim, Dong-Choon Park, Sang-Hoon Kim and Seung-Geun Yeo

Int. J. Mol. Sci. 2021, 22(12), 6619; https://doi.org/10.3390/ijms22126619 - 21 Jun 2021

Cited by 13 | Viewed by 4771

Abstract

Tinnitus is associated with increased social costs and reduced quality of life through sleep disorders or psychological distress. The pathophysiology of chronic subjective tinnitus, which accounts for most tinnitus, has not been clearly elucidated. This is because chronic subjective tinnitus is difficult to [...] Read more.

Tinnitus is associated with increased social costs and reduced quality of life through sleep disorders or psychological distress. The pathophysiology of chronic subjective tinnitus, which accounts for most tinnitus, has not been clearly elucidated. This is because chronic subjective tinnitus is difficult to evaluate objectively, and there are no objective markers that represent the diagnosis or therapeutic effect of tinnitus. Based on the results of studies on patients with chronic subjective tinnitus, objective and measurable biomarkers that help to identify the pathophysiology of tinnitus have been summarized. A total of 271 studies in PubMed, 303 in EMBASE, and 45 in Cochrane Library were found on biomarkers related to chronic subjective tinnitus published until April 2021. Duplicate articles, articles not written in English, review articles, case reports, and articles that did not match our topic were excluded. A total of 49 studies were included. Three specimens, including blood, saliva, and urine, and a total of 58 biomarkers were used as indicators for diagnosis, evaluation, prognosis, and therapeutic effectiveness of tinnitus. Biomarkers were classified into eight categories comprising metabolic, hemostatic, inflammatory, endocrine, immunological, neurologic, and oxidative parameters. Biomarkers can help in the diagnosis, measure the severity, predict prognosis, and treatment outcome of tinnitus. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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31 pages, 3135 KiB

Open AccessReview

Biomarkers in Glycogen Storage Diseases: An Update

by Alberto Molares-Vila, Alberte Corbalán-Rivas, Miguel Carnero-Gregorio, José Luís González-Cespón and Carmen Rodríguez-Cerdeira

Int. J. Mol. Sci. 2021, 22(9), 4381; https://doi.org/10.3390/ijms22094381 - 22 Apr 2021

Cited by 17 | Viewed by 5946

Abstract

Glycogen storage diseases (GSDs) are a group of 19 hereditary diseases caused by a lack of one or more enzymes involved in the synthesis or degradation of glycogen and are characterized by deposits or abnormal types of glycogen in tissues. Their frequency is [...] Read more.

Glycogen storage diseases (GSDs) are a group of 19 hereditary diseases caused by a lack of one or more enzymes involved in the synthesis or degradation of glycogen and are characterized by deposits or abnormal types of glycogen in tissues. Their frequency is very low and they are considered rare diseases. Except for X-linked type IX, the different types are inherited in an autosomal recessive pattern. In this study we reviewed the literature from 1977 to 2020 concerning GSDs, biomarkers, and metabolic imbalances in the symptoms of some GSDs. Most of the reported studies were performed with very few patients. Classification of emerging biomarkers between different types of diseases (hepatics GSDs, McArdle and PDs and other possible biomarkers) was done for better understanding. Calprotectin for hepatics GSDs and urinary glucose tetrasaccharide for Pompe disease have been approved for clinical use, and most of the markers mentioned in this review only need clinical validation, as a final step for their routine use. Most of the possible biomarkers are implied in hepatocellular adenomas, cardiomyopathies, in malfunction of skeletal muscle, in growth retardation, neutropenia, osteopenia and bowel inflammation. However, a few markers have lost interest due to a great variability of results, which is the case of biotinidase, actin alpha 2, smooth muscle, aorta and fibroblast growth factor receptor 4. This is the first review published on emerging biomarkers with a potential application to GSDs. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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13 pages, 823 KiB

Open AccessReview

Endoplasmic Reticulum-Associated Biomarkers for Molecular Phenotyping of Rare Kidney Disease

by Chuang Li and Ying Maggie Chen

Int. J. Mol. Sci. 2021, 22(4), 2161; https://doi.org/10.3390/ijms22042161 - 22 Feb 2021

Cited by 13 | Viewed by 3115

Abstract

The endoplasmic reticulum (ER) is the central site for folding, post-translational modifications, and transport of secretory and membrane proteins. An imbalance between the load of misfolded proteins and the folding capacity of the ER causes ER stress and an unfolded protein response. Emerging [...] Read more.

The endoplasmic reticulum (ER) is the central site for folding, post-translational modifications, and transport of secretory and membrane proteins. An imbalance between the load of misfolded proteins and the folding capacity of the ER causes ER stress and an unfolded protein response. Emerging evidence has shown that ER stress or the derangement of ER proteostasis contributes to the development and progression of a variety of glomerular and tubular diseases. This review gives a comprehensive summary of studies that have elucidated the role of the three ER stress signaling pathways, including inositol-requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6) signaling in the pathogenesis of kidney disease. In addition, we highlight the recent discovery of ER-associated biomarkers, including MANF, ERdj3, ERdj4, CRELD2, PDIA3, and angiogenin. The implementation of these novel biomarkers may accelerate early diagnosis and therapeutic intervention in rare kidney disease. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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