title: Neurological Dysfunction in Early Maturity of a Model for Niemann-Pick C1 Carrier Status.
abstract: 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.
authors.affiliation: Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Ya Hui
authors.initials: YH
authors.lastname: Hung
authors.affiliation: Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.|Neuropsychiatry Unit, Royal Melbourne Hospital and Melbourne Neuropsychiatry Centre, Melbourne, Victoria, 3050, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Walterfang
authors.affiliation: Statistics and Informatics Platform, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.|School of Mathematics and Geospatial Sciences, RMIT University, Melbourne, Victoria, 3000, Australia.
authors.forename: Leonid
authors.initials: L
authors.lastname: Churilov
authors.affiliation: Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bray
authors.affiliation: Neurotherapeutics Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.affiliation: Neurotherapeutics Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.|Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia.|Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Neuropsychiatry Unit, Royal Melbourne Hospital and Melbourne Neuropsychiatry Centre, Melbourne, Victoria, 3050, Australia.
authors.forename: Dennis
authors.initials: D
authors.lastname: Velakoulis
authors.affiliation: Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia. ashley.bush@florey.edu.au.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001522:Behavior, Animal; D004195:Disease Models, Animal; D005684:Gait; D057895:Haploinsufficiency; D047908:Intracellular Signaling Peptides and Proteins; D008124:Locomotion; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009043:Motor Activity; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000150:complications / Q000235:genetics* / Q000523:psychology; D011506:Proteins / Q000235:genetics*; D045442:Rotarod Performance Test
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins
keywords: Carrier; Heterozygote disease; NPC1; Neurological; Niemann–Pick disease type C; haploinsufficiency