Npc1 deficiency in the C57BL/6J genetic background enhances Niemann–Pick disease type C spleen pathology Julio Parra 1 , Andrés D. Klein 1 , Juan Castro, María Gabriela Morales, Matías Mosqueira, Ilse Valencia, Victor Cortés, Attilio Rigotti, Silvana Zanlungo ⇑ Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile article info Article history: Received 17 August 2011 Available online 2 September 2011 Keywords: Niemann–Pick type C disease NPC1 Cholesterol Liver Spleen abstract Niemann–Pick type C (NPC) disease is an autosomal recessive neurovisceral lipid storage disorder. The affected genes are NPC1 and NPC2. Mutations in either gene lead to intracellular cholesterol accumula- tion. There are three forms of the disease, which are categorized based on the onset and severity of the disease: the infantile form, in which the liver and spleen are severely affected, the juvenile form, in which the liver and brain are affected, and the adult form, which affects the brain. In mice, a sponta- neous mutation in the Npc1 gene originated in the BALB/c inbred strain mimics the juvenile form of the disease. To study the influence of genetic background on the expression of NPC disease in mice, we trans- ferred the Npc1 mutation from the BALB/c to C57BL/6J inbred background. We found that C57BL/6J- Npc1 À/À mice present with a much more aggressive form of the disease, including a shorter lifespan than BALB/c-Npc1 À/À mice. Surprisingly, there was no difference in the amount of cholesterol in the brains of Npc1 À/À mice of either mouse strain. However, Npc1 À/À mice with the C57BL/6J genetic background showed striking spleen damage with a marked buildup of cholesterol and phospholipids at an early age, which correlated with large foamy cell clusters. In addition, C57BL/6J Npc1 À/À mice presented red cell abnormalities and abundant ghost erythrocytes that correlated with a lower hemoglobin concentration. We also found abnormalities in white cells, such as cytoplasmic granulation and neutrophil hyperseg- mentation that included lymphopenia and atypias. In conclusion, Npc1 deficiency in the C57BL6/J back- ground is associated with spleen, erythrocyte, and immune system abnormalities that lead to a reduced lifespan. Ó 2011 Elsevier Inc. All rights reserved. 1. Introduction Niemann–Pick type C (NPC) disease is a fatal autosomal reces- sive lipid storage disorder [1,2]. NPC1 and NPC2 are the affected genes [3,4]. NPC1 encodes a late endosomal transmembrane pro- tein that binds cholesterol in a luminal domain, and NPC2 encodes a small soluble lysosomal cholesterol binding and transport pro- tein [3–6]. Mutations in either of the NPC proteins cause intracel- lular accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes in all tissues [7,8]. The initial clinical manifestation of NPC is neonatal jaundice and an enlarged liver and/or spleen, but the disease manifestations are very heterogeneous with respect to time of appearance and progression [1,9,10]. Three different forms of the disease can be distinguished: the infantile form, in which hepatosplenomegaly is almost invariably present and patients die before the age of 5; the classic disease with neurological onset during childhood and adolescence, in which neurodegeneration and motor coordination problems are hallmarks of the disease and majority of patients die in their teenage years; and the adult form, in which late neuro- logic symptomatology and progressive dementia are characteristic, and patients live into adulthood [1,9,10]. Mutations that inactivate NPC1 have been described not only in humans but also in other species, including mice [11,12]. Two murine models of NPC1 disease, BALB/c npc nih and C57BL/KsJ spm (sphingomyelinosis or spm), arose by spontaneous mutation [11–13]. Both of the murine NPC1 models were found to be allelic by crossbreeding and belong to the same complementation group as human NPC1 [14]. The Npc1 mutation in the BALB/c npc nih murine model results in early protein truncation [15]. This model has been extensively uti- lized and characterized. In this model, animals present with high levels of neuron loss, particularly of Purkinje cells in the 0006-291X/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2011.08.096 Abbreviations: NPC, Niemann–Pick type C; NPC1, Niemann–Pick C1 protein. ⇑ Corresponding author. Address: Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Marcoleta 367, Casilla 114-D, Santiago, Chile. Fax: +56 2 639 7780. E-mail address: silvana@med.puc.cl (S. Zanlungo). 1 These authors contributed equally. Biochemical and Biophysical Research Communications 413 (2011) 400–406 Contents lists available at SciVerse ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc