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Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV)

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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 (30 December 2022) | Viewed by 30689

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Prof. Dr. Lidia Larizza

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Experimental Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy
Interests: rare disorders of chromatin regulators; Rubinstein-Taybi and related syndromes of the epigenetic machinery; chromosomal/genomic instability syndromes with cancer predisposition; imprinting disorders affecting growth; neurodevelopmental imprinting disorders; genomic disorders; MARK4 gene; c-kit gene
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Prof. Dr. Maria Vittoria Cubellis

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Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy
Interests: protein stability; bioinformatics; PMM2-CDG; Fabry disease; pharmacological chaperones
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

A rare disease is any disease that affects a small percentage of the population. The quantification of “small” is variable and represents an artificial border that will necessarily change with the diffusion of genetic screening. More than 5000 rare diseases have been described. Nonsense mutations, deletions, and insertions abolish the function of the affected proteins, but missense mutations have variable effects that go from complete inactivation to a mild reduction in activity. At present, more than 70,000 missense mutations have been reported. Taken together, these findings imply that there are different genotypes and phenotypes for any given disease. Bare figures give a flavor of the great challenge represented by rare diseases in terms of both diagnosis and therapy.

We seek papers that look into rare diseases with a genetic, biochemical, or bioinformatic approach. Papers addressing specific pharmacological therapies for rare diseases are especially welcome.

Prof. Dr. Lidia Larizza
Prof. Dr. Maria Vittoria Cubellis
Guest Editors

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

rare diseases
genetic diseases, inborn
diagnosis
mutations
epigenetics
drugs
molecular chaperones
drug repositioning
bioinformatics
integrated omics approaches
precision medicine

Published Papers (13 papers)

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Editorial

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6 pages, 223 KiB

Open AccessEditorial

Rare Diseases: Implementation of Molecular Diagnosis, Pathogenesis Insights and Precision Medicine Treatment

by Lidia Larizza and Maria Vittoria Cubellis

Int. J. Mol. Sci. 2023, 24(10), 9064; https://doi.org/10.3390/ijms24109064 - 22 May 2023

Viewed by 1158

Abstract

Rare Diseases (RD) do not have an exact definition since local authorities define the criteria in different ways, from fewer than 5 people in 10,000, according to the European Union, to the standard world average of 40 cases per 100,000 people [...] Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

Research

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19 pages, 3504 KiB

Open AccessArticle

Germline NUP98 Variants in Two Siblings with a Rothmund–Thomson-Like Spectrum: Protein Functional Changes Predicted by Molecular Modeling

by Elisa Adele Colombo, Michele Valiante, Matteo Uggeri, Alessandro Orro, Silvia Majore, Paola Grammatico, Davide Gentilini, Palma Finelli, Cristina Gervasini, Pasqualina D’Ursi and Lidia Larizza

Int. J. Mol. Sci. 2023, 24(4), 4028; https://doi.org/10.3390/ijms24044028 - 16 Feb 2023

Cited by 2 | Viewed by 1702

Abstract

Two adult siblings born to first-cousin parents presented a clinical phenotype reminiscent of Rothmund–Thomson syndrome (RTS), implying fragile hair, absent eyelashes/eyebrows, bilateral cataracts, mottled pigmentation, dental decay, hypogonadism, and osteoporosis. As the clinical suspicion was not supported by the sequencing of RECQL4, the RTS2-causative gene, whole exome sequencing was applied and disclosed the homozygous variants c.83G>A (p.Gly28Asp) and c.2624A>C (p.Glu875Ala) in the nucleoporin 98 (NUP98) gene. Though both variants affect highly conserved amino acids, the c.83G>A looked more intriguing due to its higher pathogenicity score and location of the replaced amino acid between phenylalanine-glycine (FG) repeats within the first NUP98 intrinsically disordered region. Molecular modeling studies of the mutated NUP98 FG domain evidenced a dispersion of the intramolecular cohesion elements and a more elongated conformational state compared to the wild type. This different dynamic behavior may affect the NUP98 functions as the minor plasticity of the mutated FG domain undermines its role as a multi-docking station for RNA and proteins, and the impaired folding can lead to the weakening or the loss of specific interactions. The clinical overlap of NUP98-mutated and RTS2/RTS1 patients, accounted by converging dysregulated gene networks, supports this first-described constitutional NUP98 disorder, expanding the well-known role of NUP98 in cancer. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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9 pages, 2536 KiB

