Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C.
Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal lipidosis that is most often the result of biallelic mutations in NPC1, and is characterized by a fatal neurological degeneration. The pathophysiology is complex, and the natural history of the disease is poorly understood. Recent findings from patients with NPC1 and hearing loss suggest that multiple steps along the auditory pathway are affected. The current study was undertaken to determine the auditory phenotype in the Npc1 (nih) mutant mouse model, to extend analyses to histologic evaluation of the inner ear, and to compare our findings to those reported from human patients. Auditory testing revealed a progressive high-frequency hearing loss in Npc1 (-/-) mice that is present as early as postnatal day 20 (P20), well before the onset of overt neurological symptoms, with evidence of abnormalities involving the cochlea, auditory nerve, and brainstem auditory centers. Distortion product otoacoustic emission amplitude and auditory brainstem response latency data provided evidence for a disruption in maturational development of the auditory system in Npc1 (-/-) mice. Anatomical study demonstrated accumulation of lysosomes in neurons, hair cells, and supporting cells of the inner ear in P30 Npc1 (-/-) mice, as well as increased numbers of inclusion bodies, myelin figures, and swollen nerve endings in older (P50-P70) mutant animals. These findings add unique perspective to the pathophysiology of NPC disease and suggest that hearing loss is an early and sensitive marker of disease progression.
National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892, USA, kingke@nidcd.nih.gov.
Kelly A
KA
King
Sandra
S
Gordon-Salant
Karen S
KS
Pawlowski
Anna M
AM
Taylor
Andrew J
AJ
Griffith
Ari
A
Houser
Kiyoto
K
Kurima
Christopher A
CA
Wassif
Charles G
CG
Wright
Forbes D
FD
Porter
Joyce J
JJ
Repa
Carmen C
CC
Brewer
D000818:Animals; D001933:Brain Stem / Q000503:physiopathology; D003051:Cochlea / Q000473:pathology / Q000503:physiopathology; D003056:Cochlear Nerve / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006320:Hearing Tests; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D011506:Proteins / Q000235:genetics* / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins