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Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases
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Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 35662

Special Issue Editor

Dr. Angel L. Pey

E-Mail Website
Guest Editor
Department of Physical Chemistry, University of Granada, Granada, Spain
Interests: protein biophysics; protein–ligand interactions; protein structure and dynamics; protein stability; protein degradation; enzymology; conformational diseases; pharmacological therapies; genotype–phenotype correlations; pathogenic mechanisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Background: Advances in whole-genome sequencing technologies are unraveling an enormous genetic variability in the human population. However, our ability to establish the pathogenicity and disease severity of frequent and rare mutations is still very limited. This ability can be improved by obtaining a deep understanding of the molecular mechanisms leading to disease, thus paving the way for the development novel therapeutic approaches targeting specific mechanisms.

Aim and Scope: To provide an updated view on research aimed at establishing genotype–phenotype correlations, characterizing pathogenic mechanisms at the molecular level, and to developing genotype-specific therapies in metabolic diseases.

History: Inherited metabolic diseases are often caused by missense mutations that lead to enzyme loss-of-function. These diseases may affect approximately one hundred million people worldwide. In many cases, these diseases are life-threatening and lack efficient treatments. The development of novel and efficient therapies would certainly benefit from an increased capacity to establish genotype–phenotype correlations through a detailed understanding of the molecular mechanisms underlying these diseases.

Cutting-edge research: We aim to publish studies that use state-of-the-art approaches from molecular genetics, biochemistry, biophysics, molecular and structural biology, and medicinal chemistry. Multidisciplinary studies combining several of these approaches are particularly welcome.

We are soliciting papers addressing mainly (but not limited to) the following issues on metabolic diseases: i) studies on genotype–phenotype correlations carried out using experimental, computational, or bioinformatic approaches; ii) manuscripts that improve our understanding of allele-specific pathogenic mechanisms; iii) research on the development and validation of novel therapeutic approaches.

Dr. Angel L. Pey
Guest Editor

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. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • genetic mutation
  • metabolic disease
  • pathogenic mechanism
  • genotype–phenotype correlations
  • protein structure and function
  • therapeutic approaches

Published Papers (8 papers)

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Editorial

Jump to: Research, Review

4 pages, 7727 KiB  
Editorial
Molecular Mechanisms, Genotype–Phenotype Correlations and Patient-Specific Treatments in Inherited Metabolic Diseases
by Angel L. Pey
J. Pers. Med. 2023, 13(1), 117; https://doi.org/10.3390/jpm13010117 - 05 Jan 2023
Viewed by 835
Abstract
Advances in DNA sequencing technologies are revealing a vast genetic heterogeneity in human population, which may predispose to metabolic alterations if the activity of metabolic enzymes is affected [...] Full article
(This article belongs to the Special Issue Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases)
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Research

