Hearing Loss is an Early Consequence of Npc1 Gene Deletion in the Mouse Model of Niemann–Pick Disease, Type C
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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.
KeywordsNPC hearing auditory maturation auditory brainstem response (ABR)
This work was supported by intramural research funds Z01 DC 000060 and Z01 DC 000064 of the National Institute on Deafness and Other Communication Disorders and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (to AJG, FDP, CCB) and the Ara Parseghian Medical Research Foundation (to JJR). Further support came from training grants from the National Institute on Deafness and Other Communication Disorders (T32DC000046 supporting KAK), and the National Institute of General Medical Sciences (T32GM007062 supporting AMT) of the National Institutes of Health. The authors would like to acknowledge the assistance of Katherine Luby-Phelps (Director) and the UT Southwestern Live Cell Imaging Facility, a Shared Resource of the Harold C. Simmons Cancer Center, supported in part by an NCI Cancer Center Support Grant, 1P30 CA142543-01. The authors are grateful to Robert Dooling, Tracy Fitzgerald, Arthur Popper, and Thomas Friedman for their insightful feedback on methodology and careful review of the manuscript. Thanks to Suzanne Lenhard and Elena Koulich for technical assistance and to the veterinary staff at NIDCD who provided exceptional support, most notably Pat Diers, Donny Catts, and James McGehee.
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