Using chanarin-dorfman syndrome patient fibroblasts to explore disease mechanisms and new treatment avenues.

Publisher: BioMed Central Country of Publication: England NLM ID: 101266602 Publication Model: Electronic Cited Medium: Internet ISSN: 1750-1172 (Electronic) Linking ISSN: 17501172 NLM ISO Abbreviation: Orphanet J Rare Dis Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2006-

Ichthyosiform Erythroderma, Congenital*/metabolism ; Ichthyosiform Erythroderma, Congenital*/genetics ; Ichthyosiform Erythroderma, Congenital*/drug therapy ; Ichthyosiform Erythroderma, Congenital*/pathology ; Fibroblasts*/metabolism ; Lipid Metabolism, Inborn Errors*/metabolism ; Lipid Metabolism, Inborn Errors*/genetics ; Lipid Metabolism, Inborn Errors*/drug therapy ; Muscular Diseases*/genetics ; Muscular Diseases*/metabolism ; Muscular Diseases*/pathology ; Muscular Diseases*/drug therapy ; Lysosomal Storage Diseases*/metabolism ; Lysosomal Storage Diseases*/genetics; Humans ; 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics ; 1-Acylglycerol-3-Phosphate O-Acyltransferase/metabolism ; Lipid Droplets/metabolism

Competing Interests: Declarations. Ethics approval and consent to participate: Family consented to this study according to an approved institutional review board (IRB) protocol (0038 − 14). Consent for publication: The patients’ parents signed on a consent for publication. Competing interests: The authors have no conflict of interest.
Background: Chanarin-Dorfman syndrome (CDS) is a multisystemic autosomal recessive rare disorder. CDS is caused by variants in the abhydrolase domain containing 5 (ABHD5) encoding gene (CGI-58), which ultimately leads to excessive lipid storage, and therefore a high abundance of cellular lipid droplets (LDs). Although the molecular etiology of the disease was described many years ago, no treatment for CDS is currently available.
Results: To further characterize the molecular basis of the disease and to uncover new treatment avenues, we used skin fibroblasts originating from a young patient diagnosed with CDS due to a homozygous nonsense mutation. We show that dysfunctional ABHD5 does not only affect LDs, but also influences other metabolic-related organelles; the mitochondria and peroxisomes. Additionally, we found that expressing functional ABHD5 in CDS patient cells reduced LD number. Finally, we developed and applied a high content-based drug repurposing screen based on a collection of ∼2500 FDA approved compounds, yielding several compounds that affected LD total area and size.
Conclusions: Our findings enhance the understanding of the dysfunction underlying CDS and propose new avenues for the treatment of CDS patients.
(© 2025. The Author(s).)

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NSERC- PIN303585-2023 NSERC; The David and Fela Shapell Family Center for Genetic Disorders Research The David and Fela Shapell Family Center for Genetic Disorders Research

Keywords: Chanarin-Dorfman syndrome; Drug repurposing; Lipid droplets; Mitochondria; Neutral lipid storage; Peroxisomes

EC 2.3.1.51 (1-Acylglycerol-3-Phosphate O-Acyltransferase)
EC 2.3.1.51 (ABHD5 protein, human)

Chanarin-Dorfman Syndrome

Date Created: 20250424 Date Completed: 20250425 Latest Revision: 20250427

20250428

PMC12020101

10.1186/s13023-025-03711-6

40275410