Jump to: Editorial, Review

11 pages, 1419 KiB  
Article
Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria
by Ganeko Bernardo-Seisdedos, Jorge M. Charco, Itxaso SanJuan, Sandra García-Martínez, Pedro Urquiza, Hasier Eraña, Joaquín Castilla and Oscar Millet
J. Pers. Med. 2021, 11(6), 485; https://doi.org/10.3390/jpm11060485 - 28 May 2021
Cited by 2 | Viewed by 2657
Abstract
Congenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown that [...] Read more.
Congenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown that it also acts as a pharmacological chaperone in CEP, presenting a specific activity in deleterious mutations in UROIIIS. Despite CPX is active at subtoxic concentrations, acute gastrointestinal (GI) toxicity was found due to the precipitation in the stomach of the active compound and subsequent accumulation in the intestine. To increase its systemic availability, we carried out pharmacokinetic (PK) and pharmacodynamic (PD) studies using alternative formulations for CPX. Such strategy effectively suppressed GI toxicity in WT mice and in a mouse model of the CEP disease (UROIIISP248Q/P248Q). In terms of activity, phosphorylation of CPX yielded good results in CEP cellular models but showed limited activity when administered to the CEP mouse model. These results highlight the need of a proper formulation for pharmacological chaperones used in the treatment of rare diseases. Full article
(This article belongs to the Special Issue Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases)
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19 pages, 2094 KiB  
Article
Dimerization Drives Proper Folding of Human Alanine:Glyoxylate Aminotransferase But Is Dispensable for Peroxisomal Targeting
by Mirco Dindo, Giulia Ambrosini, Elisa Oppici, Angel L. Pey, Peter J. O’Toole, Joanne L. Marrison, Ian E. G. Morrison, Elena Butturini, Silvia Grottelli, Claudio Costantini and Barbara Cellini
J. Pers. Med. 2021, 11(4), 273; https://doi.org/10.3390/jpm11040273 - 06 Apr 2021
Cited by 6 | Viewed by 2355
Abstract
Peroxisomal matrix proteins are transported into peroxisomes in a fully-folded state, but whether multimeric proteins are imported as monomers or oligomers is still disputed. Here, we used alanine:glyoxylate aminotransferase (AGT), a homodimeric pyridoxal 5′-phosphate (PLP)-dependent enzyme, whose deficit causes primary hyperoxaluria type I [...] Read more.
Peroxisomal matrix proteins are transported into peroxisomes in a fully-folded state, but whether multimeric proteins are imported as monomers or oligomers is still disputed. Here, we used alanine:glyoxylate aminotransferase (AGT), a homodimeric pyridoxal 5′-phosphate (PLP)-dependent enzyme, whose deficit causes primary hyperoxaluria type I (PH1), as a model protein and compared the intracellular behavior and peroxisomal import of native dimeric and artificial monomeric forms. Monomerization strongly reduces AGT intracellular stability and increases its aggregation/degradation propensity. In addition, monomers are partly retained in the cytosol. To assess possible differences in import kinetics, we engineered AGT to allow binding of a membrane-permeable dye and followed its intracellular trafficking without interfering with its biochemical properties. By fluorescence recovery after photobleaching, we measured the import rate in live cells. Dimeric and monomeric AGT displayed a similar import rate, suggesting that the oligomeric state per se does not influence import kinetics. However, when dimerization is compromised, monomers are prone to misfolding events that can prevent peroxisomal import, a finding crucial to predicting the consequences of PH1-causing mutations that destabilize the dimer. Treatment with pyridoxine of cells expressing monomeric AGT promotes dimerization and folding, thus, demonstrating the chaperone role of PLP. Our data support a model in which dimerization represents a potential key checkpoint in the cytosol at the crossroad between misfolding and correct targeting, a possible general mechanism for other oligomeric peroxisomal proteins. Full article
(This article belongs to the Special Issue Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases)
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18 pages, 3169 KiB  
Article
Genetic Ablation of MiR-22 Fosters Diet-Induced Obesity and NAFLD Development
by Monika Gjorgjieva, Cyril Sobolewski, Anne-Sophie Ay, Daniel Abegg, Marta Correia de Sousa, Dorothea Portius, Flavien Berthou, Margot Fournier, Christine Maeder, Pia Rantakari, Fu-Ping Zhang, Matti Poutanen, Didier Picard, Xavier Montet, Serge Nef, Alexander Adibekian and Michelangelo Foti
J. Pers. Med. 2020, 10(4), 170; https://doi.org/10.3390/jpm10040170 - 14 Oct 2020
Cited by 22 | Viewed by 3904
Abstract
miR-22 is one of the most abundant miRNAs in the liver and alterations of its hepatic expression have been associated with the development of hepatic steatosis and insulin resistance, as well as cancer. However, the pathophysiological roles of miR-22-3p in the deregulated hepatic [...] Read more.
miR-22 is one of the most abundant miRNAs in the liver and alterations of its hepatic expression have been associated with the development of hepatic steatosis and insulin resistance, as well as cancer. However, the pathophysiological roles of miR-22-3p in the deregulated hepatic metabolism with obesity and cancer remains poorly characterized. Herein, we observed that alterations of hepatic miR-22-3p expression with non-alcoholic fatty liver disease (NAFLD) in the context of obesity are not consistent in various human cohorts and animal models in contrast to the well-characterized miR-22-3p downregulation observed in hepatic cancers. To unravel the role of miR-22 in obesity-associated NAFLD, we generated constitutive Mir22 knockout (miR-22KO) mice, which were subsequently rendered obese by feeding with fat-enriched diet. Functional NAFLD- and obesity-associated metabolic parameters were then analyzed. Insights about the role of miR-22 in NAFLD associated with obesity were further obtained through an unbiased proteomic analysis of miR-22KO livers from obese mice. Metabolic processes governed by miR-22 were finally investigated in hepatic transformed cancer cells. Deletion of Mir22 was asymptomatic when mice were bred under standard conditions, except for an onset of glucose intolerance. However, when challenged with a high fat-containing diet, Mir22 deficiency dramatically exacerbated fat mass gain, hepatomegaly, and liver steatosis in mice. Analyses of explanted white adipose tissue revealed increased lipid synthesis, whereas mass spectrometry analysis of the liver proteome indicated that Mir22 deletion promotes hepatic upregulation of key enzymes in glycolysis and lipid uptake. Surprisingly, expression of miR-22-3p in Huh7 hepatic cancer cells triggers, in contrast to our in vivo observations, a clear induction of a Warburg effect with an increased glycolysis and an inhibited mitochondrial respiration. Together, our study indicates that miR-22-3p is a master regulator of the lipid and glucose metabolism with differential effects in specific organs and in transformed hepatic cancer cells, as compared to non-tumoral tissue. Full article
(This article belongs to the Special Issue Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases)
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Review

