Abstract
The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of NPC1, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various Npc1 mutant alleles but have not studied the potential mechanisms underlying this phenotype. We performed the first developmental analysis of a Npc1 mouse model, Npc1em1Pav, and discovered significant fetal growth restriction in homozygous mutants beginning at E16.5. Npc1em1Pav/em1Pav mice also exhibited cyanosis, increased respiratory effort, and over 50% lethality at birth. Analysis of neonatal lung tissues revealed lipid accumulation, notable abnormalities in surfactant, and enlarged alveolar macrophages, suggesting that lung abnormalities may be associated with neonatal lethality in Npc1em1Pav/em1Pav mice. The phenotypic severity of the Npc1em1Pav model facilitated this first analysis of perinatal lethality and lung pathology in an NPC1 model organism, and this model may serve as a useful resource for developing treatments for respiratory complications seen in NPC1 patients.
Highlights
Niemann-Pick disease, type C (NPC) is a rare, autosomal recessive, lysosomal storage disorder affecting approximately 1 in 120,000 to 150,000 live births [1,2]
While performing routine genotyping at postnatal day (P) 10 for mice from crosses between two Npc1em/+ heterozygous mice, we consistently observed a reduced number of Npc1em/em homozygous mice
Npc1I1060T, each on a C57BL/6J background, found significantly reduced percentages of homozygous Npc1 mutants (Table 1). These results show that lethality occurs in Npc1 homozygotes from these three mutant strains prior to P10, and are consistent with previously published reports of sub-Mendelian ratios of mutant offspring in other Npc1 alleles, including the Npc1nmf164, Npc1pioneer, Npc1imagine and Npc1m1N alleles [30,31]
Summary
Niemann-Pick disease, type C (NPC) is a rare, autosomal recessive, lysosomal storage disorder affecting approximately 1 in 120,000 to 150,000 live births [1,2]. We present the first developmental analysis of a Npc mouse model as well as detailed characterization of a neonatal lethality phenotype associated with novel abnormal lung pathology in a mouse model of NPC1, using the recently described Npc1em1Pav mouse model (hereafter abbreviated Npc1em , Rodriguez-Gil et al, under revision). These results suggest a potentially unifying explanation for the sub-Mendelian ratio observed in multiple Npc mutant mouse strains and may have implications for treatment/diagnosis of pre/perinatal NPC1 patients
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