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Cells
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Molecular and Cellular Mechanisms of Rare Diseases
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Molecular and Cellular Mechanisms of Rare Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 23962

Special Issue Editor

Prof. Dr. Ritva Tikkanen

E-Mail Website
Guest Editor
Institute of Biochemistry, Medical Faculty, Justus-Liebig University of Giessen, Friedrichstrasse 24, D-35392 Giessen, Germany
Interests: lysosomal storage disorders; vesicular trafficking; endosomal sorting; lysosome biogenesis; mitochondrial diseases; autoimmune disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

According to the European definition, a disease is considered as a rare one if it affects less than 1 person in 2.000. However, there are about 7 to 8 thousand different rare diseases. Therefore, even though a single rare disease may only affect a few patients, all rare diseases together place a substantial health burden. Some rare diseases also show a varying geographical distribution, being rare in most parts of the world, but more common in specific, restricted areas. Many rare diseases are of genetic origin and show an enrichment in specific populations.

The patients suffering from rare diseases frequently face the fact that there is no specific or curative therapy available for the disease, and the treatment frequently remains symptomatic. However, in recent years, there has been substantial interest arising towards the characterization of the molecular mechanisms of rare diseases. One important factor that has boosted the interest is the realization that some of the rare diseases may share common molecular mechanisms with more common diseases, and that the information gained over the mechanisms of the rare diseases may help to develop therapies for the common ones. For example, endosomal dysfunction appears to be a common feature between lysosomal diseases, which are rare, and blockbuster diseases such as Alzheimer's disease.

The purpose of this Special Issue is to provide an overview of the cellular and molecular mechanisms of rare diseases, especially of the genetic ones. Both original research articles and reviews are suitable for this special issue. We especially welcome contributions that address the cellular and molecular features that may connect rare diseases to more common ones. Manusripts addressing novel therapeutic prospects are also highly welcome.

Prof. Dr. Ritva Tikkanen
Guest Editor

Manuscript Submission Information

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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. Cells is an international peer-reviewed open access semimonthly 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 2700 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

  • Rare diseases
  • genetic diseases
  • Orphan diseases

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Published Papers (6 papers)

