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Genetic and Metabolic Molecular Research of Lysosomal Storage Disease 4.0
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Genetic and Metabolic Molecular Research of Lysosomal Storage Disease 4.0

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: 30 September 2024 | Viewed by 3746

Special Issue Editor

Prof. Dr. Grzegorz Wegrzyn

E-Mail Website
Guest Editor
Department of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland
Interests: gene expression regulation; DNA replication; bacteriophages; plasmids; human genetic diseases; neurodegeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders in which the defects of various lysosomal enzymes and regulatory proteins result in the accumulation of different macromolecules in these organelles. Over 50 LSDs are described in the literature, and they are among the most intensively studied genetic disorders. They are also model genetic diseases for the development of various therapeutic approaches. The introduction of enzyme replacement therapy for LSDs created a breakthrough in treating genetic diseases, and several different therapeutic options are currently being studied, including hematopoietic stem cell transplantation, gene therapy and substrate reduction therapy. However, to develop new therapies, the molecular mechanisms of LSDs must be understood in great detail. Now is the time for extensive molecular research on LSDs. This Special Issue is devoted to publishing the results of such studies, including basic research on the molecular mechanisms of LSDs, translational studies on novel therapies, and clinical investigations performed at the molecular level. Review articles on all these aspects are also welcome. Therefore, this Special Issue shall provide a comprehensive view on the molecular aspects of various LSDs.

This issue is devoted to presenting research on the molecular aspects of lysosomal storage diseases. This group of diseases is at the forefront of genetic and metabolic disorders that are studied at the molecular level, and our understanding of molecular mechanisms, molecular pharmacology and clinical aspects at the molecular level is crucial for further research in this field, as well as opening new ways of thinking about other less-understood diseases.

Prof. Dr. Grzegorz Wegrzyn
Guest Editor

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Keywords

  • lysosomal storage diseases
  • molecular mechanisms of genetic disorders metabolic diseases
  • accumulation of macromolecules in cells
  • enzyme replacement therapy
  • hematopoietic stem cell transplantation gene therapy
  • substrate reduction therapy
  • translational research
  • novel therapies for genetic diseases

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Related Special Issues

Published Papers (5 papers)

