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

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

doi:10.1242/dmm.042614

Abstract

ABSTRACTNiemann-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, Npc1em1Pav. Npc1em1Pav/em1Pav mutants showed notably reduced NPC1 protein compared to controls and displayed the pathological and biochemical hallmarks of NPC1. Interestingly, Npc1em1Pav/em1Pav mutants on a C57BL/6J genetic background showed more severe visceral pathology and a significantly shorter lifespan compared to Npc1em1Pav/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.

Highlights

Niemann-Pick disease type C (NPC) is a rare, fatal neurodegenerative disorder that exhibits intracellular accumulation of unesterified cholesterol in late endosomes/lysosomes and marked accumulation of glycosphingolipids in neuronal tissue
Generation of Npc1em mice The Npc1em allele was identified by screening founders from CRISPR/Cas9 injections of a single guide RNA targeted within the cysteine-rich loop domain of exon 21 of Npc1
Protein analysis by western blot revealed a notably reduced amount of Niemann-Pick disease type C1 (NPC1) in Npc1em/em homozygotes compared to control littermates that was evident in both brain and liver tissues (Fig. 1C). These results suggest the Npc1em allele acts as a severe hypomorph rather than a null, as Npc1em/em mutants still retained low levels of NPC1 protein

Summary

Introduction

Niemann-Pick disease type C (NPC) is a rare, fatal neurodegenerative disorder that exhibits intracellular accumulation of unesterified cholesterol in late endosomes/lysosomes and marked accumulation of glycosphingolipids in neuronal tissue. Some mutations are frequently seen with specific phenotypic presentations, and some genotype-phenotype correlations are suggested based on patient analysis and cell culture studies, many exceptions exist (Benussi et al, 2015; Imrie et al, 2015; Millat et al, 1999, 2005, 2001; Shammas et al, 2019; Vanier, 2010; Vanier and Millat, 2003; Vanier et al, 1991; Walterfang et al, 2009). Differences in severity (Miyawaki et al, 1986), onset (Zhang and Erickson, 2000), survival (Liu et al, 2008; Marshall et al, 2018; Parra et al, 2011; Praggastis et al, 2015) and treatment response (Calderón and Klein, 2018) have all been reported, strongly suggesting that mouse models carry genetic variants capable of modifying the NPC1 phenotype

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