Defective iron homeostasis and hematological abnormalities in Niemann-Pick disease type C1

Wellcome Open Research

article

Oscar C W Chen¹  Stephan Siebel²  Alexandria Colaco¹  Elena-Raluca Nicoli¹  Nick Platt¹  Dawn Shepherd¹  Stephanie Newman¹  Andrew E Armitage³  Nicole Y Farhat²  George Seligmann¹  Claire Smith¹  David A Smith¹  Alaa Abdul-Sada⁴  Mylvaganam Jeyakumar¹  Hal Drakesmith³  Forbes D Porter²  Frances M Platt¹ 

[1]Department of Pharmacology, University of Oxford

[2]Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services

[3]MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford

[4]Chemistry Department, School of Life Sciences, University of Sussex

关键词: Niemann-Pick disease type C;    iron;    haematology;    lysosome;    lysosomal storage diseases;   

DOI  :  10.12688/wellcomeopenres.17261.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal storage disorder characterized by the accumulation of multiple lipids in the late endosome/lysosomal system and reduced acidic store calcium. The lysosomal system regulates key aspects of iron homeostasis, which prompted us to investigate whether there are hematological abnormalities and iron metabolism defects in NPC1.Methods: Iron-related hematological parameters, systemic and tissue metal ion and relevant hormonal and proteins levels, expression of specific pro-inflammatory mediators and erythrophagocytosis were evaluated in an authentic mouse model and in a large cohort of NPC patients.Results: Significant changes in mean corpuscular volume and corpuscular hemoglobin were detected inNpc1-/- mice from an early age. Hematocrit, red cell distribution width and hemoglobin changes were observed in late-stage disease animals. Systemic iron deficiency, increased circulating hepcidin, decreased ferritin and abnormal pro-inflammatory cytokine levels were also found. Furthermore, there is evidence of defective erythrophagocytosis inNpc1-/- mice and in anin vitro NPC1 cellular model. Comparable hematological changes, including low normal serum iron and transferrin saturation and low cerebrospinal fluid ferritin were confirmed in NPC1 patients.Conclusions: These data suggest loss of iron homeostasis and hematological abnormalities in NPC1 may contribute to the pathophysiology of this disease.

【 授权许可】

CC BY