Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C

Kelly A. King, Sandra Gordon-Salant, Karen S. Pawlowski, Anna M. Taylor, Andrew J. Griffith, Ari Houser, Kiyoto Kurima, Christopher A. Wassif, Charles G. Wright, Forbes D. Porter, Joyce J. Repa, Carmen C. Brewer

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)529-541
Number of pages13
JournalJARO - Journal of the Association for Research in Otolaryngology
Volume15
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Type C Niemann-Pick Disease
Gene Deletion
Hearing Loss
Inner Ear
High-Frequency Hearing Loss
Lipidoses
Auditory Pathways
Cochlear Nerve
Auditory Cortex
Nerve Endings
Brain Stem Auditory Evoked Potentials
Cochlea
Inclusion Bodies
Myelin Sheath
Lysosomes
Brain Stem
Reaction Time
Disease Progression
Phenotype
Neurons

Keywords

  • auditory brainstem response (ABR)
  • auditory maturation
  • hearing
  • NPC

ASJC Scopus subject areas

  • Otorhinolaryngology
  • Sensory Systems
  • Medicine(all)

Cite this

Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C. / King, Kelly A.; Gordon-Salant, Sandra; Pawlowski, Karen S.; Taylor, Anna M.; Griffith, Andrew J.; Houser, Ari; Kurima, Kiyoto; Wassif, Christopher A.; Wright, Charles G.; Porter, Forbes D.; Repa, Joyce J.; Brewer, Carmen C.

In: JARO - Journal of the Association for Research in Otolaryngology, Vol. 15, No. 4, 2014, p. 529-541.

Research output: Contribution to journalArticle

King, KA, Gordon-Salant, S, Pawlowski, KS, Taylor, AM, Griffith, AJ, Houser, A, Kurima, K, Wassif, CA, Wright, CG, Porter, FD, Repa, JJ & Brewer, CC 2014, 'Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C', JARO - Journal of the Association for Research in Otolaryngology, vol. 15, no. 4, pp. 529-541. https://doi.org/10.1007/s10162-014-0459-7
King, Kelly A. ; Gordon-Salant, Sandra ; Pawlowski, Karen S. ; Taylor, Anna M. ; Griffith, Andrew J. ; Houser, Ari ; Kurima, Kiyoto ; Wassif, Christopher A. ; Wright, Charles G. ; Porter, Forbes D. ; Repa, Joyce J. ; Brewer, Carmen C. / Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C. In: JARO - Journal of the Association for Research in Otolaryngology. 2014 ; Vol. 15, No. 4. pp. 529-541.
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