Matrix Recruitment and Calcium Sequestration for Spatial Specific Otoconia Development

Otoconia are bio-crystals anchored to the macular sensory epithelium of the utricle and saccule in the inner ear for motion sensing and bodily balance. Otoconia dislocation, degeneration and ectopic calcification can have detrimental effects on balance and vertigo/dizziness, yet the mechanism underlying otoconia formation is not fully understood. In this study, we show that selected matrix components are recruited to form the crystal matrix and sequester Ca2+ for spatial specific formation of otoconia. Specifically, otoconin-90 (Oc90) binds otolin through both domains (TH and C1q) of otolin, but full-length otolin shows the strongest interaction. These proteins have much higher expression levels in the utricle and saccule than other inner ear epithelial tissues in mice. In vivo, the presence of Oc90 in wildtype (wt) mice leads to an enrichment of Ca2+ in the luminal matrices of the utricle and saccule, whereas absence of Oc90 in the null mice leads to drastically reduced matrix-Ca2+. In vitro, either Oc90 or otolin can increase the propensity of extracellular matrix to calcify in cell culture, and co-expression has a synergistic effect on calcification. Molecular modeling and sequence analysis predict structural features that may underlie the interaction and Ca2+-sequestering ability of these proteins. Together, the data provide a mechanism for the otoconial matrix assembly and the role of this matrix in accumulating micro-environmental Ca2+ for efficient CaCO3 crystallization, thus uncover a critical process governing spatial specific otoconia formation

Vestibular Dysfunction, Altered Macular Structure and Trait Localization in A/J Inbred Mice

A/J mice develop progressive hearing loss that begins before one month of age and is attributed to cochlear hair cell degeneration. Screening tests indicated 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, SEM, TEM, 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 agematched controls (C57BL/6J). 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 17A/J/NaJ), thus indicating that Chr 17A/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

Gender-based comorbidity in benign paroxysmal positional vertigo.

It has been noted that benign paroxysmal positional vertigo (BPPV) may be associated with certain disorders and medical procedures. However, most studies to date were done in Europe, and epidemiological data on the United States (US) population are scarce. Gender-based information is even rarer. Furthermore, it is difficult to assess the relative prevalence of each type of association based solely on literature data, because different comorbidities were reported by various groups from different countries using different patient populations and possibly different inclusion/exclusion criteria. In this study, we surveyed and analyzed a large adult BPPV population (n = 1,360 surveyed, 227 completed, most of which were recurrent BPPV cases) from Omaha, NE, US, and its vicinity, all diagnosed at Boys Town National Research Hospital (BTNRH) over the past decade using established and consistent diagnostic criteria. In addition, we performed a retrospective analysis of patients' diagnostic records (n = 1,377, with 1,360 adults and 17 children). The following comorbidities were found to be significantly more prevalent in the BPPV population when compared to the age- and gender-matched general population: ear/hearing problems, head injury, thyroid problems, allergies, high cholesterol, headaches, and numbness/paralysis. There were gender differences in the comorbidities. In addition, familial predisposition was fairly common among the participants. Thus, the data confirm some previously reported comorbidities, identify new ones (hearing loss, thyroid problems, high cholesterol, and numbness/paralysis), and suggest possible predisposing and triggering factors and events for BPPV

Age and gender distribution of non-recurrent (A, n = 1,185 total) and recurrent (B, 192 total) BPPV cases diagnosed at BTNRH from 2002–11.

<p>Age and gender distribution of non-recurrent (A, n = 1,185 total) and recurrent (B, 192 total) BPPV cases diagnosed at BTNRH from 2002–11.</p

Demographics of the study population.

<p>Demographics of the study population.</p

Family history of BPPV.

<p>Family history of BPPV.</p

Factors associated with BPPV in females.

<p>The age- and gender-matched control statistics are on the general population in the size of thousands to hundreds of thousands. To simplify the analysis and to provide a conservative estimate of statistical significance, the control population size is set at 1,000 for all diseases for Fisher’s exact test in the table. If no mean prevalence data by meta-analysis are available, the highest prevalence data available for each disease in the control population is used to obtain the two-tailed p values. Significant (or nearly significant) comorbidities are bolded.</p><p>Factors associated with BPPV in females.</p

Age and gender distribution of BPPV survey participants (n = 227 total) (A), BPPV cases diagnosed at BTNRH in 2002–2011 (n = 1,377 total) (B), and Nebraska population in year 2010 (n = 1,826,341 total) [73] (C). Recurrent cases are counted only once (the first occurrence).

<p>Age and gender distribution of BPPV survey participants (n = 227 total) (A), BPPV cases diagnosed at BTNRH in 2002–2011 (n = 1,377 total) (B), and Nebraska population in year 2010 (n = 1,826,341 total) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105546#pone.0105546-USCensus1" target="_blank">[73]</a> (C). Recurrent cases are counted only once (the first occurrence).</p

Incidents and conditions immediately preceding the first BPPV symptoms.

<p>Only those who answered “yes” or “no” were included in the total or subtotal to obtain the percentages. Those who answered “does not apply” or “do not know/remember” were not included in the presented percentages.</p><p>Incidents and conditions immediately preceding the first BPPV symptoms.</p