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

Jorge L Rodriguez-Gil; Dawn E Watkins-Chow; Laura L Baxter; Gene Elliot; Ursula L Harper; Stephen M Wincovitch; Julia C Wedel; Arturo A Incao; Mylene Huebecker; Frederick J Boehm; William S Garver; Forbes D Porter; Karl W Broman; Frances M Platt; William J Pavan

doi:10.1242/dmm.042614

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

Dis Model Mech. 2020 Mar 13;13(3):dmm042614. doi: 10.1242/dmm.042614.

Authors

Jorge L Rodriguez-Gil^{1

2

3}, Dawn E Watkins-Chow¹, Laura L Baxter¹, Gene Elliot⁴, Ursula L Harper⁵, Stephen M Wincovitch⁶, Julia C Wedel¹, Arturo A Incao¹, Mylene Huebecker², Frederick J Boehm⁷, William S Garver⁸, Forbes D Porter⁹, Karl W Broman¹⁰, Frances M Platt¹¹, William J Pavan¹²

Affiliations

¹ Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
³ Medical Scientist Training Program, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53726, USA.
⁴ Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Genomics Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁸ Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131, USA.
⁹ 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.
¹⁰ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53726, USA.
¹¹ Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK bpavan@mail.nih.gov frances.platt@pharm.ox.ac.uk.
¹² 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.

Abstract

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^em1PavNpc1^{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.

Keywords: Genetic modifiers; Mouse models; NPC1; Niemann-Pick disease type C1.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Base Sequence
Chromosomes, Mammalian / genetics
Disease Models, Animal
Genetic Background*
Intracellular Signaling Peptides and Proteins / genetics
Longevity*
Lysosomes / metabolism
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Mutant Strains
Nerve Degeneration / pathology
Niemann-Pick C1 Protein
Niemann-Pick Disease, Type C / pathology*
Phenotype
Quantitative Trait Loci / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism
Severity of Illness Index*
Survival Analysis
Viscera / pathology
Weight Loss

Substances

Intracellular Signaling Peptides and Proteins
Niemann-Pick C1 Protein
Npc1 protein, mouse
RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding