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Molecular Research on Inherited Disorders
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Molecular Research on Inherited Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 22156

Special Issue Editors

Prof. Dr. Margherita Ruoppolo

E-Mail Website
Guest Editor
Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
Interests: inherited metabolic disorders; metabolomics; newborn screening; proteomics; protein-protein interaction
Special Issues, Collections and Topics in MDPI journals
Dr. Ida Chiara Guerrera

E-Mail Website
Guest Editor
Proteomics Platform 3P5-Necker, Université Paris Descartes - Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, 75014 Paris, France
Interests: rare genetic disease; proteomics; glycoproteomics; multi-omics; system biology; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rapid advances have been made in the prediction, detection, understanding, and monitoring of inherited disorders in humans using proteomic and metabolomic technologies. These disorders are genetic conditions that result in metabolism problems. Most people with inherited disorders have a defective gene that results in an enzyme deficiency and/or gain of function. There are hundreds of different genetic metabolic disorders, and their symptoms, treatments, and prognoses vary widely. Examples of these disorders include aminoacidopathies, defects of the oxidation of fatty acids, organic acidemias, lysosomal storage disease, and disorders of glycosylation.

The rarity of these conditions places a considerable burden on the individuals affected, and contributes to significant challenges in the medical care of these patients. It is clear that treatments applied as early as possible could greatly improve outcomes for patients.

Molecular research and in  particular proteomics and metabolomics offers great promise in this field. On one hand, they leat to the discovery of new, biologically and clinically relevant biomarkers for inherited metabolic disorders, for both diagnosis and prognosis. On the other hand, they contribute new knowledge in terms of the molecular mechanisms of inherited metabolic disorders. Furthermore the combined proteo-mebtabolomic approaches are developing rapidely, and are particularly relevant in unserstanding metabolic diseases.

The special issue will be devoted to molecular research in Inherited Disorders. It will contain up-to-date review articles, plus original research, concerning any aspect of molecular mechanism, diagnosis and treatment of Inherited Disorders to provide a state-of-the-art overview of this fast moving area.

Prof. Margherita Ruoppolo
Dr. Ida Chiara Guerrera
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Differential proteomics
  • Fluxomics
  • Glycoproteomics
  • Human disease model
  • Inherited disorders
  • Mass spectrometry
  • Multi-omics
  • Protein–protein interactions
  • NMR
  • Targeted metabolomics
  • Untargeted metabolomics

Published Papers (5 papers)

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Research

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15 pages, 2465 KiB  
Article
Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1
by Heiko Brennenstuhl, Miroslava Didiasova, Birgit Assmann, Mariarita Bertoldi, Gianluca Molla, Sabine Jung-Klawitter, Oya Kuseyri Hübschmann, Julian Schröter, Thomas Opladen and Ritva Tikkanen
Int. J. Mol. Sci. 2020, 21(22), 8578; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228578 - 13 Nov 2020
Cited by 5 | Viewed by 2108
Abstract
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of [...] Read more.
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including γ-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)+ binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of ALDH5A1 to identify mutational hotspots. Full article
(This article belongs to the Special Issue Molecular Research on Inherited Disorders)
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14 pages, 1867 KiB  
Article
Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease
by Sebastien Gauthier, Iwona Pranke, Vincent Jung, Loredana Martignetti, Véronique Stoven, Thao Nguyen-Khoa, Michaela Semeraro, Alexandre Hinzpeter, Aleksander Edelman, Ida Chiara Guerrera and Isabelle Sermet-Gaudelus
Int. J. Mol. Sci. 2020, 21(18), 6625; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186625 - 10 Sep 2020
Cited by 5 | Viewed by 2663
Abstract
Background: The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Methods: Urine samples were collected from 19 CF patients (among those 7 [...] Read more.
Background: The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Methods: Urine samples were collected from 19 CF patients (among those 7 were treated by cystic fibrosis transmembrane conductance regulator (CFTR) modulators), and 8 healthy subjects. Urine exosomal protein content was determined by high resolution mass spectrometry. Results: A heatmap of the differentially expressed proteins in urinary exosomes showed a clear separation between control and CF patients. Seventeen proteins were upregulated in CF patients (including epidermal growth factor receptor (EGFR); proteasome subunit beta type-6, transglutaminases, caspase 14) and 118 were downregulated (including glutathione S-transferases, superoxide dismutase, klotho, endosomal sorting complex required for transport, and matrisome proteins). Gene set enrichment analysis revealed 20 gene sets upregulated and 74 downregulated. Treatment with CFTR modulators yielded no significant modification of the proteomic content. These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Increased expression of EGFR and decreased expression of klotho and matrisome might play a central role in this CF kidney signature by inducing oxidation, inflammation, accelerated senescence, and abnormal tissue repair. Conclusions: Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications. Full article
(This article belongs to the Special Issue Molecular Research on Inherited Disorders)
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29 pages, 6222 KiB  
Article
Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress
by Michele Costanzo, Marianna Caterino, Armando Cevenini, Vincent Jung, Cerina Chhuon, Joanna Lipecka, Roberta Fedele, Ida Chiara Guerrera and Margherita Ruoppolo
Int. J. Mol. Sci. 2020, 21(14), 4998; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144998 - 15 Jul 2020
Cited by 36 | Viewed by 3312
Abstract
Methylmalonic acidemia (MMA) is a rare inborn error of metabolism caused by deficiency of the methylmalonyl-CoA mutase (MUT) enzyme. Downstream MUT deficiency, methylmalonic acid accumulates together with toxic metabolites from propionyl-CoA and other compounds upstream of the block in the enzyme pathway. The [...] Read more.
Methylmalonic acidemia (MMA) is a rare inborn error of metabolism caused by deficiency of the methylmalonyl-CoA mutase (MUT) enzyme. Downstream MUT deficiency, methylmalonic acid accumulates together with toxic metabolites from propionyl-CoA and other compounds upstream of the block in the enzyme pathway. The presentation is with life-threatening acidosis, respiratory distress, brain disturbance, hyperammonemia, and ketosis. Survivors develop poorly understood multi-organ damage, notably to the brain and kidneys. The HEK 293 cell line was engineered by CRISPR/Cas9 technology to knock out the MUT gene (MUT-KO). Shotgun label-free quantitative proteomics and bioinformatics analyses revealed potential damaging biological processes in MUT-deficient cells. MUT-KO induced alteration of cellular architecture and morphology, and ROS overproduction. We found the alteration of proteins involved in cytoskeleton and cell adhesion organization, cell trafficking, mitochondrial, and oxidative processes, as validated by the regulation of VIM, EXT2, SDC2, FN1, GLUL, and CHD1. Additionally, a cell model of MUT-rescuing was developed in order to control the specificity of MUT-KO effects. Globally, the proteomic landscape of MUT-KO suggests the cell model to have an increased susceptibility to propionate- and H2O2-induced stress through an impairment of the mitochondrial functionality and unbalances in the oxidation-reduction processes. Full article
(This article belongs to the Special Issue Molecular Research on Inherited Disorders)
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Review

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18 pages, 1219 KiB  
Review
Retinal Inflammation, Cell Death and Inherited Retinal Dystrophies
by Lorena Olivares-González, Sheyla Velasco, Isabel Campillo and Regina Rodrigo
Int. J. Mol. Sci. 2021, 22(4), 2096; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042096 - 20 Feb 2021
Cited by 57 | Viewed by 5645
Abstract
Inherited retinal dystrophies (IRDs) are a group of retinal disorders that cause progressive and severe loss of vision because of retinal cell death, mainly photoreceptor cells. IRDs include retinitis pigmentosa (RP), the most common IRD. IRDs present a genetic and clinical heterogeneity that [...] Read more.
Inherited retinal dystrophies (IRDs) are a group of retinal disorders that cause progressive and severe loss of vision because of retinal cell death, mainly photoreceptor cells. IRDs include retinitis pigmentosa (RP), the most common IRD. IRDs present a genetic and clinical heterogeneity that makes it difficult to achieve proper treatment. The progression of IRDs is influenced, among other factors, by the activation of the immune cells (microglia, macrophages, etc.) and the release of inflammatory molecules such as chemokines and cytokines. Upregulation of tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, is found in IRDs. This cytokine may influence photoreceptor cell death. Different cell death mechanisms are proposed, including apoptosis, necroptosis, pyroptosis, autophagy, excessive activation of calpains, or parthanatos for photoreceptor cell death. Some of these cell death mechanisms are linked to TNFα upregulation and inflammation. Therapeutic approaches that reduce retinal inflammation have emerged as useful therapies for slowing down the progression of IRDs. We focused this review on the relationship between retinal inflammation and the different cell death mechanisms involved in RP. We also reviewed the main anti-inflammatory therapies for the treatment of IRDs. Full article
(This article belongs to the Special Issue Molecular Research on Inherited Disorders)
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14 pages, 1316 KiB  
Review
Biomarkers for Lysosomal Storage Disorders with an Emphasis on Mass Spectrometry
by Ryuichi Mashima, Torayuki Okuyama and Mari Ohira
Int. J. Mol. Sci. 2020, 21(8), 2704; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082704 - 14 Apr 2020
Cited by 11 | Viewed by 7403
Abstract
Lysosomal storage disorders (LSDs) are characterized by an accumulation of various substances, such as sphingolipids, mucopolysaccharides, and oligosaccharides. The LSD enzymes responsible for the catabolism are active at acidic pH in the lysosomal compartment. In addition to the classically established lysosomal degradation biochemistry, [...] Read more.
Lysosomal storage disorders (LSDs) are characterized by an accumulation of various substances, such as sphingolipids, mucopolysaccharides, and oligosaccharides. The LSD enzymes responsible for the catabolism are active at acidic pH in the lysosomal compartment. In addition to the classically established lysosomal degradation biochemistry, recent data have suggested that lysosome plays a key role in the autophagy where the fusion of autophagosome and lysosome facilitates the degradation of amino acids. A failure in the lysosomal function leads to a variety of manifestations, including neurovisceral disorders. While affected individuals appear to be normal at birth, they gradually become symptomatic in childhood. Biomarkers for each condition have been well-documented and their proper selection helps to perform accurate clinical diagnoses. Based on the natural history of disorders, it is now evident that the existing treatment becomes most effective when initiated during presymptomatic period. Neonatal screening provides such a platform for inborn error of metabolism in general and is now expanding to LSDs as well. These are implemented in some areas and countries, including Taiwan and the U.S. In this short review, we will discuss several issues on some selected biomarkers for LSDs involving Fabry, Niemann–Pick disease type C, mucopolysaccharidosis, and oligosaccharidosis, with a focus on mass spectrometry application to biomarker discovery and detection. Full article
(This article belongs to the Special Issue Molecular Research on Inherited Disorders)
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