Open AccessArticle

Novel Variants of SOX4 in Patients with Intellectual Disability

by Martin Grosse, Alma Kuechler, Tabib Dabir, Stephanie Spranger, Stefanie Beck-Wödl, Miriam Bertrand, Tobias B. Haack, Corinna Grasemann, Eva Manka, Christel Depienne and Frank J. Kaiser

Int. J. Mol. Sci. 2023, 24(4), 3519; https://doi.org/10.3390/ijms24043519 - 09 Feb 2023

Cited by 2 | Viewed by 1859

Abstract

SOX4 is a transcription factor with pleiotropic functions required for different developmental processes, such as corticogenesis. As with all SOX proteins, it contains a conserved high mobility group (HMG) and exerts its function via interaction with other transcription factors, such as POU3F2. Recently, pathogenic SOX4 variants have been identified in several patients who had clinical features overlapping with Coffin–Siris syndrome. In this study, we identified three novel variants in unrelated patients with intellectual disability, two of which were de novo (c.79G>T, p.Glu27*; c.182G>A p.Arg61Gln) and one inherited (c.355C>T, p.His119Tyr). All three variants affected the HMG box and were suspected to influence SOX4 function. We investigated the effects of these variants on transcriptional activation by co-expressing either wildtype (wt) or mutant SOX4 with its co-activator POU3F2 and measuring their activity in reporter assays. All variants abolished SOX4 activity. While our experiments provide further support for the pathogenicity of SOX4 loss-of-function (LOF) variants as a cause of syndromic intellectual disability (ID), our results also indicate incomplete penetrance associated with one variant. These findings will improve classification of novel, putatively pathogenic SOX4 variants. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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15 pages, 3009 KiB

Open AccessCommunication

Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease

by Maria Monticelli, Bruno Hay Mele, Mariateresa Allocca, Ludovica Liguori, Jan Lukas, Maria Chiara Monti, Elva Morretta, Maria Vittoria Cubellis and Giuseppina Andreotti

Int. J. Mol. Sci. 2023, 24(2), 1095; https://doi.org/10.3390/ijms24021095 - 06 Jan 2023

Cited by 7 | Viewed by 2412

Abstract

Fabry disease is a lysosomal storage disease caused by mutations in the GLA gene that encodes alpha-galactosidase (AGAL). The disease causes abnormal globotriaosylceramide (Gb3) storage in the lysosomes. Variants responsible for the genotypic spectrum of Fabry disease include mutations that abolish enzymatic activity and those that cause protein instability. The latter can be successfully treated with small molecules that either bind and stabilize AGAL or indirectly improve its cellular activity. This paper describes the first attempt to reposition curcumin, a nutraceutical, to treat Fabry disease. We tested the efficacy of curcumin in a cell model and found an improvement in AGAL activity for 80% of the tested mutant genotypes (four out of five tested). The fold-increase was dependent on the mutant and ranged from 1.4 to 2.2. We produced evidence that supports a co-chaperone role for curcumin when administered with AGAL pharmacological chaperones (1-deoxygalactonojirimycin and galactose). The combined treatment with curcumin and either pharmacological chaperone was beneficial for four out of five tested mutants and showed fold-increases ranging from 1.1 to 2.3 for DGJ and from 1.1 to 2.8 for galactose. Finally, we tested a long-term treatment on one mutant (L300F) and detected an improvement in Gb3 clearance and lysosomal markers (LAMP-1 and GAA). Altogether, our findings confirmed the necessity of personalized therapies for Fabry patients and paved the way to further studies and trials of treatments for Fabry disease. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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17 pages, 5356 KiB

Open AccessArticle

Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants

by Sara Perego, Valentina Alari, Gianluca Pietra, Andrea Lamperti, Alessandro Vimercati, Nicole Camporeale, Maria Garzo, Francesca Cogliati, Donatella Milani, Aglaia Vignoli, Angela Peron, Lidia Larizza, Tommaso Pizzorusso and Silvia Russo

Int. J. Mol. Sci. 2022, 23(22), 14491; https://doi.org/10.3390/ijms232214491 - 21 Nov 2022

Cited by 4 | Viewed by 1871

Abstract

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls’ isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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10 pages, 1390 KiB