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14 pages, 1558 KiB  
Article
Mutation Spectrum of GAA Gene in Pompe Disease: Current Knowledge and Results of an Italian Study
by Marta Moschetti, Alessia Lo Curto, Miriam Giacomarra, Daniele Francofonte, Carmela Zizzo, Elisa Messina, Giovanni Duro and Paolo Colomba
Int. J. Mol. Sci. 2024, 25(17), 9139; https://doi.org/10.3390/ijms25179139 - 23 Aug 2024
Viewed by 288
Abstract
Studying a patient with Pompe disease (PD) is like opening Pandora’s box. The specialist is faced with numerous clinical features similar to those of several diseases, and very often the symptoms are well hidden and none is associated with this rare disease. In [...] Read more.
Studying a patient with Pompe disease (PD) is like opening Pandora’s box. The specialist is faced with numerous clinical features similar to those of several diseases, and very often the symptoms are well hidden and none is associated with this rare disease. In recent years, scientific interest in this disease has been growing more and more, but still no symptom is recognized as key to a correct diagnosis of it, nor is there any specific disease marker to date. New diagnostic/therapeutic proposals on disease allow for the diffusion of knowledge of this pathology for timely diagnosis of the patient. Due to unawareness and difficulty in diagnosis, many adults with PD are diagnosed with great delay. In this article, we report and discuss current knowledge of PD and provide new data from work conducted on a cohort of 2934 Italian subjects recruited in recent years. A genetic analysis of the GAA gene was performed on patients with significant clinical signs and pathological enzyme activity to define the genetic profile of subjects. This identified 39 symptomatic PD subjects with low acid alpha-glucosidase enzyme activity and the presence of two causative mutations in GAA gene regions. Furthermore, 22 subjects with genetic variants of uncertain significance (GVUS) were identified. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease 4.0)
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18 pages, 1403 KiB  
Article
Machine Learning-Driven Biomarker Discovery for Skeletal Complications in Type 1 Gaucher Disease Patients
by Jorge J. Cebolla, Pilar Giraldo, Jessica Gómez, Carmen Montoto and Javier Gervas-Arruga
Int. J. Mol. Sci. 2024, 25(16), 8586; https://doi.org/10.3390/ijms25168586 - 6 Aug 2024
Viewed by 594
Abstract
Type 1 Gaucher disease (GD1) is a rare, autosomal recessive disorder caused by glucocerebrosidase deficiency. Skeletal manifestations represent one of the most debilitating and potentially irreversible complications of GD1. Although imaging studies are the gold standard, early diagnostic/prognostic tools, such as molecular biomarkers, [...] Read more.
Type 1 Gaucher disease (GD1) is a rare, autosomal recessive disorder caused by glucocerebrosidase deficiency. Skeletal manifestations represent one of the most debilitating and potentially irreversible complications of GD1. Although imaging studies are the gold standard, early diagnostic/prognostic tools, such as molecular biomarkers, are needed for the rapid management of skeletal complications. This study aimed to identify potential protein biomarkers capable of predicting the early diagnosis of bone skeletal complications in GD1 patients using artificial intelligence. An in silico study was performed using the novel Therapeutic Performance Mapping System methodology to construct mathematical models of GD1-associated complications at the protein level. Pathophysiological characterization was performed before modeling, and a data science strategy was applied to the predicted protein activity for each protein in the models to identify classifiers. Statistical criteria were used to prioritize the most promising candidates, and 18 candidates were identified. Among them, PDGFB, IL1R2, PTH and CCL3 (MIP-1α) were highlighted due to their ease of measurement in blood. This study proposes a validated novel tool to discover new protein biomarkers to support clinician decision-making in an area where medical needs have not yet been met. However, confirming the results using in vitro and/or in vivo studies is necessary. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease 4.0)
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9 pages, 598 KiB  
Article
Diagnosis of Fabry Disease Using Alpha-Galactosidase A Activity or LysoGb3 in Blood Fails to Identify Up to Two Thirds of Female Patients
by Giovanni Duro, Monia Anania, Carmela Zizzo, Daniele Francofonte, Irene Giacalone, Annalisa D’Errico, Emanuela Maria Marsana and Paolo Colomba
Int. J. Mol. Sci. 2024, 25(10), 5158; https://doi.org/10.3390/ijms25105158 - 9 May 2024
Cited by 1 | Viewed by 955
Abstract
Anderson–Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene, which encodes the enzyme α-galactosidase A. The GLA gene is located on the X-chromosome, causing an X-linked pathology: due to lyonization, female patients usually manifest a variable symptomatology, ranging [...] Read more.
