Neurological Dysfunction in Early Maturity of a Model for Niemann-Pick C1 Carrier Status

Neurotherapeutics. 2016 Jul;13(3):614-22. doi: 10.1007/s13311-016-0427-5.


Autosomal recessive inheritance of NPC1 with loss-of-function mutations underlies Niemann-Pick disease, type C1 (NP-C1), a lysosomal storage disorder with progressive neurodegeneration. It is uncertain from limited biochemical studies and patient case reports whether NPC1 haploinsufficiency can cause a partial NP-C1 phenotype in carriers. In the present study, we examined this possibility in heterozygotes of a natural loss-of-function mutant Npc1 mouse model. We found partial motor dysfunction and increased anxiety-like behavior in Npc1 (+/-) mice by 9 weeks of age. Relative to Npc1 (+/+) mice, Npc1 (+/-) mice failed to show neurodevelopmental improvements in motor coordination and balance on an accelerating Rotarod. In the open-field test, Npc1 (+/-) mice showed an intermediate phenotype in spontaneous locomotor activity compared with Npc1 (+/+) and Npc1 (-/-) mice, as well as decreased center tendency. Together with increased stride length under anxiogenic conditions on the DigiGait treadmill, these findings are consistent with heightened anxiety. Our findings indicate that pathogenic NPC1 allele carriers, who represent about 0.66 % of humans, could be vulnerable to motor and anxiety disorders.

Keywords: Carrier; Heterozygote disease; NPC1; Neurological; Niemann–Pick disease type C; haploinsufficiency.

MeSH terms

  • Animals
  • Anxiety / genetics*
  • Behavior, Animal
  • Disease Models, Animal*
  • Gait
  • Haploinsufficiency
  • Intracellular Signaling Peptides and Proteins
  • Locomotion
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Motor Activity*
  • Niemann-Pick C1 Protein
  • Niemann-Pick Disease, Type C / complications
  • Niemann-Pick Disease, Type C / genetics*
  • Niemann-Pick Disease, Type C / psychology
  • Proteins / genetics*
  • Rotarod Performance Test


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