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Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis.
Gomez-Mariano, Gema; Perez-Luz, Sara; Ramos-Del Saz, Sheila; Matamala, Nerea; Hernandez-SanMiguel, Esther; Fernandez-Prieto, Marta; Gil-Martin, Sara; Justo, Iago; Marcacuzco, Alberto; Martinez-Delgado, Beatriz.
Affiliation
  • Gomez-Mariano G; Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain.
  • Perez-Luz S; Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain.
  • Ramos-Del Saz S; Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain.
  • Matamala N; Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain.
  • Hernandez-SanMiguel E; Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain.
  • Fernandez-Prieto M; Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain.
  • Gil-Martin S; Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain.
  • Justo I; CIBER de Enfermedades Raras, CIBERER U758, 28029 Madrid, Spain.
  • Marcacuzco A; General and Digestive Surgery Department, Hospital 12 de Octubre, 28041 Madrid, Spain.
  • Martinez-Delgado B; General and Digestive Surgery Department, Hospital 12 de Octubre, 28041 Madrid, Spain.
Int J Mol Sci ; 24(16)2023 Aug 10.
Article in En | MEDLINE | ID: mdl-37628828
Acid sphingomyelinase deficiency (ASMD) or Niemann-Pick disease type A (NPA), type B (NPB) and type A/B (NPA/B), is a rare lysosomal storage disease characterized by progressive accumulation of sphingomyelin (SM) in the liver, lungs, bone marrow and, in severe cases, neurons. A disease model was established by generating liver organoids from a NPB patient carrying the p.Arg610del variant in the SMPD1 gene. Liver organoids were characterized by transcriptomic and lipidomic analysis. We observed altered lipid homeostasis in the patient-derived organoids showing the predictable increase in sphingomyelin (SM), together with cholesterol esters (CE) and triacylglycerides (TAG), and a reduction in phosphatidylcholine (PC) and cardiolipins (CL). Analysis of lysosomal gene expression pointed to 24 downregulated genes, including SMPD1, and 26 upregulated genes that reflect the lysosomal stress typical of the disease. Altered genes revealed reduced expression of enzymes that could be involved in the accumulation in the hepatocytes of sphyngoglycolipids and glycoproteins, as well as upregulated genes coding for different glycosidases and cathepsins. Lipidic and transcriptome changes support the use of hepatic organoids as ideal models for ASMD investigation.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Niemann-Pick Diseases / Niemann-Pick Disease, Type A Type of study: Prognostic_studies Limits: Humans Language: En Journal: Int J Mol Sci Year: 2023 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Niemann-Pick Diseases / Niemann-Pick Disease, Type A Type of study: Prognostic_studies Limits: Humans Language: En Journal: Int J Mol Sci Year: 2023 Document type: Article