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Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

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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 (15 September 2021) | Viewed by 62794

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Dr. Ivano Condò

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Department of Biomedicine and Prevention, School of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: frataxin; Friedreich’s ataxia; mitochondria; programmed cell death; molecular medicine
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(This is a new joint type of Special Issue belongs to IJMS journal and Encyclopedia platfrom, you can get more information from https://encyclopedia.pub about Encyclopedia platfrom)

Dear Colleagues,

Most rare diseases we know arise from single gene mutations. In fact, the number of rare monogenic diseases is growing continuously, and to date, near 4000 single-gene inherited disorders have been characterized. Pathogenic mutations typically affect the coding regions, thus resulting in classical amino acid substitutions responsible for loss- or gain-of-function in protein products. However, several disease-causing defects originate from regulatory and non-coding DNA regions, ultimately affecting gene expression by transcriptional and/or post-transcriptional mechanisms.

Understanding the molecular pathophysiology of a rare monogenic disease has a double value. The identification of alterations that occur in specific genes, proteins, and pathways allows the translation of scientific advances into novel therapeutic approaches for these traits. Moreover, the investigation of rare monogenic diseases has the power to reveal fundamental biological mechanisms that would otherwise remain unknown.

This Special Issue will focus on the key molecular mechanisms that are affected within a rare monogenic disorder, such as those involving gene expression, molecular pathways, redox homeostasis, organelle stress, and cell death. Studies addressing new experimental therapies to target specific mechanisms in a monogenic disease, including drug discovery, drug repositioning, gene therapy, and protein- and nucleic acid-based therapeutics are relevant to this Special Issue. Original research articles and systematic reviews are welcome.

Dr. Ivano Condò
Guest Editor

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Keywords

Monogenic disease
Gene expression
Molecular pathways
Organelle dysfunctions
Molecular medicine
Drug discovery
Molecular therapy

Related Special Issues

Published Papers (13 papers)

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Editorial

Jump to: Research, Review

4 pages, 215 KiB

Open AccessEditorial

Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

by Ivano Condò

Int. J. Mol. Sci. 2022, 23(12), 6525; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126525 - 10 Jun 2022

Cited by 1 | Viewed by 1578

Abstract

A rare disease is defined by its low prevalence in the general population [...] Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

Research

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17 pages, 3290 KiB

Open AccessArticle

Treatment of Erythroid Precursor Cells from β-Thalassemia Patients with Cinchona Alkaloids: Induction of Fetal Hemoglobin Production

by Cristina Zuccato, Lucia Carmela Cosenza, Matteo Zurlo, Ilaria Lampronti, Monica Borgatti, Chiara Scapoli, Roberto Gambari and Alessia Finotti

Int. J. Mol. Sci. 2021, 22(24), 13433; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413433 - 14 Dec 2021

Cited by 16 | Viewed by 2751

Abstract

β-thalassemias are among the most common inherited hemoglobinopathies worldwide and are the result of autosomal mutations in the gene encoding β-globin, causing an absence or low-level production of adult hemoglobin (HbA). Induction of fetal hemoglobin (HbF) is considered to be of key importance for the development of therapeutic protocols for β-thalassemia and novel HbF inducers need to be proposed for pre-clinical development. The main purpose on this study was to analyze Cinchona alkaloids (cinchonidine, quinidine and cinchonine) as natural HbF-inducing agents in human erythroid cells. The analytical methods employed were Reverse Transcription quantitative real-time PCR (RT-qPCR) (for quantification of γ-globin mRNA) and High Performance Liquid Chromatography (HPLC) (for analysis of the hemoglobin pattern). After an initial analysis using the K562 cell line as an experimental model system, showing induction of hemoglobin and γ-globin mRNA, we verified whether the two more active compounds, cinchonidine and quinidine, were able to induce HbF in erythroid progenitor cells isolated from β-thalassemia patients. The data obtained demonstrate that cinchonidine and quinidine are potent inducers of γ-globin mRNA and HbF in erythroid progenitor cells isolated from nine β-thalassemia patients. In addition, both compounds were found to synergize with the HbF inducer sirolimus for maximal production of HbF. The data obtained strongly indicate that these compounds deserve consideration in the development of pre-clinical approaches for therapeutic protocols of β-thalassemia. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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23 pages, 2451 KiB

Open AccessArticle

High Mutational Heterogeneity, and New Mutations in the Human Coagulation Factor V Gene. Future Perspectives for Factor V Deficiency Using Recombinant and Advanced Therapies

by Sara Bernal, Irene Pelaez, Laura Alias, Manel Baena, Juan A. De Pablo-Moreno, Luis J. Serrano, M. Dolores Camero, Eduardo F. Tizzano, Ruben Berrueco and Antonio Liras

Int. J. Mol. Sci. 2021, 22(18), 9705; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189705 - 08 Sep 2021

Cited by 9 | Viewed by 4225

Abstract

Factor V is an essential clotting factor that plays a key role in the blood coagulation cascade on account of its procoagulant and anticoagulant activity. Eighty percent of circulating factor V is produced in the liver and the remaining 20% originates in the α-granules of platelets. In humans, the factor V gene is about 80 kb in size; it is located on chromosome 1q24.2, and its cDNA is 6914 bp in length. Furthermore, nearly 190 mutations have been reported in the gene. Factor V deficiency is an autosomal recessive coagulation disorder associated with mutations in the factor V gene. This hereditary coagulation disorder is clinically characterized by a heterogeneous spectrum of hemorrhagic manifestations ranging from mucosal or soft-tissue bleeds to potentially fatal hemorrhages. Current treatment of this condition consists in the administration of fresh frozen plasma and platelet concentrates. This article describes the cases of two patients with severe factor V deficiency, and of their parents. A high level of mutational heterogeneity of factor V gene was identified, nonsense mutations, frameshift mutations, missense changes, synonymous sequence variants and intronic changes. These findings prompted the identification of a new mutation in the human factor V gene, designated as Jaén-1, which is capable of altering the procoagulant function of factor V. In addition, an update is provided on the prospects for the treatment of factor V deficiency on the basis of yet-to-be-developed recombinant products or advanced gene and cell therapies that could potentially correct this hereditary disorder. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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17 pages, 6123 KiB

Open AccessArticle

Gender-Dependent Phenotype in Polycystic Kidney Disease Is Determined by Differential Intracellular Ca²⁺ Signals

by Khaoula Talbi, Inês Cabrita, Rainer Schreiber and Karl Kunzelmann

Int. J. Mol. Sci. 2021, 22(11), 6019; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116019 - 02 Jun 2021

Cited by 10 | Viewed by 3083

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by loss of function of PKD1 (polycystin 1) or PKD2 (polycystin 2). The Ca²⁺-activated Cl⁻ channel TMEM16A has a central role in ADPKD. Expression and function of TMEM16A is upregulated in ADPKD which causes enhanced intracellular Ca²⁺ signaling, cell proliferation, and ion secretion. We analyzed kidneys from Pkd1 knockout mice and found a more pronounced phenotype in males compared to females, despite similar levels of expression for renal tubular TMEM16A. Cell proliferation, which is known to be enhanced with loss of Pkd1^−/−, was larger in male when compared to female Pkd1^−/− cells. This was paralleled by higher basal intracellular Ca²⁺ concentrations in primary renal epithelial cells isolated from Pkd1^−/− males. The results suggest enhanced intracellular Ca²⁺ levels contributing to augmented cell proliferation and cyst development in male kidneys. Enhanced resting Ca²⁺ also caused larger basal chloride currents in male primary cells, as detected in patch clamp recordings. Incubation of mouse primary cells, mCCDcl1 collecting duct cells or M1 collecting duct cells with dihydrotestosterone (DHT) enhanced basal Ca²⁺ levels and increased basal and ATP-stimulated TMEM16A chloride currents. Taken together, the more severe cystic phenotype in males is likely to be caused by enhanced cell proliferation, possibly due to enhanced basal and ATP-induced intracellular Ca²⁺ levels, leading to enhanced TMEM16A currents. Augmented Ca²⁺ signaling is possibly due to enhanced expression of Ca²⁺ transporting/regulating proteins. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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24 pages, 6340 KiB

Open AccessArticle

Treatment with a GSK-3β/HDAC Dual Inhibitor Restores Neuronal Survival and Maturation in an In Vitro and In Vivo Model of CDKL5 Deficiency Disorder

by Manuela Loi, Laura Gennaccaro, Claudia Fuchs, Stefania Trazzi, Giorgio Medici, Giuseppe Galvani, Nicola Mottolese, Marianna Tassinari, Roberto Rimondini Giorgini, Andrea Milelli and Elisabetta Ciani

Int. J. Mol. Sci. 2021, 22(11), 5950; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115950 - 31 May 2021

Cited by 8 | Viewed by 3020

Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a rare neurodevelopmental disorder characterized by early-onset seizures and severe cognitive, motor, and visual impairments. To date there are no therapies for CDKL5 deficiency disorder (CDD). In view of the severity of the neurological phenotype of CDD patients it is widely assumed that CDKL5 may influence the activity of a variety of cellular pathways, suggesting that an approach aimed at targeting multiple cellular pathways simultaneously might be more effective for CDD. Previous findings showed that a single-target therapy aimed at normalizing impaired GSK-3β or histone deacetylase (HDAC) activity improved neurodevelopmental and cognitive alterations in a mouse model of CDD. Here we tested the ability of a first-in-class GSK-3β/HDAC dual inhibitor, Compound 11 (C11), to rescue CDD-related phenotypes. We found that C11, through inhibition of GSK-3β and HDAC6 activity, not only restored maturation, but also significantly improved survival of both human CDKL5-deficient cells and hippocampal neurons from Cdkl5 KO mice. Importantly, in vivo treatment with C11 restored synapse development, neuronal survival, and microglia over-activation, and improved motor and cognitive abilities of Cdkl5 KO mice, suggesting that dual GSK-3β/HDAC6 inhibitor therapy may have a wider therapeutic benefit in CDD patients. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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Review

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24 pages, 12765 KiB

Open AccessReview

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Bartter and Gitelman Syndromes: A Primer for Clinicians

by Laura Nuñez-Gonzalez, Noa Carrera and Miguel A. Garcia-Gonzalez

Int. J. Mol. Sci. 2021, 22(21), 11414; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111414 - 22 Oct 2021

Cited by 25 | Viewed by 9165

Abstract

Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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25 pages, 1111 KiB

Open AccessReview

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

by Luis M. Valor, Jorge C. Morales, Irati Hervás-Corpión and Rosario Marín

Int. J. Mol. Sci. 2021, 22(16), 8368; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168368 - 04 Aug 2021

Cited by 7 | Viewed by 3507

Abstract

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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20 pages, 643 KiB

Open AccessReview

Gene Therapy in Hemophilia: Recent Advances

by E. Carlos Rodríguez-Merchán, Juan Andres De Pablo-Moreno and Antonio Liras

Int. J. Mol. Sci. 2021, 22(14), 7647; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147647 - 17 Jul 2021

Cited by 26 | Viewed by 12339

Abstract

Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. However, these therapies are associated with immunogenicity and hepatotoxicity. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. It is essential that both physicians and patients be informed about the potential benefits and risks of the new therapies, and a register of gene therapy patients be kept with information of the efficacy and long-term adverse events associated with the treatments administered. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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13 pages, 544 KiB

Open AccessReview

Role of miR-24 in Multiple Endocrine Neoplasia Type 1: A Potential Target for Molecular Therapy

by Francesca Marini and Maria Luisa Brandi

Int. J. Mol. Sci. 2021, 22(14), 7352; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147352 - 08 Jul 2021

Cited by 9 | Viewed by 2422

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited multiple cancer syndrome of neuroendocrine tissues. Tumors are caused by an inherited germinal heterozygote inactivating mutation of the MEN1 tumor suppressor gene, followed by a somatic loss of heterozygosity (LOH) of the MEN1 gene in target neuroendocrine cells, mainly at parathyroids, pancreas islets, and anterior pituitary. Over 1500 different germline and somatic mutations of the MEN1 gene have been identified, but the syndrome is completely missing a direct genotype-phenotype correlation, thus supporting the hypothesis that exogenous and endogenous factors, other than MEN1 specific mutation, are involved in MEN1 tumorigenesis and definition of individual clinical phenotype. Epigenetic factors, such as microRNAs (miRNAs), are strongly suspected to have a role in MEN1 tumor initiation and development. Recently, a direct autoregulatory network between miR-24, MEN1 mRNA, and menin was demonstrated in parathyroids and endocrine pancreas, showing a miR-24-induced silencing of menin expression that could have a key role in initiation of tumors in MEN1-target neuroendocrine cells. Here, we review the current knowledge on the post-transcriptional regulation of MEN1 and menin expression by miR-24, and its possible direct role in MEN1 syndrome, describing the possibility and the potential approaches to target and silence this miRNA, to permit the correct expression of the wild type menin, and thereby prevent the development of cancers in the target tissues. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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17 pages, 1602 KiB

