title: Npc1 deficiency in the C57BL/6J genetic background enhances Niemann-Pick disease type C spleen pathology.
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 accumulation. 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 spontaneous 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 transferred the Npc1 mutation from the BALB/c to C57BL/6J inbred background. We found that C57BL/6J-Npc1(-/-) mice present with a much more aggressive form of the disease, including a shorter lifespan than BALB/c-Npc1(-/-) mice. Surprisingly, there was no difference in the amount of cholesterol in the brains of Npc1(-/-) mice of either mouse strain. However, Npc1(-/-) 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(-/-) 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 hypersegmentation that included lymphopenia and atypias. In conclusion, Npc1 deficiency in the C57BL6/J background is associated with spleen, erythrocyte, and immune system abnormalities that lead to a reduced lifespan.
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile.
authors.forename: Julio
authors.initials: J
authors.lastname: Parra
authors.forename: Andrés D
authors.initials: AD
authors.lastname: Klein
authors.forename: Juan
authors.initials: J
authors.lastname: Castro
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Morales
authors.forename: Matías
authors.initials: M
authors.lastname: Mosqueira
authors.forename: Ilse
authors.initials: I
authors.lastname: Valencia
authors.forename: Victor
authors.initials: V
authors.lastname: Cortés
authors.forename: Attilio
authors.initials: A
authors.lastname: Rigotti
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000473:pathology; D018450:Disease Progression; D004912:Erythrocytes / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008136:Longevity / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D009929:Organ Size / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D013154:Spleen / Q000473:pathology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins