Genetic background modifies phenotypic severity and longevity in a mouse model of Niemann-Pick disease type C1.

Autor:	Rodriguez-Gil JL; Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.; Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.; Medical Scientist Training Program, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53726, USA., Watkins-Chow DE; Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Baxter LL; Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Elliot G; Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Harper UL; Genomics Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Wincovitch SM; Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Wedel JC; Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Incao AA; Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Huebecker M; Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK., Boehm FJ; Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA., Garver WS; Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131, USA., Porter FD; Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA., Broman KW; Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53726, USA., Platt FM; Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK bpavan@mail.nih.gov frances.platt@pharm.ox.ac.uk., Pavan WJ; Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA bpavan@mail.nih.gov frances.platt@pharm.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	Disease models & mechanisms [Dis Model Mech] 2020 Mar 13; Vol. 13 (3). Date of Electronic Publication: 2020 Mar 13.
DOI:	10.1242/dmm.042614
Abstrakt:	Niemann-Pick disease type C1 (NPC1) is a rare, fatal neurodegenerative disorder characterized by lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. NPC1 is extremely heterogeneous in the timing of clinical presentation and is associated with a wide spectrum of causative NPC1 mutations. To study the genetic architecture of NPC1, we have generated a new NPC1 mouse model, Npc1 em1Pav Npc1 em1Pav/em1Pav mutants showed notably reduced NPC1 protein compared to controls and displayed the pathological and biochemical hallmarks of NPC1. Interestingly, Npc1 em1Pav/em1Pav mutants on a C57BL/6J genetic background showed more severe visceral pathology and a significantly shorter lifespan compared to Npc1 em1Pav/em1Pav mutants on a BALB/cJ background, suggesting that strain-specific modifiers contribute to disease severity and survival. QTL analysis for lifespan of 202 backcross N2 mutants on a mixed C57BL/6J and BALB/cJ background detected significant linkage to markers on chromosomes 1 and 7. The discovery of these modifier regions demonstrates that mouse models are powerful tools for analyzing the genetics underlying rare human diseases, which can be used to improve understanding of the variability in NPC1 phenotypes and advance options for patient diagnosis and therapy.This article has an associated First Person interview with the first author of the paper. Competing Interests: Competing interestsThe authors declare no competing or financial interests. (© 2020. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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