Open AccessReview

Purine Nucleotides Metabolism and Signaling in Huntington’s Disease: Search for a Target for Novel Therapies

by Marta Tomczyk, Talita Glaser, Ewa M. Slominska, Henning Ulrich and Ryszard T. Smolenski

Int. J. Mol. Sci. 2021, 22(12), 6545; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126545 - 18 Jun 2021

Cited by 13 | Viewed by 3230

Abstract

Huntington’s disease (HD) is a multi-system disorder that is caused by expanded CAG repeats within the exon-1 of the huntingtin (HTT) gene that translate to the polyglutamine stretch in the HTT protein. HTT interacts with the proteins involved in gene transcription, endocytosis, and metabolism. HTT may also directly or indirectly affect purine metabolism and signaling. We aimed to review existing data and discuss the modulation of the purinergic system as a new therapeutic target in HD. Impaired intracellular nucleotide metabolism in the HD affected system (CNS, skeletal muscle and heart) may lead to extracellular accumulation of purine metabolites, its unusual catabolism, and modulation of purinergic signaling. The mechanisms of observed changes might be different in affected systems. Based on collected findings, compounds leading to purine and ATP pool reconstruction as well as purinergic receptor activity modulators, i.e., P2X7 receptor antagonists, may be applied for HD treatment. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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22 pages, 2724 KiB

Open AccessReview

Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

by Adrian Cordido, Marta Vizoso-Gonzalez and Miguel A. Garcia-Gonzalez

Int. J. Mol. Sci. 2021, 22(12), 6523; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126523 - 17 Jun 2021

Cited by 16 | Viewed by 7020

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. Here, we review the clinics, treatment, genetics, and molecular basis of ARPKD, highlighting the most recent findings in the field. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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17 pages, 1625 KiB

Open AccessReview

Human α-Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease

by Andrea Modrego, Marilla Amaranto, Agustina Godino, Rosa Mendoza, José Luis Barra and José Luis Corchero

Int. J. Mol. Sci. 2021, 22(12), 6518; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126518 - 17 Jun 2021

Cited by 9 | Viewed by 4029

Abstract

Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the α-galactosidase A (GLA) enzyme. The absence of the enzyme or its activity results in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in different tissues, leading to a wide range of clinical manifestations. More than 1000 natural variants have been described in the GLA gene, most of them affecting proper protein folding and enzymatic activity. Currently, FD is treated by enzyme replacement therapy (ERT) or pharmacological chaperone therapy (PCT). However, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, organ/cell transplant, substrate reduction therapy, or gene therapy) are under extensive study. In this review, we summarize GLA mutants described so far and discuss their putative application for the development of novel drugs for the treatment of FD. Unfavorable mutants with lower activities and stabilities than wild-type enzymes could serve as tools for the development of new pharmacological chaperones. On the other hand, GLA mutants showing improved enzymatic activity have been identified and produced in vitro. Such mutants could overcome several complications associated with current ERT, as lower-dose infusions of these mutants could achieve a therapeutic effect equivalent to that of the wild-type enzyme. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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14 pages, 256 KiB

Open AccessReview

Gene Therapy for Mucopolysaccharidosis Type II—A Review of the Current Possibilities

by Paweł Zapolnik and Antoni Pyrkosz

Int. J. Mol. Sci. 2021, 22(11), 5490; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115490 - 23 May 2021

Cited by 16 | Viewed by 4478

Abstract

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder based on a mutation in the IDS gene that encodes iduronate 2-sulphatase. As a result, there is an accumulation of glycosaminoglycans—heparan sulphate and dermatan sulphate—in almost all body tissues, which leads to their dysfunction. Currently, the primary treatment is enzyme replacement therapy, which improves the course of the disease by reducing somatic symptoms, including hepatomegaly and splenomegaly. The enzyme, however, does not cross the blood–brain barrier, and no improvement in the function of the central nervous system has been observed in patients with the severe form of the disease. An alternative method of treatment that solves typical problems of enzyme replacement therapy is gene therapy, i.e., delivery of the correct gene to target cells through an appropriate vector. Much progress has been made in applying gene therapy for MPS II, from cellular models to human clinical trials. In this article, we briefly present the history and basics of gene therapy and discuss the current state of knowledge about the methods of this therapy in mucopolysaccharidosis type II. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies)

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