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 ??/em> 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 ??/em> mice. Anatomical study demonstrated accumulation of lysosomes in neurons, hair cells, and supporting cells of the inner ear in P30 Npc1 ??/em> 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." />
Hearing Loss is an Early Consequence of Npc1 Gene Deletion in the Mouse Model of Niemann–Pick Disease, Type C
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  • 作者：Kelly A. King (1)
    Sandra Gordon-Salant (2)
    Karen S. Pawlowski (5)
    Anna M. Taylor (6)
    Andrew J. Griffith (1)
    Ari Houser (3)
    Kiyoto Kurima (1)
    Christopher A. Wassif (4)
    Charles G. Wright (5)
    Forbes D. Porter (4)
    Joyce J. Repa (6) (7)
    Carmen C. Brewer (1)
  • 关键词：NPC ; hearing ; auditory maturation ; auditory brainstem response (ABR)
  • 刊名：JARO - Journal of the Association for Research in Otolaryngology
  • 出版年：2014
  • 出版时间：August 2014
  • 年：2014
  • 卷：15
  • 期：4
  • 页码：529-541
  • 全文大小：2,352 KB
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    6. Garver WS, Francis GA, Jelinek D, Shepherd G, Flynn J, Castro G, Walsh Vockley C, Coppock DL, Pettit KM, Heidenreich RA et al (2007) The National Niemann–Pick C1 disease database: report of clinical features and health problems. Am J Med Genet A 143:1204-211 CrossRef
    7. German DC, Quintero EM, Liang CL, Ng B, Punia S, Xie C, Dietschy JM (2001) Selective neurodegeneration, without neurofibrillary tangles, in a mouse model of Niemann–Pick C disease. J Comp Neurol 433:415-25 CrossRef
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    11. King KA, Gordon-Salant S, Yanjanin N, Zalewski C, Houser A, Porter FD, Brewer CC (2014) Auditory phenotype of Niemann–Pick disease, type C1. Ear Hearing 35:110-17 CrossRef
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    13. Levic S, Yamoah E (2011) Plasticity in membrane cholesterol contributes toward electrical maturation of hearing. J Biol Chem 7:5768-773 CrossRef
    14. Li H, Repa JJ, Valasek MA, Beltroy EP, Turley SD, German DC, Dietschy JM (2005) Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann–Pick type C disease. J Neuropathol Exp Neurol 64:323-33
    15. Liberman MC, Zuo J, Guinan JJ Jr (2004) Otoacoustic emissions without somatic motility: can stereocilia mechanics drive the mammalian cochlea? J Acoust Soc Am 116:1649-655 CrossRef
    16. Liscum L, Faust JR (1987) Low density lipoprotein (LDL)-mediated suppression of cholesterol synthesis and LDL uptake is defective in Niemann–Pick type C fibroblasts. J Biol Chem 262:17002-7008
    17. Liscum L, Ruggiero RM, Faust JR (1989) The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann–Pick type C fibroblasts. J Cell Biol 108:1625-636 CrossRef
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    21. Maue RA, Burgess RW, Wang B, Wooley CM, Seburn KL, Vanier MT, Rogers MA, Change CC, Chang TY, Harris BT et al (2011) A novel mouse model of Niemann–Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations. Hum Mol Genet 21:730-50 CrossRef
    22. Narui Y, Minekawa A, Iizuka T, Furukawa M, Kusunoki T, Koike T, Ikeda K (2009) Development of distortion product otoacoustic emission in C57BL/6 J mice. Int J Audiol 48:576-81 CrossRef
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    27. Pikus A (1991) Audiologic profile in Niemann–Pick C. Ann N Y Acad Sci 630:313-14 CrossRef
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    29. Purcell EK, Liu L, Thomas PV, Duncan RK (2011) Cholesterol influences voltage-gated calcium channels and BK-type potassium channels in auditory hair cells. PLoS ONE 6(10):e26289. doi:10.1371/journal.pone.0026289 CrossRef
    30. Rajagopalan L, Greeson JN, Xia A, Liu H, Sturm A, Raphael RM, Davidson AL, Oghalai JS, Pereira FA, Brownell WE (2007) Tuning of the outer hair cell motor by membrane cholesterol. J Biol Chem 282:36659-6670 CrossRef
    31. Vincent I, Bu B, Erickson RP (2003) Understanding Niemann–Pick type C disease: a fat problem. Curr Opin Neurol 16:155-61 CrossRef
    32. V?ikar V, Rauvala H, Ikonen E (2002) Cognitive deficit and development of motor impairment in a mouse model of Niemann–Pick type C disease. Behav Brain Res 132:1-0 CrossRef
    33. Walkley S, Suzuki K (2004) Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochem et Biophys Acta 1685:48-2
    34. Ward S, O’Donnell P, Fernandez S, Vite CH (2010) 2-hydroxypropyl-?-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann–Pick type C disease. Pediatr Res 68:52-6 CrossRef
    35. Weintraub H, Abramovici A, Amichai D, Eldar T, Ben-Dor L, Pentchev PG, Hammel I (1992) Morphometric studies of pancreatic acinar granule formation in NCTR-Balb/c mice. J Cell Sci 102(Pt 1):141-47
    36. Willott JF, Turner JG, Carlson S, Ding D, Bross LS, Falls WM (1998) The BALB/c mouse as an animal model for progressive sensorineural hearing loss. Hear Res 115:162-74 CrossRef
  • 作者单位：Kelly A. King (1)
    Sandra Gordon-Salant (2)
    Karen S. Pawlowski (5)
    Anna M. Taylor (6)
    Andrew J. Griffith (1)
    Ari Houser (3)
    Kiyoto Kurima (1)
    Christopher A. Wassif (4)
    Charles G. Wright (5)
    Forbes D. Porter (4)
    Joyce J. Repa (6) (7)
    Carmen C. Brewer (1)

    1. National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892, USA
    2. Department of Hearing and Speech Sciences, University of Maryland College Park, College Park, MD, 20742, USA
    5. Department of Otolaryngology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
    6. Department of Physiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
    3. Department of Human Development and Quantitative Methodology, University of Maryland College Park, College Park, MD, 20742, USA
    4. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
    7. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, 75390, USA
  • ISSN：1438-7573
文摘
Niemann-a href='/search?dc.title=Pick&facet-content-type=ReferenceWorkEntry&sortOrder=relevance' class='reference-link webtrekk-track' gaCategory="internal-link" gaLabel="Pick" gaAction="reference-keyword">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 ??/em> 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 ??/em> mice. Anatomical study demonstrated accumulation of lysosomes in neurons, hair cells, and supporting cells of the inner ear in P30 Npc1 ??/em> 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.

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