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Title: Discovering genetic modifiers in Niemann-Pick Disease Type C
Author: Rodriguez-Gil, Jorge L.
ISNI:       0000 0004 7971 6385
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Niemann-Pick Disease, Type C (NPC) is a rare, fatal neurodegenerative disorder characterized by lysosomal accumulation of unesterified cholesterol and sphingolipids. These subcellular pathologies eventually cause phenotypes of hepatosplenomegaly and neurological degeneration leading to premature death. NPC is extremely heterogeneous in the timing of clinical presentation (prenatal to adulthood) and is associated with a wide spectrum of causative NPC1 mutations. Miglustat (Zavesca) is the only approved therapy for NPC, and while it has been shown to improve clinical outcomes it is not a cure. To study the genetic architecture of NPC, including the clinical and genetic heterogeneity seen in this patient population, we have generated a new mouse model (Npc1em1Pav). Using this model, we identified strain- specific quantitative trait loci (QTL) affecting lifespan and characterized a novel lung phenotype causing neonatal lethality. Interestingly, Npc1em1Pav mutants on a C57BL/6J (B6J) genetic background had a more severe visceral pathology of foam cell accumulation than Npc1em1Pav mutants on a BALB/cJ background. These underlying pathological changes translated into B6J mutants having a significantly shorter lifespan (70 + 4.30 days) than mutants on a BALB/cJ background (84 + 7.25; p<0.0001), suggesting strain- specific modifiers contribute to disease severity. QTL analysis of backcross N2 mutants detected significant linkage to markers on chromosomes 1 (LOD=5.57) and 7 (LOD=8.91). Analysis of predicted deleterious sequence variants between B6J and BALB/cJ strains at these two loci resulted in a short list of candidate genes that can now be evaluated as potential modifiers of NPC severity and progression. A significant reduction of viable Npc1em1Pav mice was also observed on the B6J background at Postnatal day 10 (P10) (10.5% vs. 25%, p<0.0001). Interestingly, the expected genotype frequency was observed at E18.5-E19.5 (26.5% % vs. 25%, p=0.034) indicating Npc1em1Pav mutants exhibit a previously uncharacterized lethal phenotype postnatally. C-sections accompanied by maternal fostering confirmed that the majority of Npc1em1Pav mutants died shortly after birth showing signs of respiratory insufficiency and abnormal surfactant pathology. A similar phenomenon reported in NPC patients with pre/perinatal onset indicates Npc1em1Pav may be the first valid animal model of this severely affected group.
Supervisor: Platt, Frances M. ; Pavan, William J. Sponsor: NIH-Oxford Scholars Program
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Neuroscience ; Genetics ; Lysosomal Storage Disorders ; Animal models in research