Open AccessArticle

Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene

by Francesca Magri, Simona Zanotti, Sabrina Salani, Francesco Fortunato, Patrizia Ciscato, Simonetta Gerevini, Lorenzo Maggi, Monica Sciacco, Maurizio Moggio, Stefania Corti, Nereo Bresolin, Giacomo Pietro Comi and Dario Ronchi

Int. J. Mol. Sci. 2022, 23(17), 9817; https://doi.org/10.3390/ijms23179817 - 29 Aug 2022

Cited by 1 | Viewed by 1729

Abstract

Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogenous presentations displaying predominantly proximal muscle weakness due to the loss of skeletal muscle fibers. Beta-sarcoglycanopathy (LGMDR4) results from biallelic molecular defects in SGCB and features pediatric onset with limb-girdle involvement, often complicated by respiratory and heart dysfunction. Here we describe a patient who presented at the age of 12 years reporting high creatine kinase levels and onset of cramps after strenuous exercise. Instrumental investigations, including a muscle biopsy, pointed towards a diagnosis of beta-sarcoglycanopathy. NGS panel sequencing identified two variants in the SGCB gene, one of which (c.243+1548T>C) was found to promote the inclusion of a pseudoexon between exons 2 and 3 in the SGCB transcript. Interestingly, we detected the same genotype in a previously reported LGMDR4 patient, deceased more than twenty years ago, who had escaped molecular diagnosis so far. After the delivery of morpholino oligomers targeting the pseudoexon in patient-specific induced pluripotent stem cells, we observed the correction of the physiological splicing and partial restoration of protein levels. Our findings prompt the analysis of the c.243+1548T>C variant in suspected LGMDR4 patients, especially those harbouring monoallelic SGCB variants, and provide a further example of the efficacy of antisense technology for the correction of molecular defects resulting in splicing abnormalities. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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21 pages, 3594 KiB

Open AccessArticle

Differential Expression of Proteins in an Atypical Presentation of Autoimmune Lymphoproliferative Syndrome

by Dulce María Delgadillo, Adriana Ivonne Céspedes-Cruz, Emmanuel Ríos-Castro, María Guadalupe Rodríguez Maldonado, Mariel López-Nogueda, Miguel Márquez-Gutiérrez, Rocío Villalobos-Manzo, Lorena Ramírez-Reyes, Misael Domínguez-Fuentes and José Tapia-Ramírez

Int. J. Mol. Sci. 2022, 23(10), 5366; https://doi.org/10.3390/ijms23105366 - 11 May 2022

Cited by 4 | Viewed by 2330

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease defined as a defect in the lymphocyte apoptotic pathway. Currently, the diagnosis of ALPS is based on clinical aspects, defective lymphocyte apoptosis and mutations in Fas, FasL and Casp 10 genes. Despite this, ALPS has been misdiagnosed. The aim of this work was to go one step further in the knowledge of the disease, through a molecular and proteomic analysis of peripheral blood mononuclear cells (PBMCs) from two children, a 13-year-old girl and a 6-year-old boy, called patient 1 and patient 2, respectively, with clinical data supporting the diagnosis of ALPS. Fas, FasL and Casp10 genes from both patients were sequenced, and a sample of the total proteins from patient 1 was analyzed by label-free proteomics. Pathway analysis of deregulated proteins from PBMCs was performed on the STRING and PANTHER bioinformatics databases. A mutation resulting in an in-frame premature stop codon and protein truncation was detected in the Fas gene from patient 2. From patient 1, the proteomic analysis showed differences in the level of expression of proteins involved in, among other processes, cell cycle, regulation of cell cycle arrest and immune response. Noticeably, the most down-regulated protein is an important regulator of the cell cycle process. This could be an explanation of the disease in patient 1. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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15 pages, 1437 KiB

Open AccessArticle

Mechanistic Insight into the Mode of Action of Acid β-Glucosidase Enhancer Ambroxol

by Supansa Pantoom, Larissa Hules, Christopher Schöll, Andranik Petrosyan, Maria Monticelli, Jola Pospech, Maria Vittoria Cubellis, Andreas Hermann and Jan Lukas

Int. J. Mol. Sci. 2022, 23(7), 3536; https://doi.org/10.3390/ijms23073536 - 24 Mar 2022

Cited by 11 | Viewed by 2321

Abstract

Ambroxol (ABX) is a mucolytic agent used for the treatment of respiratory diseases. Bioactivity has been demonstrated as an enhancement effect on lysosomal acid β-glucosidase (β-Glu) activity in Gaucher disease (GD). The positive effects observed have been attributed to a mechanism of action similar to pharmacological chaperones (PCs), but an exact mechanistic description is still pending. The current study uses cell culture and in vitro assays to study the effects of ABX on β-Glu activity, processing, and stability upon ligand binding. Structural analogues bromohexine, 4-hydroxybromohexine, and norbromohexine were screened for chaperone efficacy, and in silico docking was performed. The sugar mimetic isofagomine (IFG) strongly inhibits β-Glu, while ABX exerts its inhibitory effect in the micromolar range. In GD patient fibroblasts, IFG and ABX increase mutant β-Glu activity to identical levels. However, the characteristics of the banding patterns of Endoglycosidase-H (Endo-H)-digested enzyme and a substantially lower half-life of ABX-treated β-Glu suggest different intracellular processing. In line with this observation, IFG efficiently stabilizes recombinant β-Glu against thermal denaturation in vitro, whereas ABX exerts no significant effect. Additional β-Glu enzyme activity testing using Bromohexine (BHX) and two related structures unexpectedly revealed that ABX alone can refunctionalize β-Glu in cellula. Taken together, our data indicate that ABX has little in vitro ability to act as PC, so the mode of action requires further clarification. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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11 pages, 1665 KiB

Open AccessArticle

Neural Crest Stem Cells in Juvenile Angiofibromas

by Bernhard Schick, Lukas Pillong, Gentiana Wenzel and Silke Wemmert

Int. J. Mol. Sci. 2022, 23(4), 1932; https://doi.org/10.3390/ijms23041932 - 09 Feb 2022

Cited by 1 | Viewed by 1601

Abstract

The etiology of juvenile angiofibroma (JA) has been a controversial topic for more than 160 years. Numerous theories have been proposed to explain this rare benign neoplasm arising predominately in adolescent males, focusing mainly on either the vascular or fibrous component. To assess our hypothesis of JA’s being a malformation arising from neural crest cells/remnants of the first branchial arch plexus, we performed immunohistochemical analyses of neural crest stem cells (NCSC) and epithelial-mesenchymal transition (EMT) candidates. Immunoexpression of the NCSC marker CD271^p75 was observed in all investigated JA’s (n = 22), mainly around the pathological vessels. Close to CD271^p75-positive cells, high MMP3-staining was also observed. Additionally, from one JA with sufficient material, RT-qPCR identified differences in the expression pattern of PDGFRβ, MMP2 and MMP3 in MACS^®-separated CD271^p75positive vs. CD271^p75 negative cell fractions. Our results, together with the consideration of the literature, provide evidence that JA’s represent a malformation within the first branchial arch artery/plexus remnants deriving from NCSC. This theory would explain the typical site of tumor origin as well as the characteristic tumor blood supply, whereas the process of EMT provides an explanation for the vascular and fibrous tumor component. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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Review

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34 pages, 2714 KiB

Open AccessReview

MPSI Manifestations and Treatment Outcome: Skeletal Focus

by Giada De Ponti, Samantha Donsante, Marta Frigeni, Alice Pievani, Alessandro Corsi, Maria Ester Bernardo, Mara Riminucci and Marta Serafini

Int. J. Mol. Sci. 2022, 23(19), 11168; https://doi.org/10.3390/ijms231911168 - 22 Sep 2022

Cited by 6 | Viewed by 3187

Abstract

Mucopolysaccharidosis type I (MPSI) (OMIM #252800) is an autosomal recessive disorder caused by pathogenic variants in the IDUA gene encoding for the lysosomal alpha-L-iduronidase enzyme. The deficiency of this enzyme causes systemic accumulation of glycosaminoglycans (GAGs). Although disease manifestations are typically not apparent at birth, they can present early in life, are progressive, and include a wide spectrum of phenotypic findings. Among these, the storage of GAGs within the lysosomes disrupts cell function and metabolism in the cartilage, thus impairing normal bone development and ossification. Skeletal manifestations of MPSI are often refractory to treatment and severely affect patients’ quality of life. This review discusses the pathological and molecular processes leading to impaired endochondral ossification in MPSI patients and the limitations of current therapeutic approaches. Understanding the underlying mechanisms responsible for the skeletal phenotype in MPSI patients is crucial, as it could lead to the development of new therapeutic strategies targeting the skeletal abnormalities of MPSI in the early stages of the disease. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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11 pages, 10630 KiB

