title: Vestibular dysfunction, altered macular structure and trait localization in A/J inbred mice.
abstract: A/J mice develop progressive hearing loss that begins before 1 month of age and is attributed to cochlear hair cell degeneration. Screening tests indicated that this strain also develops early onset vestibular dysfunction and has otoconial deficits. The purpose of this study was to characterize the vestibular dysfunction and macular structural pathology over the lifespan of A/J mice. Vestibular function was measured using linear vestibular evoked potentials (VsEPs). Macular structural pathology was evaluated using light microscopy, scanning electron microscopy, transmission electron microscopy, confocal microscopy and Western blotting. Individually, vestibular functional deficits in mice ranged from mild to profound. On average, A/J mice had significantly reduced vestibular sensitivity (elevated VsEP response thresholds and smaller amplitudes), whereas VsEP onset latency was prolonged compared to age-matched controls (C57BL/6). A limited age-related vestibular functional loss was also present. Structural analysis identified marked age-independent otoconial abnormalities in concert with some stereociliary bundle defects. Macular epithelia were incompletely covered by otoconial membranes with significantly reduced opacity and often contained abnormally large or giant otoconia as well as normal-appearing otoconia. Elevated expression of key otoconins (i.e., otoconin 90, otolin and keratin sulfate proteoglycan) ruled out the possibility of reduced levels contributing to otoconial dysgenesis. The phenotype of A/J was partially replicated in a consomic mouse strain (C57BL/6J-Chr 17(A/J)/NaJ), thus indicating that Chr 17(A/J) contained a trait locus for a new gene variant responsible to some extent for the A/J vestibular phenotype. Quantitative trait locus analysis identified additional epistatic influences associated with chromosomes 1, 4, 9 and X. Results indicate that the A/J phenotype represents a complex trait, and the A/J mouse strain presents a new model for the study of mechanisms underlying otoconial formation and maintenance.
authors: Department of Special Education and Communication Disorders, University of Nebraska-Lincoln, 301 Barkley Memorial Center, Lincoln, NE, 68583, USA.
authors: Sarath
authors: S
authors: Vijayakumar
authors: Teresa E
authors: TE
authors: Lever
authors: Jessica
authors: J
authors: Pierce
authors: Xing
authors: X
authors: Zhao
authors: David
authors: D
authors: Bergstrom
authors: Yunxia Wang
authors: YW
authors: Lundberg
authors: Timothy A
authors: TA
authors: Jones
authors: Sherri M
authors: SM
authors: Jones
mesh_terms: D000818:Animals; D005075:Biological Evolution; D033481:Chromosomes, Mammalian; D003433:Crosses, Genetic; D005072:Evoked Potentials, Auditory; D005260:Female; D056726:Genetic Association Studies; D008266:Macula Lutea / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D014722:Vestibule, Labyrinth / Q000473:pathology / Q000503:physiopathology* / Q000648:ultrastructure
references: Genetics. 1996 Jan;142(1):285-94
references: 8770605
references: J Gerontol. 1982 May;37(3):275-82
references: 7069150
references: J Vestib Res. 1998 May-Jun;8(3):233-52
references: 9626650
references: Hear Res. 1998 Aug;122(1-2):60-70
references: 9714575
references: Genetics. 1998 Oct;150(2):815-22
references: 9755211
references: Hear Res. 1999 Sep;135(1-2):56-60
references: 10491954
references: Hear Res. 1999 Oct;136(1-2):75-85
references: 10511626
references: Mech Dev. 2005 Jun;122(6):791-803
references: 15905077
references: Am J Physiol Renal Physiol. 2007 May;292(5):F1314-21
references: 17200157
references: J Clin Invest. 2008 Mar;118(3):1176-85
references: 18292807
references: J Assoc Res Otolaryngol. 2008 Dec;9(4):436-51
references: 18784957
references: Nature. 2009 Jan 8;457(7226):205-9
references: 19043402
references: Brain Res. 2009 Jun 24;1277:42-51
references: 19236853
references: Neurobiol Aging. 2009 Oct;30(10):1693-705
references: 18280008
references: Nat Genet. 2012 Feb;44(2):193-9
references: 22246503
references: J Neurosci. 2012 Feb 22;32(8):2762-72
references: 22357859
references: Neurobiol Aging. 2012 Aug;33(8):1720-9
references: 21803452
references: Hear Res. 2013 Jun;300:1-9
references: 23528307
references: PLoS Genet. 2013;9(7):e1003641
references: 23874234
references: Ann Otol Rhinol Laryngol. 2005 Aug;114(8):605-13
references: 16190093
references: Biol Cell. 2005 Oct;97(10):787-98
references: 15730345
references: Int J Neurosci. 2015;125(8):593-6
references: 25135283
references: Curr Biol. 2006 Jan 24;16(2):208-13
references: 16431374
references: J Vestib Res. 2005;15(5-6):225-41
references: 16614470
references: Brain Res. 2006 May 26;1091(1):40-6
references: 16499890
references: Brain Res. 2006 May 26;1091(1):79-88
references: 16579977
references: Dev Biol. 2007 Apr 15;304(2):508-24
references: 17300776
references: Genomics. 2000 Dec 1;70(2):171-80
references: 11112345
references: Nat Genet. 2001 Jan;27(1):103-7
references: 11138008
references: Nat Genet. 2001 Feb;27(2):191-4
references: 11175788
references: Hear Res. 2002 Jul;169(1-2):13-23
references: 12121736
references: Trends Mol Med. 2002 Sep;8(9):447-51
references: 12223317
references: EMBO J. 2002 Dec 16;21(24):6689-99
references: 12485990
references: Hum Mol Genet. 2003 Apr 1;12(7):777-89
references: 12651873
references: Bioinformatics. 2003 May 1;19(7):889-90
references: 12724300
references: Nat Genet. 2003 Sep;35(1):21-3
references: 12910270
references: Science. 2003 Oct 10;302(5643):282-6
references: 14551434
references: J Comp Neurol. 2004 Jan 19;468(4):587-95
references: 14689488
references: Genes Dev. 2004 Mar 1;18(5):486-91
references: 15014044
references: Hear Res. 2004 May;191(1-2):34-40
references: 15109702
references: Biochem Biophys Res Commun. 2004 Nov 26;324(4):1283-8
references: 15504353
references: Hear Res. 1997 Dec;114(1-2):83-92
references: 9447922