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Research

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22 pages, 6180 KiB  
Article
Therapeutic Benefit of Galectin-1: Beyond Membrane Repair, a Multifaceted Approach to LGMD2B
by Mary L. Vallecillo-Zúniga, Peter Daniel Poulson, Jacob S. Luddington, Christian J. Arnold, Matthew Rathgeber, Braden C. Kartchner, Spencer Hayes, Hailie Gill, Jonard C. Valdoz, Jonathan L. Spallino, Seth Garfield, Ethan L. Dodson, Connie M. Arthur, Sean R. Stowell and Pam M. Van Ry
Cells 2021, 10(11), 3210; https://doi.org/10.3390/cells10113210 - 17 Nov 2021
Cited by 3 | Viewed by 4319
Abstract
Two of the main pathologies characterizing dysferlinopathies are disrupted muscle membrane repair and chronic inflammation, which lead to symptoms of muscle weakness and wasting. Here, we used recombinant human Galectin-1 (rHsGal-1) as a therapeutic for LGMD2B mouse and human models. Various redox and [...] Read more.
Two of the main pathologies characterizing dysferlinopathies are disrupted muscle membrane repair and chronic inflammation, which lead to symptoms of muscle weakness and wasting. Here, we used recombinant human Galectin-1 (rHsGal-1) as a therapeutic for LGMD2B mouse and human models. Various redox and multimerization states of Gal-1 show that rHsGal-1 is the most effective form in both increasing muscle repair and decreasing inflammation, due to its monomer-dimer equilibrium. Dose-response testing shows an effective 25-fold safety profile between 0.54 and 13.5 mg/kg rHsGal-1 in Bla/J mice. Mice treated weekly with rHsGal-1 showed downregulation of canonical NF-κB inflammation markers, decreased muscle fat deposition, upregulated anti-inflammatory cytokines, increased membrane repair, and increased functional movement compared to non-treated mice. Gal-1 treatment also resulted in a positive self-upregulation loop of increased endogenous Gal-1 expression independent of NF-κB activation. A similar reduction in disease pathologies in patient-derived human cells demonstrates the therapeutic potential of Gal-1 in LGMD2B patients. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Rare Diseases)
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22 pages, 7824 KiB  
Article
Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis
by Antje Banning and Ritva Tikkanen
Cells 2021, 10(11), 2813; https://doi.org/10.3390/cells10112813 - 20 Oct 2021
Cited by 7 | Viewed by 3248
Abstract
Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for [...] Read more.
Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutations have been developed in the past, but they are very expensive and require invasive, life-long administration. Thus, modulation of splicing by means of small molecules is of great interest for the therapy of genetic diseases resulting from splice-site mutations. Using minigene approaches and patient cells, we here show that methylxanthine derivatives and the food-derived flavonoid luteolin are able to enhance the correct splicing of the AGA mRNA with a splice-site mutation c.128-2A>G in aspartylglucosaminuria, and result in increased AGA enzyme activity in patient cells. Furthermore, we also show that one of the most common disease causing TPP1 gene variants in classic late infantile neuronal ceroid lipofuscinosis may also be amenable to splicing modulation using similar substances. Therefore, our data suggest that splice-modulation with small molecules may be a valid therapy option for lysosomal storage disorders. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Rare Diseases)
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24 pages, 2822 KiB  
Article
Metabolomic Fingerprint of Mecp2-Deficient Mouse Cortex: Evidence for a Pronounced Multi-Facetted Metabolic Component in Rett Syndrome
by Gocha Golubiani, Vincenzo Lagani, Revaz Solomonia and Michael Müller
Cells 2021, 10(9), 2494; https://doi.org/10.3390/cells10092494 - 21 Sep 2021
Cited by 13 | Viewed by 3138
Abstract
Using unsupervised metabolomics, we defined the complex metabolic conditions in the cortex of a mouse model of Rett syndrome (RTT). RTT, which represents a cause of mental and cognitive disabilities in females, results in profound cognitive impairment with autistic features, motor disabilities, seizures, [...] Read more.
Using unsupervised metabolomics, we defined the complex metabolic conditions in the cortex of a mouse model of Rett syndrome (RTT). RTT, which represents a cause of mental and cognitive disabilities in females, results in profound cognitive impairment with autistic features, motor disabilities, seizures, gastrointestinal problems, and cardiorespiratory irregularities. Typical RTT originates from mutations in the X-chromosomal methyl-CpG-binding-protein-2 (Mecp2) gene, which encodes a transcriptional modulator. It then causes a deregulation of several target genes and metabolic alterations in the nervous system and peripheral organs. We identified 101 significantly deregulated metabolites in the Mecp2-deficient cortex of adult male mice; 68 were increased and 33 were decreased compared to wildtypes. Pathway analysis identified 31 mostly upregulated metabolic pathways, in particular carbohydrate and amino acid metabolism, key metabolic mitochondrial/extramitochondrial pathways, and lipid metabolism. In contrast, neurotransmitter-signaling is dampened. This metabolic fingerprint of the Mecp2-deficient cortex of severely symptomatic mice provides further mechanistic insights into the complex RTT pathogenesis. The deregulated pathways that were identified—in particular the markedly affected amino acid and carbohydrate metabolism—confirm a complex and multifaceted metabolic component in RTT, which in turn signifies putative therapeutic targets. Furthermore, the deregulated key metabolites provide a choice of potential biomarkers for a more detailed rating of disease severity and disease progression. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Rare Diseases)
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21 pages, 6104 KiB  
Article
A Single Amino Acid Residue Regulates PTEN-Binding and Stability of the Spinal Muscular Atrophy Protein SMN
by Sebastian Rademacher, Nora T. Detering, Tobias Schüning, Robert Lindner, Pamela Santonicola, Inga-Maria Wefel, Janina Dehus, Lisa M. Walter, Hella Brinkmann, Agathe Niewienda, Katharina Janek, Miguel A. Varela, Melissa Bowerman, Elia Di Schiavi and Peter Claus
Cells 2020, 9(11), 2405; https://doi.org/10.3390/cells9112405 - 3 Nov 2020
Cited by 6 | Viewed by 3118
Abstract
Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our [...] Read more.
Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Rare Diseases)
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29 pages, 4333 KiB  
Article
Tafazzin Mutation Affecting Cardiolipin Leads to Increased Mitochondrial Superoxide Anions and Mitophagy Inhibition in Barth Syndrome
by Patrice X. Petit, Hector Ardilla-Osorio, Lucile Penalvia and Nathan E. Rainey
Cells 2020, 9(10), 2333; https://doi.org/10.3390/cells9102333 - 21 Oct 2020
Cited by 16 | Viewed by 4927
Abstract
Tafazzin is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mutations of the tafazzin gene cause Barth syndrome, which is characterized by mitochondrial dysfunction and dilated cardiomyopathy, leading to premature death. However, the molecular mechanisms [...] Read more.
Tafazzin is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mutations of the tafazzin gene cause Barth syndrome, which is characterized by mitochondrial dysfunction and dilated cardiomyopathy, leading to premature death. However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. We again highlight the fact that the tafazzin deficiency is also linked to defective oxidative phosphorylation associated with oxidative stress. All the mitochondrial events are positioned in a context where mitophagy is a key element in mitochondrial quality control. Here, we investigated the role of tafazzin in mitochondrial homeostasis dysregulation and mitophagy alteration. Using a HeLa cell model of tafazzin deficiency, we show that dysregulation of tafazzin in HeLa cells induces alteration of mitophagy. Our findings provide some additional insights into mitochondrial dysfunction associated with Barth syndrome, but also show that mitophagy inhibition is concomitant with apoptosis dysfunction through the inability of abnormal mitochondrial cardiolipin to assume its role in cytoplasmic signal transduction. Our work raises hope that pharmacological manipulation of the mitophagic pathway together with mitochondrially targeted antioxidants may provide new insights leading to promising treatment for these highly lethal conditions. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Rare Diseases)
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Review

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24 pages, 464 KiB  
Review
Modeling Rare Human Disorders in Mice: The Finnish Disease Heritage
by Tomáš Zárybnický, Anne Heikkinen, Salla M. Kangas, Marika Karikoski, Guillermo Antonio Martínez-Nieto, Miia H. Salo, Johanna Uusimaa, Reetta Vuolteenaho, Reetta Hinttala, Petra Sipilä and Satu Kuure
Cells 2021, 10(11), 3158; https://doi.org/10.3390/cells10113158 - 13 Nov 2021
Cited by 4 | Viewed by 4024
Abstract
The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined [...] Read more.
The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined as the Finnish disease heritage (FDH). We will highlight how gene-modified mouse models have greatly facilitated the understanding of the pathological manifestations of these diseases and how some of the diseases still lack proper models. We urge the establishment of subsequent international consortiums to cooperatively plan and carry out future human disease modeling strategies. Detailed information on disease mechanisms brings along broader understanding of the molecular pathways they act along both parallel and transverse to the proteins affected in rare diseases, therefore also aiding understanding of common disease pathologies. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Rare Diseases)
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