Open AccessReview

Molecular Basis of the Schuurs–Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches

by María Arnedo, Ángela Ascaso, Ana Latorre-Pellicer, Cristina Lucia-Campos, Marta Gil-Salvador, Ariadna Ayerza-Casas, María Jesús Pablo, Paulino Gómez-Puertas, Feliciano J. Ramos, Gloria Bueno-Lozano, Juan Pié and Beatriz Puisac

Int. J. Mol. Sci. 2022, 23(17), 9649; https://doi.org/10.3390/ijms23179649 - 25 Aug 2022

Cited by 6 | Viewed by 2635

Abstract

The Schuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopment Disorder (PACS1-NDD) is a rare autosomal dominant disease caused by mutations in the PACS1 gene. To date, only 87 patients have been reported and, surprisingly, most of them carry the same variant (c.607C>T; p.R203W). The most relevant clinical features of the syndrome include neurodevelopment delay, seizures or a recognizable facial phenotype. Moreover, some of these characteristics overlap with other syndromes, such as the PACS2 or Wdr37 syndromes. The encoded protein phosphofurin acid cluster sorting 1 (PACS-1) is able to bind to different client proteins and direct them to their subcellular final locations. Therefore, although its main function is protein trafficking, it could perform other roles related to its client proteins. In patients with PACS1-NDD, a gain-of-function or a dominant negative mechanism for the mutated protein has been suggested. This, together with the fact that most of the patients carry the same genetic variant, makes it a good candidate for novel therapeutic approaches directed to decreasing the toxic effect of the mutated protein. Some of these strategies include the use of antisense oligonucleotides (ASOs) or targeting of its client proteins. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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9 pages, 824 KiB

Open AccessReview

Ectodysplasin A (EDA) Signaling: From Skin Appendage to Multiple Diseases

by Ruihan Yang, Yilan Mei, Yuhan Jiang, Huiling Li, Ruixi Zhao, Jian Sima and Yuyuan Yao

Int. J. Mol. Sci. 2022, 23(16), 8911; https://doi.org/10.3390/ijms23168911 - 10 Aug 2022

Cited by 9 | Viewed by 3609

Abstract

Ectodysplasin A (EDA) signaling is initially identified as morphogenic signaling regulating the formation of skin appendages including teeth, hair follicles, exocrine glands in mammals, feathers in birds and scales in fish. Gene mutation in EDA signaling causes hypohidrotic ectodermal dysplasia (HED), a congenital hereditary disease with malformation of skin appendages. Interestingly, emerging evidence suggests that EDA and its receptors can modulate the proliferation, apoptosis, differentiation and migration of cancer cells, and thus may regulate tumorigenesis and cancer progression. More recently, as a newly discovered hepatocyte factor, EDA pathway has been demonstrated to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and type II diabetes by regulating glucose and lipid metabolism. In this review, we summarize the function of EDA signaling from skin appendage development to multiple other diseases, and discuss the clinical application of recombinant EDA protein as well as other potential targets for disease intervention. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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Other

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13 pages, 1356 KiB

Open AccessBrief Report

Enzyme Replacement Therapy for FABRY Disease: Possible Strategies to Improve Its Efficacy

by Ilaria Iacobucci, Bruno Hay Mele, Flora Cozzolino, Vittoria Monaco, Chiara Cimmaruta, Maria Monti, Giuseppina Andreotti and Maria Monticelli

Int. J. Mol. Sci. 2023, 24(5), 4548; https://doi.org/10.3390/ijms24054548 - 25 Feb 2023

Cited by 7 | Viewed by 2750

Abstract

Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patients and welfare/health services (i.e., society at large). In this brief report, we describe preliminary results paving the way for two possible approaches: i. the combination of enzyme replacement therapy with pharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutic targets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone, can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed the interactomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with the two rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to the one associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange). Common interactors were aggregated and screened for sensitivity to known drugs. Such an interactor-drug list represents a starting point to deeply screen approved drugs and identify those that can affect (positively or negatively) enzyme replacement therapy. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

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