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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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Published Papers (1 paper)

Research

14 pages, 1866 KiB

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms25084217 (registering DOI) - 11 Apr 2024

Viewed by 377

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 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 NPC1^I1061T 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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