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28 pages, 2253 KiB  
Review
Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency
by Gyrid Nygaard, Peter D. Szigetvari, Ann Kari Grindheim, Peter Ruoff, Aurora Martinez, Jan Haavik, Rune Kleppe and Marte I. Flydal
J. Pers. Med. 2021, 11(11), 1186; https://doi.org/10.3390/jpm11111186 - 12 Nov 2021
Cited by 8 | Viewed by 3729
Abstract
Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, GCH1 gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme [...] Read more.
Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, GCH1 gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in GCH1 are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies. Although termed DRD, a subset of patients responds poorly to L-DOPA. As this is regularly observed in severe cases of TH deficiency (THD), there is an urgent demand for more adequate or personalized treatment options. TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment. In this expert opinion review, we focus on THD pathophysiology and ongoing efforts to develop novel therapeutics for this rare disorder. We also describe how different modeling approaches can be used to improve genotype to phenotype predictions and to develop in silico testing of treatment strategies. We further discuss the current status of mathematical modeling of catecholamine synthesis and how such models can be used together with biochemical data to improve treatment of DRD patients. Full article
(This article belongs to the Special Issue Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases)
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15 pages, 1316 KiB  
Review
Galactosemia: Towards Pharmacological Chaperones
by Samantha Banford, Thomas J. McCorvie, Angel L. Pey and David J. Timson
J. Pers. Med. 2021, 11(2), 106; https://doi.org/10.3390/jpm11020106 - 07 Feb 2021
Cited by 13 | Viewed by 4336
Abstract
Galactosemia is a rare inherited metabolic disease resulting from mutations in the four genes which encode enzymes involved in the metabolism of galactose. The current therapy, the removal of galactose from the diet, is inadequate. Consequently, many patients suffer lifelong physical and cognitive [...] Read more.
Galactosemia is a rare inherited metabolic disease resulting from mutations in the four genes which encode enzymes involved in the metabolism of galactose. The current therapy, the removal of galactose from the diet, is inadequate. Consequently, many patients suffer lifelong physical and cognitive disability. The phenotype varies from almost asymptomatic to life-threatening disability. The fundamental biochemical cause of the disease is a decrease in enzymatic activity due to failure of the affected protein to fold and/or function correctly. Many novel therapies have been proposed for the treatment of galactosemia. Often, these are designed to treat the symptoms and not the fundamental cause. Pharmacological chaperones (PC) (small molecules which correct the folding of misfolded proteins) represent an exciting potential therapy for galactosemia. In theory, they would restore enzyme function, thus preventing downstream pathological consequences. In practice, no PCs have been identified for potential application in galactosemia. Here, we review the biochemical basis of the disease, identify opportunities for the application of PCs and describe how these might be discovered. We will conclude by considering some of the clinical issues which will affect the future use of PCs in the treatment of galactosemia. Full article
(This article belongs to the Special Issue Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases)
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14 pages, 1019 KiB  
Review
Current and Future Treatments for Classic Galactosemia
by Britt Delnoy, Ana I. Coelho and Maria Estela Rubio-Gozalbo
J. Pers. Med. 2021, 11(2), 75; https://doi.org/10.3390/jpm11020075 - 28 Jan 2021
Cited by 19 | Viewed by 12493
Abstract
Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models [...] Read more.
Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models of classic galactosemia that (partly) mimic the biochemical and clinical phenotypes and the resolution of the crystal structure of GALT have provided important insights; however, precise pathophysiology remains to be elucidated. Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to (i) restore GALT activity, (ii) influence the cascade of events and (iii) address the clinical picture. This review attempts to provide an overview on the latest advancements in therapy approaches. Full article
(This article belongs to the Special Issue Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases)
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30 pages, 1989 KiB  
Review
Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias
by Maria Dolores Moya-Garzon, Jose Antonio Gomez-Vidal, Alfonso Alejo-Armijo, Joaquin Altarejos, Juan Roberto Rodriguez-Madoz, Miguel Xavier Fernandes, Eduardo Salido, Sofia Salido and Monica Diaz-Gavilan
J. Pers. Med. 2021, 11(2), 74; https://doi.org/10.3390/jpm11020074 - 27 Jan 2021
Cited by 17 | Viewed by 4065
Abstract
Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread [...] Read more.
Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option. Full article
(This article belongs to the Special Issue Genotype–Phenotype Relationships, Molecular Mechanisms and Personalized Therapy of Metabolic Diseases)
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