Anderson–Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene, which encodes the enzyme α-galactosidase A. The GLA gene is located on the X-chromosome, causing an X-linked pathology: due to lyonization, female patients usually manifest a variable symptomatology, ranging from asymptomatic to severe phenotypes. The confirmation of the clinical diagnosis of Fabry disease, achieved by measuring α-galactosidase A activity, which is usually the first test used, shows differences between male and female patients. This assay is reliable in male patients with causative mutations in the GLA gene, in whom the enzymatic activity is lower than normal values; on the other hand, in female Fabry patients, the enzymatic activity is extremely variable between normal and pathological values. These fluctuations are also found in female patients’ blood levels of globotriaosylsphingosine (LysoGb3) for the same reason. In this paper, we present a retrospective study conducted in our laboratories on 827 Fabry patients with causative mutations in the GLA gene. Our results show that 100% of male patients had α-galactosidase A activity below the reference value, while more than 70% of female patients had normal values. It can also be observed that almost half of the female patients with pathogenic mutations in the GLA gene showed normal values of LysoGb3 in blood. Furthermore, in women, blood LysoGb3 values can vary over time, as we show in a clinical case presented in this paper. Both these tests could lead to missed diagnoses of Fabry disease in female patients, so the analysis of the GLA gene represents the main diagnostic test for Fabry disease in women to date. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease 4.0)
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14 pages, 1866 KiB  
Article
Sterol O-Acyltransferase 1 (SOAT1): A Genetic Modifier of Niemann-Pick Disease, Type C1
by Nicole Y. Farhat, Derek Alexander, Kyli McKee, James Iben, Jorge L. Rodriguez-Gil, Christopher A. Wassif, Niamh X. Cawley, William E. Balch and Forbes D. Porter
Int. J. Mol. Sci. 2024, 25(8), 4217; https://doi.org/10.3390/ijms25084217 - 11 Apr 2024
Cited by 1 | Viewed by 1055
Abstract
Niemann-Pick disease type C1 (NPC1) is a lysosomal disorder due to impaired intracellular cholesterol transport out of the endolysosomal compartment. Marked heterogeneity has been observed in individuals with the same NPC1 genotype, thus suggesting a significant effect of modifier genes. Prior work demonstrated [...] Read more.
Niemann-Pick disease type C1 (NPC1) is a lysosomal disorder due to impaired intracellular cholesterol transport out of the endolysosomal compartment. Marked heterogeneity has been observed in individuals with the same NPC1 genotype, thus suggesting a significant effect of modifier genes. Prior work demonstrated that decreased SOAT1 activity decreased disease severity in an NPC1 mouse model. Thus, we hypothesized that a polymorphism associated with decreased SOAT1 expression might influence the NPC1 phenotype. Phenotyping and genomic sequencing of 117 individuals with NPC1 was performed as part of a Natural History trial. Phenotyping included determination of disease severity and disease burden. Significant clinical heterogeneity is present in individuals homozygous for the NPC1I1061T variant and in siblings. Analysis of the SOAT1 polymorphism, rs1044925 (A>C), showed a significant association of the C-allele with earlier age of neurological onset. The C-allele may be associated with a higher Annualized Severity Index Score as well as increased frequency of liver disease and seizures. A polymorphism associated with decreased expression of SOAT1 appears to be a genetic modifier of the NPC1 phenotype. This finding is consistent with prior data showing decreased phenotypic severity in Npc1-/-:Soat1-/- mice and supports efforts to investigate the potential of SOAT1 inhibitors as a potential therapy for NPC1. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease 4.0)
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9 pages, 1709 KiB  
Case Report
Evaluation of 73 Enlisted Patients for Liver Transplant with Unknown Etiology Reveals a Late-Diagnosed Case of Lysosomal Acid Lipase Deficiency
by Karina Lucio de Medeiros Bastos, Bruno de Oliveira Stephan, Bianca Domit Werner Linnenkamp, Larissa Athayde Costa, Fabiana Roberto Lima, Laura Machado Lara Carvalho, Rachel Sayuri Honjo, Uenis Tannuri, Ana Cristina Aoun Tannuri and Chong Ae Kim
Int. J. Mol. Sci. 2024, 25(16), 8648; https://doi.org/10.3390/ijms25168648 - 8 Aug 2024
Viewed by 447
Abstract
Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for [...] Read more.
Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP—Brazil) who were subjected to LAL activity measurement and LIPA Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years. The LALD diagnosis confirmation was conducted at 24 years old due to low levels of LAL enzyme activity. The causal homozygous variant LIPA(NM_000235.4):c.266T>C(p.Leu89Pro) was identified, but the patient had already undergone his first LT at 18 years with several rejection episodes. Despite beginning treatment with sebelipase alfa at 26 years old (total of five infusions), this patient died at 28 years from complications after his second liver transplant. LALD is an important differential diagnosis in cases presenting with hepatomegaly, elevated liver enzymes, and dyslipidemia. Detecting low/absent LAL activity and identifying the LIPA causal variant are essential for diagnosis and specific treatment, as well as for appropriate genetic counseling. Early diagnosis, along with sebelipase alfa therapy, may improve the prognosis of affected patients. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease 4.0)
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